CIS GMP news 1 (1) / autumn 2017 by PharmProm.Ru

One and a Half Years of Russian GMP Inspectorate: Yesterday, Today, Tomorrow

page

Girish Malhotra

Gilda D'Incerti

An Alternate Look at the Pharmaceutical World page Revenues

Emerging Trends in Regulatory Expectations

Theme of the Issue:

Contract Manufacturing

1 (1) autumn / 2017

CIS GMP news EEC & CIS PHARMACEUTICAL INDUSTRY AND CURRENT GMP TRENDS REVIEW

NovaMedica has launched its R&D Center for development of new drug products in Moscow see page 134

174

page

with the support of:

CIS GMP news

Russian Pharmaceutical Industry in 2016 1 (1)Â / autumn 2017

At the end of 2016, in the Russian Federation there were:

527

operating production licenses on

Out of all plants

185

378

produce finished dosage forms and APIs

66,8%

Out of those

334 44

566

manufacturing plants in

produce both FDFs and APIs produce only APIs

produce only alcoholbased solutions, medical gases, or medicinal leeches*

32,7%

Out of those

144 33 8

regions

carry out secondary packaging exclusively

0,5%

According to the data from Ministry of Industry and Trade

produce only gases produce only solutions

Analysis by FBI "SID & GP"

produce only leeches

* - the data about the products of manufacturers are presented in accordance with the currently valid licenses; the data about the manufacture of alcohol-based solutions are presented in accordance with the data from State 2 Register of Medicinal Products www.gmpnews.net

1 (1)Â / autumn 2017

381

manufacture and package medicinal products

285

of them report to FBI "SID & GMP" about manufacturing and shipments

do not manufacture

of them do not report to FBI "SID & GMP" about manufacturing and shipments

do not report

CIS GMP news

According to the order of Rosstat No. 81 from 14th May 2009, all legal entities having the medicinal products manufacturing license and performing the manufacturing of medicinal products have to report to FBI "SID & GP" quarterly using Form No. 2, which includes the information about production, shipments, and medicinal products pricing.

state is unknown*

* - this figure includes 9 plants that got their license in 2016 for the first time

122

valid

GMPcertificates Manufacturers with GMP certificate Manufacturers without GMP certificate

22% 78% Share of the GMP certificate holders out of all production license holders

36%

30% 64%

Production volumes ratio in monetary terms*

70% Production volumes ratio in natural terms*

* - rating, preliminary data for the first 9 month of 2016. Only Russian GMP certificate

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CIS GMP news One and a Half Years of Russian GMP Inspectorate: Yesterday, Today, Tomorrow

page

Gilda D'Incerti

Girish Malhotra An Alternate Look at the Pharmaceutical World page Revenues

Theme of the Issue:

1 (1) / autumn 2017

Contract Manufacturing

Emerging Trends in Regulatory Expectations

174

page

No 1 / Review 2017

CIS GMP news EEC & CIS PHARMACEUTICAL INDUSTRY AND CURRENT GMP TRENDS REVIEW

Pharmaceutical Industry Magazine

CIS GMP News Specialized publication dedicated to Good Manufacturing Practice, modernization of pharmaceutical production, and modern pharmaceutical manufacturing technologies

NovaMedica has launched its R&D Center for development of new drug products in Moscow

This issue was published with the support from Federal Budgetary Institution “State Institute of Drugs and Good Practices” with the support of:

see page 134

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Ředitel vydání "Новости GMP" Eugenia Dorina, PhD, e.dorina@phct.ru

Editor-in-chief Vyacheslav Fedorenko, v.fedorenko@gmpnews.net

Šéfredaktor Vyacheslav Fedorenko, v.fedorenko@gmpnews.net

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The opinions and views expressed by the authors in this journal are not necessarily those of the Editor or Publisher and, while every care has been taken in preparation of the journal, the Editor and Publisher are not responsible for such opinions and views, or for any inaccuracies in the articles.

Názory vyjádřené autory v tomto časopisu nemusí být nutně názory redakce a vydavatele. Redakce a vydavatel nenese žádnou odpovědnost za názory vyjádřené autory. Přestože byla věnována veškerá péče při přípravě časopisu, redakce a vydavatel nejsou zodpovědní za jakékoli nepřesnosti v článcích.

1 (1) autumn / 2017 *** Published biannually ISSN 2570-7191

1 (1) podzim / 2017 *** Vychází 2× ročně ISSN 2570-7191

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Editor’s Note

CIS GMP news

Dear reader, First of all, allow us to thank you for Your interest in the magazine You are now holding in Your hands. Here at “CIS GMP news”, we want to bring You the most interesting news from the pharmaceutical industry of CIS and EAEU markets, and their potential from the point of view of GMP. In the last few years, the situation on these markets has changed fundamentally. That is why this is the main topic of our publication. In addition, we are going to bring to Your attention the possibilities of business cooperation in development and manufacturing of quality, effective, and safe medicinal products with manufacturing plants in CIS and EAEU markets. Contract manufacturing is gaining momentum - a win/ win for everybody! Have a look at the statistics and analytics in the articles you are about to read. This is one of the reasons why contract manufacturing was chosen as the main theme of this issue. Modernization of current manufacturing facilities, construction of new production plants, implementation of stateof-the-art pharmaceutical technologies, servicing, industrial training, and staff development are among the most important subjects discussed in this publication. Guidance and help with materials from this issue was provided by our partners' specialists and experts. Let me introduce our partners:

FAVEA Group - a leading European pharmaceutical engineering company, having successfully implemented dozens of major projects, mainly in Russia. The main focus of FAVEA Group is the modernization and construction of pharmaceutical plants.  “Pharmcontract” Group of companies is the leading chemical and pharmaceutical holding, and is the largest company in Russia that offers a full range of services - building and equipment of pharmaceutical, chemical, food, and biotechnological production plants. We would especially like to thank Federal Budgetary Institution “State Institute of Drugs and Good Practices” (FBI “SID & GP”) for their support of our publication. They are a specialized state institution that performs inspections of pharmaceutical manufacturers for compliance with GMP in Russia and abroad. We would like to extend our sincere gratitude to all of our partners that support us and help us to develop “CIS GMP news”, to specialists and experts, representatives of press services of companies, and to everybody who contributed with their unique submissions!

We are looking forward to cooperating with you!

Vyacheslav Fedorenko Editor-in-chief

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CIS GMP news

1 (1) / autumn 2017Contents

General partner:

Strategic partner:

We work closely with our main partners to promote the services and expertise that they offer. CIS GMP news magazine has a strong presence within their businesses as they do within ours.

REGULATORY ISSUES Pharmaceutical and Medical Industry Represents a Priority Area

8-11 Dmitriy Rozhdestvenskiy. Common Market of Medicines: Processes and Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . 12-16 Manufacturers of Medicines of the EAEU Countries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Andrei Meshkovki. GMP Compliance in Russia: Achievements, Shortcomings, and National Specifics . . . . . . . . . . . 18-25 Boris Romanov. Pharmacovigilance in Russia in Questions and Answers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26-29 for High-Tech Development of the Russian Economy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

GMP INSPECTION PRACTICE FBI “SID & GP“ Basic Positions in the Inspectorate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stephan Rönninger, Andrei Meshkovki. GMP Inspection Practice: a Case for Global Benchmarking, Convergence and Mutual Reliance/Recognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

30-33 34-40

ANALYTICS & STATISTICS

42-45 Mikhail Khazanchuk. Is the Russian Pharmaceutical Industry Ready for Cooperation? ....................... 46-49 Stanislav Livanskiy. Russian Pharmaceutical Industry: Cooperation in Competition .............................. 50-53

Girish Malhotra. An Alternate Look at the Pharmaceutical World Revenues and Drug Affordability ..............

Nikolay Bespalov. Selected Indicators of the Russian Pharmaceutical Market Development in 2012-2016 and in the 1st and 2nd Quarters of 2017 ..................................................................................

54-57

Alexander Toporkov, Irina Novikova. The Future of the Russian Pharmaceutical Industry is Closely Associated with Kaluga Region

.......................................................................... 58-63

CONTRACT MANUFACTURING Elena Kalinovskaya. Contract Manufacture Ensures Industrial Competition

....................................... 64-66

68-71 Sotex + Rafarma: New Pharmaceutical Synergy ........................................................................ 72-79 Pharmaceutical Company SOLOPHARM ............................................................................... 80-83 “Samson-Med” – New Contract Manufacturing Horizons .................................................................. 84-89 Acticomp Company is a Leading Manufacturer of APIs in Russia ........................................................ 90-93 Elena Kalinovskaya. Business Is Betting on High-Technology Enterprises .............................................

Research and Production Association PharmVILAR –

.............................................................. 94-98 Canonpharma Production - a New Generation of Russian Pharmaceutical Manufacturers .......................... 100-103 10 Years of Successful Contract Manufacturing in Russia

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Supported by:

MANUFACTURING & LOCALIZATION

................................................. 104-107 Novo Nordisk Continues to Invest in Russia ......................................................................... 108-111 “The Hardest Period is Over…” ........................................................................................ 112-115 In Line with the Latest Technological Trends ......................................................................... 116-118 The Kaluga Plant is Aiming for Full-Cycle Production ..................................................................... 119 GEROPHARM: Insulin Market Imports Phase-Out .................................................................... 120-123 PJSC Biokhimik Will Provide Russia with Innovative Antibiotics ....................................................... 124-128 ViiV Healthcare Localized the Manufacture of Dolutegravir in Russia .............................................. 130-133 Contract R&D Market is Developing in Russia ....................................................................... 134-137 Russian Pharmaceutical Map Has a New Point of Convergence ....................................................... 138-141 Immunobiology: From Modernization to International Cooperation ............................................. 142-149 Nacimbio - National Immunobiological Company .................................................................. 150-153 Dmitry Efimov: There is Still a Large Potential in Russian Pharmaceutical Market ................................ 154-161 Palladio BNM, a Pharmaceutical Packaging Plant, Opens in Obninsk

GOOD ENGINEERING PRACTICE

Good Engineering Practice in Russia and CIS countries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 162-166

ACTIVE PHARMACEUTICAL INGREDIENTS Bringing Solutions for CIS .............................. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

PHARMACEUTICAL QUALITY SYSTEM Gilda D'Incerti. Emerging Trends in Regulatory Expectations

168-173

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174-183

EXHIBITIONS, FORUMS, CONFERENCES

..... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184-188 Welcome to the 28th CPhI Worldwide! ............... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190-191 CPhI Worldwide: "Our Goal is to Be the Vital Conduit Connecting the Industry" . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192-193 Key Comprehensive Pharma Event of the Spring

ABOUT GMP NEWS

. ........................................ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194 Partnership........................................ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194

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CIS GMP news

1 (1)Â / autumn 2017 Regulatory Issues

Pharmaceutical and Medical Industry Represents a Priority Area for High-Tech Development of the Russian Economy

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R-Pharm Pharmaceutical Manufacturing in Yaroslavl

15 August 2017

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ince 2013, the Russian Federation is implementing its State Program â&#x20AC;&#x153;The Development of Pharmaceutical and Medical Industryâ&#x20AC;? for 2013-2020. This is a largescale integration instrument for various participants operating in the market of medicinal products and medical equipment. The Russian Ministry of Industry and Trade acts as the main Customer of the Program and coordinates the activities of all industries. The largest and globally recognized universities, scientific organizations, and Russian pharmaceutical companies are actively involved in the Program. Its participants include 600 entities with various forms of ownership. The effective collaboration between all market participants, including com-

mercial companies, scientific and educational institutions, medical and patient communities, and government institutions, plays a fundamental role in the development of the industry and achievement of established targets. These targets include bringing the share of Russian-made medicinal products to 50% in monetary terms and increasing to 90% the volume of Russian-made medicines from the list of strategically important drugs and the list of vital and essential drugs by 2020. Currently, the share of Russian-made medicines from the list of vital and essential drugs stands at 81.5%. As compared to 2009 (96 billion rubles), the manufacturing of medicinal products increased almost threefold and, in 2016, amounted to 285.87 billion rubles in manufacturer prices (+23.75% compared to 2015).

CIS GMP news

1 (1) / autumn 2017

Since 2013, the share of Russian-made medicines increased from 22.6% to 30%. The share of domestically manufactured drugs in total procurement under 7 Nosologies program increased from 4.5% to 46% in monetary terms since 2011. Comparing to 2009, the exports of pharmaceutical products rose by 37%. The State Program “The Development of Pharmaceutical and Medical Industry” for 2013-2020 set the vector for the development of the pharmaceutical industry and contributed to attracting investments in the establishment and modernization of production facilities. Over the past 5 years, the pharmaceutical industry attracted more than 120 billion rubles of private investments made by foreign and Russian companies, while the funds allocated by the federal budget amounted to 35 billion rubles. Forty four import-substituting medicinal products (as of January 1, 2017) and

2 innovative drugs have been developed and launched as a part of the State Program. Another 20 medicines are scheduled for registration in 2017. There were 35 newly opened production sites. The own production facilities were launched by world’s largest companies, including Novartis, Astra Zeneca, Abbot, Valent, KRKA, Novo Nordisk, Takeda, Teva, Servier, Berlin-Chemie (Menarini), Sanofi, Flagship Ventures, and Polpharma. There are more than 500 companies operating in Russia. 16 pharmaceutical plants were opened in 2016, including LLC NEARMEDIC PHARMA (Obninsk, Kaluga region), JSC EMPILS-FOH (Rostov-on-Don), LLC Bratskchemsyntez (Bratsk, Irkutsk region), LLC Sphera Pharma (Kaluga region), LLC NANOPHARMA DEVELOPMENT (Kazan, Republic of Tatarstan), and LLC Velfarm (Kurgan). In 2016, the pharmaceutical industry grew by 20%.

GEROPHARM Pharmaceutical Manufacturing

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NPO Microgen Manufacturer of Vaccines and immunobiological Drugs

The Russian Ministry of Industry and Trade established a whole set of measures to support the development of pharmaceutical and medical industry. There are subsidies for conducting the clinical trials, organizing the manufacturing of substances, developing improved analogs of innovative medicinal products; the mechanism provided by Special Investment Contract, preferences for industrial clusters, and preferential lending by the Industrial Development Fund. In 2016, the Ministry of Industry and Trade of Russia provided subsidies for implementing 6 projects to manufacture pharmaceutical substances, 34 projects to develop new medicines, and 10 projects to develop next-in-class drugs for a total amount of almost 470 million rubles. In 2015 â&#x20AC;&#x201C; Q1 2017, the Industrial De-

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velopment Fund approved financing of 13 projects in the area of pharmaceutical industry with a total amount of loans reaching 4.2 billion rubles, including the manufacturing of pharmaceutical substances and finished drugs for immunology, gynecology, urology, surgery, and pediatrics. Today, the Russian industry can satisfy needs of the country in highly effective medicinal products and high-quality medical equipment to ensure national security in the area of healthcare. In 2017, the manufacturing of drugs is expected to grow by 20% and the pharmaceutical market by 8% in value terms compared to 2016. The total investment budget planned for supporting the pharmaceutical industry under the State Program will amount to 7.16 billion rubles in 2017.

CIS GMP news

1 (1)Â / autumn 2017 Regulatory Issues

Common Market of Medicines: Processes and Approaches

24 August 2017

Dmitriy Rozhdestvenskiy Director of Coordination Department in the field of Circulation of Medicines of the Department of Technical Regulation and Accreditation of Eurasian Economic Commission

Mr. Rozhdestvenskiy, could you explain to our foreign readers what the Eurasian Economic Union is in more detail? The Eurasian Economic Union (EAEU) is an integration alliance that possesses international legal personality and was founded by the Treaty on the Eurasian Economic Union dated May 29, 2014. The Union started functioning on January 1, 2015, which was the effective date of the Treaty. The EAEU comprises five countries: Armenia, Belarus, Kazakhstan, Russia, and Kyrgyzstan. Their total territory exceeds 20 million km2, which is approximately 14% of the world's land surface. This territory is inhabited by 182.7 million people. The Union member states rank first in the world in terms of oil production (about 15% of global production), second in terms of gas production (over 18%), third in terms of wheat and potato production (9% and 11% of global production, respectively), fourth in terms of electricity generation (over 5% of global generation), and sixth in terms of industrial production (about 4%). The EAEU member states also rank second in the world in terms of railway mileage, and fifth in the world in terms of highway mileage.

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GENERAL DOCUMENTS (7 documents) Rules of registration and expert examination + Labeling requirements Requirements to instructions for medical use + Criteria for OTC medicinal products Nomenclatureof dosage forms + Register and reference databases Expert Committee on Medicines

SAFETY (2 documents) GLP guidelines GVP guidelines

EFFICACY (3 documents)

QUALITY (11 documents) Manufacture

Control

GCP guidelines

GMP guidelines

Bioequivalence study guidelines

GDP guidelines

Quality system of pharmaceutical inspectorates

Qualification and register of qualified persons

Rules and procedure of pharmaceutical inspections

Guidelines for research and developing of biological products

Standardization Concept of harmonization of pharmacopoeias Pharmacopoeial Committee Interaction for identifying substandard and counterfeit medicinal products

The texts of all documents are available on the legal portal of the Eurasian Economic Commission on the Internet at http://www.eurasiancommission.org/ru/act/texnreg/deptexreg/LS1/Pages/drug_products.aspx

The Union was formed to facilitate comprehensive modernization and cooperation, make the national economies more competitive and foster the environment for sustainable development with a view to improving the quality of life of the population in the member states. The EAEU ensures free movement of goods, services, capital, and labor, as well as the pursuit of coordinated, harmonized, or common policy in different sectors of economy by all EAEU member states. The most important decisions within the EAEU are taken by the supreme body of the EAEU, the Supreme Eurasian Economic Council, which includes the presidents of the member states, and by the Eurasian Intergovernmental Council, which consists of the heads of governments. The standing regulatory body of the Union is the Eurasian Economic Commission (EEC), whose governing bodies are the EEC Council (it includes the Deputy Prime Ministers of

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the EAEU member states) and the EEC Board (composed of the ministers of the Commission responsible for various areas, such as integration and macroeconomics, trade, customs cooperation, economy and financial policy, internal markets, informatization, development of information and communication technologies, industry and agro-industrial complex, energy, and infrastructure, technical regulation, competition and anti-monopoly regulation, etc.). In accordance with the principle of annual rotation, in 2017, the Union bodies are chaired by Kyrgyztan, with the President of Kyrgyzstan being Chairman of the Supreme Eurasian Economic Council accordingly. Since we are a pharmaceutical journal, we, and our readers would like to know more about the common market of medicinal products and medical devices within the EAEU, which started its operation on May 6, 2017. What

benefits does this alliance offer to local manufacturers? Which documents have already been adopted and which documents are still under development? Indeed, this year, on May 6, the national pharmaceutical markets of the five member states of the Eurasian Economic Union merged and started functioning in the format of a Common Economic Space (CES). Manufacturers from the EAEU member states may file applications for registration and release into circulation of medicinal products, following common procedures for all EAEU member states. The Eurasian Economic Commission in cooperation with the leading experts from the five member states of the Union prepared all documents necessary for the effective operation of the common market taking into account global experience. They are aimed at removing the administrative barriers in the field of production and sale of medicinal products within the Unionâ&#x20AC;&#x2122;s

CIS GMP news

1 (1) / autumn 2017

CES. These documents will also ensure a kind of “sanitation” of the pharmaceutical market, removing medicinal products, whose effectiveness and safety have not been fully studied and whose production does not comply with the Good Manufacturing Practice (GMP) from the market. The regulation of the common pharmaceutical market is based on Article 30 of the EAEU Treaty. In accordance with this article, a three-level regulatory system has been developed, which comprises a basic document, the Agreement on Common Principles and Rules for Circulation of Medicinal Products within the EAEU dated December 23, 2014 (this is a “first-level” document). At the level of national regulation, the following processes are kept intact:  administration of granting authorization to conduct preclinical and clinical trials of medicinal products;  pricing of medicinal products;  retail trade in medicinal products;  procedures connected with the reimbursement of costs involved in supply of medicinal products;  regulation of medical advertisements. The “second-level” documents that were drafted in elaboration of the provisions of the Agreement include 26 regulations (21 decisions of the EEC Council, and 4 decisions, and 1 recommendation of the EC Board). These documents form

a system of interrelated regulations that set out the requirements for a medicinal product as a pharmaceutical product (i.e. its safety, quality, and efficacy) and also as an object of legal regulation (i.e. from the perspective of the processes of its admission to the market, accounting, and withdrawal from the market). The figure below shows the main types of these documents, grouped in four blocks. On June 30, 2017, the Eurasian Economic Commission adopted two more important decisions (Decisions of the EEC Board Nos. 78 and 79), which lay down the requirements regarding the type of electronic documents and application submitted as part of a dossier for registration of medicinal products and medical devices according to common rules of the Union. Overall, the ICH (International Conference on Harmonization) approaches to the electronic format of the registration dossier were used, which allow manufacturers to prepare a registration dossier in electronic format, or the so-called eCTD. Is there any transitional period for companies to seamlessly switch from their national rules and standards to the EAEU’s common requirements, Mr. Rozhdestvenskiy? Of course, there will be a transitional period to ensure a smooth transition from national to common regulation. This will prevent disruptions in the function-

ing of health care systems of the EAEU member states and help pharmaceutical manufacturers comfortably adapt to new requirements. All medicinal products registered under the national procedure before January 1, 2016, will continue to be marketed until December 31, 2025. Up until 1 January 2021, all newly registered medicinal product may be registered either under the common procedures, or under national procedures at the applicant’s discretion. However, in the case of registration under the national procedure, the medicinal product concerned will be marketed only within the relevant state, and its registration certificate (even if granted for an indefinite period of time) will cease to be effective from 1 January 2026. After 1 January 2021, an applicant will be able to register its new medicinal products only under the common procedures. These include two common procedures (either should be chosen at the applicant’s discretion):   decentralized registration procedure (DP), when expert examination is carried out simultaneously (in parallel) in the reference state and in the concerned states and the medicinal product is launched to the market at the same time in all the states that have performed expert examination (see fig.1). Since the minimal duration of DP is 210 days, this is exactly the period of time that a particular medicinal product will need to reach the market;

Figure 1

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Figure 2

registration through the Mutual Recognition Procedure (MRP), when expert examination of the dossier is first conducted by the reference state, and the concerned states sequentially, in the order determined by the applicant, join the registration approval process after the preceding state completes its work, and the medicinal product is successively launched in the markets of all relevant states (see fig.2). Since the minimal MRP

duration is 210 days for the reference states and 100 days for each of the concerned states, the minimal period of time required for a medicinal product to reach the market can be estimated using the following formula: 210+(n-1)×100, where n is the number of states where registration is to be effected. All medicinal products registered under the national procedures before 1 January 2016, and also during the transi-

tional period from 1 January 2016 to 31 December 2021, should have their registration dossiers aligned with the EAEU rules by 31 December, 2025 in order to remain in the common market after the said deadline (i.e. 31 December, 2025). This procedure was called the “dossier alignment procedure” (DAP) (see fig.3): The information system of the EAEU common pharmaceutical market will be based on the EAEU integrated

Figure 3

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CIS GMP news

1 (1)Â / autumn 2017

INFORMATION AND DIGITAL PROCESSES

ORGANIZATIONAL

CONTROL

DB Of Substandard, Counterfeit And Falsified Medicinal Products

DB Of Adverse Reactions And Lack Of Efficacy Cases

DB Of Registered Prices Of Medicinal Products Register Of Patients (Nosologies)

DB Of Quality Parameters Of Released Batches

DB Of Identification (Traceability) Of Released Batches Of Medicinal Products

DB Of Gxp Inspection Results

DB Of Recalled And Prohibited ÂMedicinal Products

Control Of Review Of Registration Applications Control Of Product Quality Drift

ANALYTICAL

Nominal Market Analysis Analysis Of Therapeutic Compliance Pharmacoeconomic Analysis At The Level Of Healthcare Systems (Cuac8a)

Figure 4

information system of external and mutual trade (IISEMT), which will have a separate segment dedicated for the creation of the Common register of medicines and related databases (DB) (see fig.4). If we now look at this economic community from the point of view of a western pharmaceutical company willing to localize its production in one of the Union member states, what regulations and laws should it be guided by in the first place? When localizing production in the territory of a EAEU member state, first of all, it is necessary to be guided by the legislation of that state and by the requirements of the Union GMP guidelines. Is there any single regulatory authority in the Union which is responsible for controlling pharmaceutical manufacture, or is everything done locally, but according to the EAEU rules? Control and supervision within the Union are carried out by the national competent authorities in accordance

with the unified rules of the EAEU. Since the territory covered by these five states is quite large, any manufacturer, whether a western or a local one, is concerned about the distribution of their pharmaceutical products. Is transport and overall logistics structure ready for a common market? Until April 26, 2018, there is a transitional extension period for the application of the Union's GDP guidelines, which is connected with the need to prepare the transport and logistics structures. A key role in the process of standardization of medicinal products and substances is played by Pharmacopoeia. What stage is the process of creation of the EAEU Pharmacopoeia currently in? Will it be based on one of the pharmacopoeias of the EAEU member states, or will a whole new collection of monographs be created? The EAEU Pharmacopoeial Committee was set up within the Eurasian Economic Commission. It includes experts in the fields of pharmacy, medicinal chemistry, and analytical chemistry from

the Union member states. The Pharmacopoeial Committee has an equally proportional number of representatives of every member state. The main task of the experts of the Pharmacopoeial Committee is to develop the Union Pharmacopoeia as quickly as possible. It will establish the required quality standard for pharmaceutical manufacturers and will provide consumers with safeguards to guarantee that the medicinal products launched in the entire market of the EAEU meet a harmonized standard. Now the Pharmacopoeia Committee is working intensively on the first volume of the Union Pharmacopoeia. Its development is carried out in accordance with the concept of harmonization of pharmacopoeias of the EAEU member states on the basis of their national pharmacopoeias and basic pharmacopoeias (EP, BP, and USP). In parallel, since August 2017, the EAEU Pharmacopoeia has been included as one of the regional quality standards in the WHO list of world pharmacopoeias and pharmacopoeial bodies.

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Manufacturers of Medicines of the EAEU Countries until the End of 2020 Can Choose How to Register Medicines Under National Law or Under the Rules of the Union 11 July 2017 Source: Press Service of the Eurasian Economic Commission eec.eaeunion.org

egulation of operation of the common market of medicines and administrative procedures governing registration of medicines and circulation of previously registered products on the Union common market became topics of speeches delivered by representatives of the Eurasian Economic Commission (EEC) at the IV All-Russian Congress â&#x20AC;&#x153;Legal Regulation of Pharmaceutical Activity in Russia and the EAEUâ&#x20AC;? held in Moscow. All documents of the Commission that were developed and entered into force on May 6, 2017 are directly applicable documents. This means that they do not require adoption of any national regulations governing their use in each of the Member States. Thus, from May 6 this year, all stages of development, production, study of medicines in preclinical and clinical studies should be carried out in accordance with the requirements of the relevant decisions of the Commission. Currently, there is a transitional period in respect of the registration of medicines till the end of 2020, during which each producer may choose to register a medicine under national law

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or under the rules of the Union. While the competent bodies of the Member States may not refuse manufacturers of medicines in receiving a product specification file for registration under the rules of the Union. Talking about the administrative procedures of the registration authorities, representatives of the Commission noted that, till December 31, 2025, all medicines registered in the Member States under national procedures, should bring their product specification files in compliance with the rules of the Union. This can cause some difficulties for those manufacturers in the Russian Federation that registered synthetic medicines for oral use without performing any clinical or bioequivalent studies, exclusively on the basis of submission of literature reviews (so-called "well-established medicines"). The Union registration rules for this group of medicines provide for dissolution kinetics test and a special procedure for consideration, if the medicine has grade I or III of the biopharmaceutical systems or bioequivalence studies, if the product has grade II or IV under

this system. The Eurasian Economic Commission plans to establish an Expert Committee, which will deal with the registration of medicines in the EAEU. It will include three representatives from each Member State. The EEC Minister will be the Chairman of the Committee. Specialized groups will begin their work under the Committee. The tasks of the Committee will include resolution of differences in circulation of medicines, preparation of recommendations within the period of up to 60 days, as well as elaboration of proposals on harmonization and unification of the laws of the EAEU Member States. Within the EAEU, no common authority for the registration of medicines will be established, like the European Medical Agency (EMA) in the European Union or the Food and Drug Administration (FDA) in the United States. The authorities for registration and monitoring of circulation of medicines remain at the level of the Union Member States. At the Congress, participants also discussed pricing for medicines, determining their interchangeability within the territory of the Russian Federation.

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1 (1)Â / autumn 2017 Regulatory Issues

GMP Compliance in Russia: Achievements, Shortcomings, and National Specifics

Andrey Meshkovsky

Valery Beregovykh

Natalia Pyatigorskaya

Associate Professor, I.M.Sechenov First Moscow State Medical University, Chair of Industrial Pharmacy

Doctor of Technical Science, Full Professor, Corresponding member of the Russian academy of sciences. I.M. Sechenov First Moscow State Medical University, Chair of Industrial Pharmacy

Institute of Pharmacy and Translational Medicine I.M. Sechenov First Moscow State Medical University, Dr. Deputy Director Institute, Professor, Head of the Chair of Industrial Pharmacy

21 August 2017Â

has been three and a half years since the deadline for GMP implementation in Russia, which had been last postponed to January 01, 2014. There is therefore a reason to review some intermediate results, summarizing both the achievements and the failures. The current state of affairs should be analyzed against international experience, focusing on practices of countries with well-developed regulatory systems in the Pharma Sector. According to WHO, the ICH Members, and Observers prior to 2015 are the regulatory authorities following strict requirements. They include the

agencies of the European Union member states, the United States, Japan, as well as Canada and Switzerland. Close to them are competent authorities that have concluded mutual recognition agreements with the aforementioned bodies. This group comprises the respective agencies of Australia, Norway, Israel, and some other small countries. Essentially, the experience accumulated by these countries is reflected in documents published by international organizations, including those of which Russia is a member (WHO), or is going to be a member (PIC/S), and those to develop economic cooperation with (European Union).

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Andrey Meshkovsky Batumi, Georgia, June 2017, 8th International Conference "Ensuring the Quality of Medicines"

1. ACHIEVEMENTS The state policy concerning the introduction of the GMP regulations has dramatically changed for the better in the last few years. The delay has been significant in comparison with the industrialized countries and a number of developing states (India), and yet, it has happened. A vicious circle had been hampering this side of the industry in the preceding decades. Deadlines had been set, but with no enforcement. In view of this, the majority of manufacturers had not taken proper measures. As there had been no progress, deadlines had been postponed, thus giving rise to a new cycle. With this background, the political will shown by the governing bodies, the Ministry of Industry and Trade (Minpromtorg) and the Government of the Russian Federation as a whole, was really remarkable. In the period of 2012 - 2014, the willingness not to allow any further delay in introducing GMP compliance was voiced at the highest level again and again, even though proposals regarding further postponement had been abundant. Apparently, this had its

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effect: the statements made previously that the GMP regulations could not be introduced in Russia for financial, technological, or other reasons practically ceased1. The generally negative attitude towards the GMP concept displayed by many professionals gradually gave way to an understanding of the need to work in a new way. The Russian GMP regulations (Orders No. 916 and No. 1997 of the Ministry of Industry and Trade of the Russian Federation) were approved in 2013. At that time, the text of these regulations was close to that of the European Union GMP Guide, with the exception of a few discrepancies (see below). The adoption of these documents stood out from the preceding attempts to create the country’s own regulations that would 1 It should be mentioned in this connection that the bottleneck in the last phase of the industry’s transition to GMP compliance was the state machine’s unpreparedness to approve the modern regulations rather than a lack of funds at the manufacturing sites as had been prophesied by some “experts”. It took about two years for lawyers of the concerned authorities to familiarize themselves with the specifics of the GMP guidelines.

resemble and at the same time differ from the international ones (Industrial Standard 42-510, State Industrial Standard R 52249, etc.). Achievements of the last few years include a substantial improvement in the training of the industry’s professionals in product quality assurance-related issues, including the traditional GMP regulations and new approaches concerning quality assurance systems, risk management, etc. Seemingly, enterprise employees have started to obtain necessary information through various channels. Mention should go to the training programs implemented by the leading universities (I. M. Sechenov First Moscow State Medical University, Saint Petersburg State Chemical and Pharmaceutical Academy, Peoples' Friendship University of Russia, etc.), private educational initiatives (GMProject, Vialek, etc.), and partnership ties of domestic manufacturers with foreign companies. It should be underlined at the same time that the latter form of personnel training is an aspect of the extremely important, positive trend that involves Russian manufacturing sites into the global contract manufacturing system.

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1 (1) / autumn 2017

Valery Beregovykh Obninsk, Russia, November 2012, 3rd Obninsk Innovative Forum. PharmEvolution: Pharmaceutical Production and R&D Localization in Russia: Practice, Trends, Outlook. (Photo: www.airko.org)

The Federal Budget-funded Establishment “State Institute of Drugs and Good Practices” of the Ministry of Industry and Trade of the Russian Federation has lately taken on the personnel training for domestic enterprises. Seminars, both for directors of the industry’s enterprises, and for all other specialists, have been arranged. Furthermore, an All-Russian GMP conference has been convened, and a second conference is in preparation. The active attitude of the responsible agency allowed to exclude self-declared “experts” from participation in a national GMP personnel training program and the rulemaking process. In the past years, some engineering specialists had insistently enforced their

own beliefs and opinions upon the industry’s professionals with no due regard to available international experience. In particular, representatives of this group had insisted that the principles of quality risk management could not be used in the drug quality assurance practice. At present, risk management is generally considered to be an important component of the pharmaceutical quality system. The setting up of a professional inspection agency for GMP compliance monitoring proved to be an extremely important decision of the Government of the Russian Federation. It seems appropriate, in this connection, to remember that the State Inspection for the Quality of Drugs and Medical Equip-

ment of the Ministry of Health was responsible for supervising the operation of manufacturing sites during the Soviet era and in the first years of the sovereign Russia. However, after it was disestablished in the 1990’s, control of domestic manufacturers was relegated to commissions, i.e. temporary teams consisting of specialists from different organizations that were ad-hoc by nature. The attempts, aborted, deo gratias, to set up a private pharmaceutical inspection have to be mentioned as well. Implementation of these plans could have resulted in considerable damage both to the industry and to patients. At present, the inspection service consists of two parts. Control of domestic manufacturers has been delegated to the Manufacture Licensing Division of the Department for Development of Medical and Pharmaceutical Industry of the Ministry of Industry and Trade of the Russian Federation. Foreign sites that supply drugs to Russia are examined by employees of the Inspection Division of the Federal Budget-funded Establishment “State Institute for Drugs and Good Practices”, reporting to the same Ministry. In either case, the enterprise is visited by inspectors for whom this work is the main field of activity. Systematic inspection of foreign pharmaceutical manufacturers supplying their products to the Russian market has been initiated for the first time in this country. The Ministry of Health of the Russian Federation began its involvement in the GMP compliance process by setting up a system of attestation for manufacturers’ Qualified Persons that utilizes educational programs located in various regions of the country (Moscow, Saint Petersburg, Samara, Volgograd, Novosibirsk). A rather demanding candidate assessment procedure has been established, which consists of the filing-out of an online questionnaire covering the key GMP sections, an interview within one of the educational programs, and approval by a standing commission comprising officials of responsible departments. The total number of already attested persons is 691, as of mid-2017. The majority of candidates (458) have been interviewed at the I. M. Sechenov First Moscow State Medical University.

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2. DIFFERENCES WITH INTERNATIONAL PRACTICE Having pointed out the achievements, we can now move on to GAP analysis, centering upon the essential discrepancies between domestic practice and international experience. To that end, we shall touch upon the pharmaceutical legislation, internal documents of the inspection service and the organizational aspect of its function.

Shortcomings of the regulatory legal basis There are significant terminological differences between normative documents adopted in Russia and at the international level. In particular, quality of a drug is officially defined as its conformity to the requirements of the Pharmacopoeia Monograph, or a similar document (Federal Law 61FZ, Article 4). Elsewhere in the world, however, this term is related to the suitability of a drug substance or drug product for the intended use. It is essential to underline for the purpose of this article that the respective provision is included in the Russian GMP requirements (Section “Pharmaceutical quality system”, Subsection “The basic principle”). However, the Law still retains a formulation that is outdated by 50 years. There was a detailed discussion of this aspect in REMEDIUM journal [1]. What should be added here is that the definition of the term “quality of a drug” in the Federal Law 61-FZ is logically incompatible with the contents of Article 45 of the same Law, according to which marketed medicinal products should be manufactured in accordance with the GMP regulations and comply with the registration requirements rather than the compendial ones (Paragraph 6). The term “drug (medicinal, pharmaceutical) product”, i.e. a preparation produced industrially using a certain formulation and technology, has not been recognized officially, despite its very common use in international practice. This term can also be found in a few Russian publications, particularly those using foreign sources. Instead, legal and normative documents employ the term “medicinal preparation”, usually without due

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regard to it being an umbrella term2. As a result, the terminological confusion is still maintained, as the terms “medicinal preparation”, “drug”, and “pharmaceutical product” are often confounded. The Russian GMP regulations (Orders No. 916 and No. 1997 of the Ministry of Industry and Trade of the Russian Federation) are known to be a translation of the European Union GMP Guide. On the whole, this translation is of rather good quality, though a number of flaws can still be found. Firstly, the translation contains some inaccuracies. In particular, Part I of the EU Guide is titled “Basic requirements for medicinal products”. The corresponding section in Order 916 has a different title: “Basic requirements for the organization of manufacture and control of the quality of drugs" (underlined here for the purpose of this article), although a due reference to the original document is included: “Part I *(7).” As a result of the substitution of the word “drug” for “medicinal product”, the purport of the document has been changed considerably from the practical standpoint by this translation. Whereas all provisions of Part I of the EU Guide concerning the role and functions of the Qualified Person (in Chapters 1, 2, 6, etc.) apply to the manufacture of finished medicinal products only, in the domestic regulations they equally cover the manufacture of active pharmaceutical ingredients. In other words, the EU regulations mean that drug substances may be released at the discretion of the Quality Unit, i.e. the way it was done in the USSR and in Russia previously and how it is still done in the United States. The same order is required by the PIC/S and WHO documents. In contrast, Order 916 demands that drug substances be released following a decision of the Qualified Person. It is clear that national authorities may approve GMP regulations somewhat different from the international ones. In this case, it appears, the change was not deliberate, it rather arose from a technical mistake and remained unnoticed both by the regulators and by the industry’s professionals. This may be considered an example of a national specific that had no negative effect on the quality of the document. The Russian sectoral legislation contains no “investigational medici2 A preparation may be obtained ex tempore, as a pharmacy formulation or industrial product.

nal product (or preparation) dossier” concept. The “Pharmaceutical quality system” section of Order 916 states that drugs should meet the requirements of the Registration Dossier or Clinical Study Protocol. The latter, apparently, should apply to investigational medicinal products for which no Registration Dossiers are available. In the original document, however, the clinical trial authorization rather than the clinical study protocol is mentioned in relation to the manufacture of investigational products. It should be clarified in this connection that references to clinical trial authorization included in the international GМP regulations (WHO, EU, PIC/S) should be understood in a broader sense, as a set of documents allowing authorization of the conduct of a clinical study for the medicinal product in question. In actual fact, the manufacturing conditions for a medicinal preparation of this category should correspond to the materials included in the investigational medicinal product dossier, which is part of the set of documents allowing authorization of the conduct of a clinical study for the medicinal product in question. Since the clinical study protocol is in no way connected with either the GМP regulations, or the manufacturing conditions as a whole, the reference to this document made in Order 916 is an unfeasible requirement and therefore has no practical sense. We will mention here, by the way, that the same inaccuracy of translation (the phrase “clinical trial authorization” was translated as “clinical study protocol”) was repeated in the text of the GМP regulations of the Eurasian Economic Union (Decision No. 77 of the Council of the Eurasian Economic Commission dated November 03, 2016, “On approval of the Good Manufacturing Practice Guidelines of the Eurasian Economic Union”). The “Personnel” section (Chapter 2) in Order 916 contains a subsection titled “Responsible personnel”, which includes the Head of Production, the Head of Quality Assurance, and the Qualified Person. In the original document, this subsection is titled “Key personnel”. The error of translation appears evident if one considers the fact that the circle of an enterprise’s employees that could be described as responsible personnel is significantly broader (Director and Deputy Directors, Chief Engineer, Chief Technology Officer, Head of Security, Head of the Garage, etc.). This error was

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1 (1) / autumn 2017

Natalia Pyatigorskaya Voronezh, Russia, April 2016, 6th International Research and Methodology Conference "Approaches to Improving Pharmaceutical Education. Creation of New Physiologically Active Substances". (Photo: www.vsu.ru)

corrected in the Eurasian Economic Union GМP Guidelines. An example of erroneous interpretation of some of the provisions of the international regulations is Subparagraph b) of Paragraph 28 in the same subsection “Responsible personnel” of the “Personnel” section in Order 916. In the original document, the corresponding text describes the procedure of importing finished medicinal products from third countries, whereby each production batch is released on the European Union market by a Qualified Person located in one of the European Union member states. Since the procedure for licensing importers of finished medicinal products and the procedure for release of imported batches is different in Russia, this Paragraph of the Order is inappropriate. At present, changes in the Russian regulations are being prepared with regard to the procedure of releasing batches of imported products. Hopefully the changes will include a correction of the aforementioned error in Order 916. Appendix No. 13 to the Russian GМP Guidelines covering the manufacturing conditions for investigational products contains additional provisions with re-

gard to assuring the quality of this particular category of medicinal products. However, inaccuracies of translation can be found here as well. Section II of the “Terms and definitions” appendix includes the term “Medicinal Product Dossier”, which has no clear definition and is not commonly used in international practice. The corresponding term in the original document (EU GМP) is the “Product Specifications File”. This term is also erroneously translated in Appendix No. 13 to the Eurasian Economic Union GМP Guidelines, however differently from Order 016, specifically as the “Investigational Product Dossier”. As mentioned above, this term does exist in international practice, but it is applied to the regulation of clinical studies rather than to GМP. Here we should clarify that an important difference between a Product Specifications File and similar sets of documents is that the former retains previous versions of the quality specifications and processing instructions along with the current versions of these documents. This Dossier facilitates traceability in the process of preparing final versions of essential production and control documents, which will be

used in commercial production. The Product Specifications File is an internal reference document of the manufacturer, and is not submitted to the regulatory authority. Its contents are regularly updated. Its format and details of the contents are not regulated. However, documents of this type may be assessed at the discretion of inspectors within an inspection of the manufacturing site for compliance with the GMP guidelines.

The time-lag between the Russian GMP Guidelines and the original document: The EU GMP Guide Orders No. 916 and No. 1997 of the Ministry of Industry and Trade of the Russian Federation signed in 2013 reflect the contents of the European Union Guide as of that year. After the approval, the Russian GMP Guidelines have not been revised. At the same time, the EU GMP regulations are continuously updated, thus the Guide is no longer available on paper. Changes in these regulations are monitored by concerned organizations and specialists at the EudraLex website. The following changes have been made in the EU GMP Guide in recent years.

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Personnel (Chapter 2) - clarification of the role of company management, - clarification of the structure of the Quality Unit: Quality Control and Quality Assurance departments. Production (Chapter 5) - toxicological assessment of materials - risk management with regard to prevention of cross-contamination - exclusive use of active pharmaceutical ingredients manufactured in accordance with GMP - supply chain traceability - clarification of the procedure for the testing of starting materials - notification of restrictions in supply  Quality Control (Chapter 6) - transfer of technology with regard to test methods - Out of Specification and Out of Trend results (OOS and ООТ)  Complaints, product recalls, and quality defects (Chapter 8) - Quality Risk Management when investigating complaints and defects - identification of the root cause - CAPA’s - reporting of quality defects to competent authorities  Annex 15 Qualification and validation - consideration of the ICH Q8-11 guidelines  Annex 16 Certification by a qualified person and Batch Release - clarification of the procedure for certification of batches manufactured at different sites - confirmation of conformity in case of partial manufacturing.

Apart from that, the Russian regulations contain no matches of the new EU documents closely associated with the GMP requirements: The Guideline for formalized risk assessment for ascertaining of appropriate GMP for excipients and the Guidance on Good Distribution Practice (GDP) for importers and distributors of active pharmaceutical substances. The absence of a constant program for revision of the Russian GMP guidelines results in a time-lag between these most important industrial regulations and the EU GMP Guide, and consequently the other international standards as well (PIC/S, WHO).

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Internal documentation of the inspection service According to the international documents, an essential requirement for a GMP/GDP inspectorate is the availability of an internal quality system. Recommendations in this respect were formulated over 20 years ago by PICPIC/S and WHO. A Russian translation of the PIC-PIC/S document was published in 2001 [2]. Afterwards, they were codified in the European Union’s documents. The most important objective of this document is to ensure independence of personnel from possible external influences. In turn, this is necessary to inspire confidence of the regulated industry and the medical and pharmaceutical community in this service. Without a quality system, the national inspectorate cannot be fully recognized by foreign partners. In the current practice, the work of the pharmaceutical inspectorate is regulated, apart from the quality system, by an extensive set of job descriptions, SOP’s, codes of conduct for inspectors, and other documents. Instructions envisage various types of inspections (routine, pre-registration, abridged, special, repeated, etc.), procedures for appealing against decisions taken, the complaints handling procedure, guidelines for preventing conflicts of interests and for maintaining the confidentiality of information obtained by inspectors during their visits to the enterprises. Many countries employ classifications of GMP violations by consumer’s risk. Use of the quality management risk principles is being introduced into the inspection planning practice. Functioning of the inspectorate’s quality system is analyzed at certain intervals in accordance with internal documents. For this purpose, internal and external quality audits are conducted and complaints against the actions of inspectors are analyzed. Identified shortcomings are eliminated using the algorithms envisaged by the pharmaceutical quality system and used by regulated enterprises: identification of the root cause(s), CAPA’s, and evaluation of the effectiveness of adopted measures. No quality system exists in the Russian inspection service. The corresponding document of the Eurasian Economic Union is only a framework, which is intended to form the basis for the development and approval of national regu-

lations. Furthermore, as shown below, launching an effective quality system is an unfeasible task with the existing structure of this service. Procedural aspects of the function of the Russian inspection service are determined by its internal documents; however, their scale and level of detailing cannot stand comparison with the inspectorate practices in countries with well-developed regulatory systems. As an example, the wordings used in the discussion of the plans for introducing pre-registration inspections indicate that their authors are unfamiliar with the international experience in this area.

Institutional aspects of the inspection service The organizational aspects of the inspection service should be considered within the framework of the general structure of the national regulatory system. As pointed out numerous times by the industry’s specialists, the organization of the control and authorization system in Russia is, on the whole, totally different from the international experience and recommendations of the international organizations. This refers to organizations of which Russia is a member (WHO) and those Russia is planning to join (PIC/S). It should be mentioned in this connection that, in international practice, the convergence of the organizational approaches adopted by industrial regulatory systems is lagging behind the harmonization of regulations and rules. National traditions, customs, and preferences still play a significant role in this area. At the same time, a trend towards use of common principles in the organization of control and supervisory authorities has been evident in the last 30 years. In the overwhelming majority of countries, the national health care system contains an autonomous centralized structure (agency) that performs the essential regulatory functions to ensure the efficacy, safety, and pharmaceutical quality aspects of drugs. These functions include assessment and marketing authorization of new medicinal products, licensing and inspection of manufacturers and other market operators, subsequent quality control, pharmacovigilance, etc. The pharmaceutical inspectorate or GMP/ GDP inspectorate is an important subdivision of the agency.

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1 (1) / autumn 2017

It should be pointed out that bringing the main regulatory functions into the hands of a single administration is not simply a trendy matter. It reflects the current concept of the need for an integrated approach to ensure the efficacy, safety, and pharmaceutical quality aspects of medicinal products at the national level, as it is done within a single enterprise. It is for this reason that the general state of the “regulatorics” (as some health care officials term it) has to be taken into consideration when analyzing the GMP compliance situation. In view of the above, the most important discrepancy between the domestic regulatory system and international experience is that individual functions are scattered not just over different departments, but throughout each of them as well. Within the Ministry of Health, medicinal product registration and related functions are performed by two departments, plus the expert organization (Federal State Budget-funded Establishment “Research Centre for Expert Examination of Health Care Products”), plus the semi-autonomous Federal Service for Surveillance in Healthcare. On the side of the Ministry of Industry and Trade, the manufacturer control functions are shared by the Department for Development of Medical and Pharmaceutical Industry and the Federal Budget-funded Establishment “State Institute of Drugs and Good Practices”, sponsored by the said Ministry. The Federal Antimonopoly Service (FAS) is an active participant of the revision of legal and regulatory documents. The impression of complete decentralization is accentuated by the certification centers that are formally independent, but affiliated with local executive authorities; they participate in the batch declaration of manufactured medicinal products3. The practical result of the existence of this decentralized regulatory system is that the general function of the regulatory system is nobody’s responsibility. The unfavorable state of affairs in this field has been underlined by the industry’s professionals many times.

3 Changes in the legislation are currently being prepared concerning replacement of the requirements of batch declaration of conformity with state control of the first three batches of a manufactured or imported medicinal product.

3. SHORTCOMINGS OR NATIONAL SPECIFICS? The aforementioned differences in the GMP regulations, the structure, and function of the Russian inspection service from those in the countries with well-developed regulatory systems may be seen either as shortcomings, or as national specifics. In the former case, the work to harmonize the domestic laws, regulations, and rules with the international regulations and standards should be continued. If the latter is true, one can rest on the laurels. The choice of attitude in this case is determined by the goals set for the introduction of these regulations. In Russia, as well as in the majority of other countries, the GMP regulations were introduced with two aims: to protect patients in this country from drugs with suspicious quality, efficacy, and safety, and to support export of the produce of local manufacturers. Yet each of these goals may be achieved to a different extent. If the objective is only to partially limit risks associated with the quality of marketed drugs, and to focus on export into countries with loose regulatory requirements, one can consider the current state of affairs satisfactory. Most statements made by representatives of the competent authorities today reflect this kind of attitude. On the other hand, a number of facts indicate that the current situation with the introduction of GMP is not completely satisfactory yet. According to Federal Service for Surveillance in Healthcare (Roszdravnadzor) data, 7.2 million drug packages (3,800 batches) were destroyed in the Russian Federation in 2016, as compared with 2.7 million packages in 2015. There were also reports of decreasing numbers of poor-quality drugs this year; however, no specific figures have been published yet. It appears evident, therefore, that the use of simplified and abridged GMP guidelines in combination with sub-optimal GMP enforcement means that the protection of the interests of Russian patients is not as it should be today (i.e. defective) as far as drug efficacy and safety are concerned. A comparison with a motorcycle helmet in which some details are made of cardboard suggests itself here. Such item will be cheaper and lighter, but in a road accident it will not protect the user from injuries as reliably as a solid metal one would.

Speaking of the second goal of the introduction of the GMP regulations, i.e. promotion of export, the overall weakness of the domestic system, including the drug product registration and manufacturers’ inspection procedures, considerably interferes with the efforts to market domestically produced medicinal products in well-off countries. At present, the Russian pharmaceutical industry is making little use of the capacity of the international drug market. The total cost of drugs exported from Russia is over 30 times less than India’s respective revenue. Going back to the problem of poor coordination of the domestic regulatory system, some additional considerations should be included. Firstly, the licensing and inspection control of manufactures exercised by the Ministry of Industry and Trade is detached, from the organizational point of view, from the product registration function performed by the Ministry of Health. At the same time, the functions of product registration and manufacturing control are brought together more and more in the practices of countries with well-developed regulatory systems. Secondly, the manufacturing control function is exercised, not within the public health care system, as it is done worldwide, but by an agency responsible for the expansion of the pharmaceutical industry. The situation, in which the Manufacture Licensing Division is part of the Department for Development of Medical and Pharmaceutical Industry of the Ministry of Industry and Trade, resembles the bygone structure of an enterprise within which the Technical Control Department was subordinate to the Head of Production. It seems apparent that the existing organization objectively supports the import substitution policy by setting lower requirements in the process of licensing and inspection of local manufacturers, and simultaneously setting the bar of expectations much higher for overseas sites. This results in a conflict of interests within the ministry: promotion of the import substitution policy declared at the high level on the one hand, and consideration of the needs of the health care system on the other hand. In this connection, a few words have to be said on the terminology. In the Russian pharmaceutical industry, the term “inspectorate” is frequently used when discussing problems associated with in-

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spection of domestic and foreign drug manufacturers. The “foreign contour”, i.e. the FBE “State Institute of Drugs and Good Practices” is usually referred to in this case, its successes having started to overshadow the Manufacture Licensing Division of the Ministry of Industry and Trade. It should be taken into account in this connection that this term, as many others, can have different meanings. In view of the aforementioned considerable progress of the domestic regulatory system in setting up a professional inspection service that has allowed departure from the commission forms of inspection, both inspecting subdivisions can be called an inspectorate. At the same time, this term used in current international practice means something more than a group of inspectors. Its meaning was explained in the European Union’s guidelines [3] consisting of over 200 pages and in the recommendations of other international organizations (WHO, PIC/S). Vialek Group of Companies mentioned above has prepared a translation of the European Union’s set of documents that regulates the work of the inspectorates in the EU member states. The Eurasian Economic Union materials outlining procedures to be followed by inspection services and complying with the PIC/S recommendations have been published [4]. Repeating ourselves somewhat, we would like to underline that the availability of a quality system, which can only be set up within a rather independent administrative body, is an essential requirement for inspectorate. Both Russian inspection groups do not constitute any independent structures. Furthermore, they are parts of a department whose top priority is import substitution rather than drug

quality assurance. As a result, one could hardly imagine that the Head of the Manufacture Licensing Division of the Department for Development of Medical and Pharmaceutical Industry, or the Chief of the Inspection Group of the FBI “State Institute of Drugs and Good Practices” have the power to protect their staff from “influences,” or rather directions of the Office’s management. It appears that, from this point of view, the Russian inspection groups have not yet attained the “inspectorate” status. Documents from EAEU point to in the same direction. By definition included in directions of the quality managements system of the inspectorate, the pharmaceutical inspectorate is a structural subdivision of the regulatory body [5]. Federal Budget-funded Establishment "State Institute of Drugs and Good Practices" is an institute subordinate to The Ministry of industry

and trade of the Russian Federation, and therefore can not be considered a regulatory body. With this in mind, it has to be noted that in accordance with the established process of control of foreign manufacturers, inspection is performed by the employees of the Institute who do not have de jure regulatory powers, and the decisions about the GMP compliance of manufacturers are made by the employees of The Ministry, who do not see those enterprises themselves These facts, as well as some others, imply that the policy of international harmonization in drug quality, efficacy, and safety assurance, which has been adopted in the last few years, should be continued. This will allow better protection of patients’ interests from poor-quality drugs and facilitate international marketing of domestic medicinal products.

LITERATURE 1. 2. 3. 4. 5.

Р. Р. Ниязов с соавт. Качество лекарственных препаратов: связь нормативной документации со спецификацией, регистрационным досье, фармакопеей и GMP. РЕМЕДИУМ, 4/2017, с. 64-71. Требования к системе качества фармацевтических инспекций: в кн. «Надлежащая производственная практика лекарственных средств». Киев «Морион» 2001. АРФП: Вопросы Министру промышленности и торговли РФ Денису Мантурову. Фармацевтическая промышленность 3/2017, с. 32. Compilation of Community Procedures on Inspections and Exchange of Information. EUROPEAN COMMISSION. European Medicines Agency, 2014. 3 October 2014. EMA/572454/2014 Rev 17. Общие требования к системе качества фармацевтических инспекторатов государств – членов Евразийского экономического союза: в кн. Нормативные правовые акты в сфере обращения лекарственных средств в рамках Евразийского экономического союза. Том 1. М. 2017.

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1 (1) / autumn 2017 Regulatory Issues

Pharmacovigilance in Russia: Questions and Answers

Boris Romanov Deputy Director General for Research, Federal State Budget-funded Establishment “Research Centre for Expert Assessment of Health Care Products” of the Ministry of Health of the Russian Federation, Doctor of Medical Sciences

23 June 2017

May 6, 2017, the second-level documents prepared by the Eurasian Economic Commission (referred to herein as the Commission) together with concerned competent authorities of the Union’s member states with the aim to launch a common drug market within the Union and implement the provisions of the Agreement on Unified Principles and Rules for Marketing Medicinal Products in the Union, came into force in the Eurasian Economic Union member states (Armenia, Belarus, Kazakhstan, Kyrgyzstan, and the Russian Federation). These documents are freely available on the website of the Eurasian Economic Commission, and include the Guidelines on Good Pharmacovigilance Practices in the Eurasian

Economic Union (EAEU GVP). The EAEU GVP Guidelines are a supranational (international) special direct-action normative document that has been ratified in the Russian Federation, and is therefore superior to the national (Russian) regulatory legal documents and must be followed in the Union’s member states. Employees of Russian and international pharmaceutical companies holding Registration Certificates (RCH) for medicinal products for human use (as well as of drug developers) are at different levels of pharmacovigilance training. The EAEU GVP Guidelines require basic pharmacovigilance training for each employee of such companies, as well as training of Qualified Persons Responsible for Pharmacovigilance. For the purpose of standardization of this training, the materials of this article are presented in the form of questions and answers.

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WHAT IS PHARMACOVIGILANCE? The term “Pharmacovigilance” was derived from two words: the Ancient Greek “Pharmacon” (drug) and the Latin “Vigilare” (vigilance). According to the GVP Guidelines adopted in the Eurasian Economic Union (EAEU), “Pharmacovigilance” in Russia, as well as in the other EAEU member states, means “activities intended to detect, evaluate, understand, and prevent undesirable consequences of the use of medicinal products.” As in most other countries, the Russian pharmacovigilance system consists of the pharmacovigilance systems of pharmaceutical organizations, health centres, and regulators. This system was designed for drug safety monitoring, timely detection of all changes in the risk-benefit ratio, and development, and introduction of public drug provision measures.

WHAT ARE “THE UNDESIRABLE CONSEQUENCES OF THE USE OF MEDICINAL PRODUCTS”? Unfortunately, any use of medicinal products may be associated not only with the “principal action” (for which they are given), but also with a risk of development of undesirable consequences: I. Financial and reputational losses for business and science. II. The same losses for consumers and society, coupled in this case with the following: 1. Insufficient efficacy of medicinal products (treatment failure). 2. Excessive effect of medicinal products (overdose).

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3. Side effects of medicinal products (i. e. effects other than the principal ones; such effects may be desirable):   adverse events;   adverse reactions, including complications of vaccination. 4. Unfavourable interactions of medicinal products (drug-drug or drugfood interactions). 5. Improper use of medicinal products:   deliberate use for unlisted indications (off-label use);  deliberate and improper use (misuse);   medication errors;   abuse. III. The ecological problem - the contamination of the environment with medicinal product. If the ratio of potential benefits to possible risks associated with the use of a medicinal product is considered to be favourable and the drug quality and manufacturing conditions are deemed appropriate (i. e. meeting claimed standards and established requirements), a clinical trial may be authorized for such medicinal product and the product may be entered into the State Register of Medicinal Products (registered), i. e. officially approved for use.

WHAT MANIFESTATIONS OF UNDESIRABLE CONSEQUENCES ARE ENCOMPASSED BY PHARMACOVIGILANCE? The realm of medical pharmacovigilance currently encompasses only undesirable consequences of the use of medicinal products for consumers and society. Veterinary pharmacovigilance encompasses medicinal products used in domestic and farm animals.

WHO IS RESPONSIBLE FOR DRUG SAFETY IN RUSSIA? At present, the responsibility for the safety of a medicinal product for human use registered in the Russian Federation lies with the Marketing Authorization Holder (MAH) of this medicinal product. A Marketing Authorization (MA) is a valid record on the medicinal product in the State Register of Medicinal Products (SRMP) of the Ministry of Health of the Russian Federation. The Marketing Authorization Holder is either the manufacturer of the medicinal product, or the representative of the manufacturing company in the Russian Federation (Representative Office or distributor) in whose name the active Marketing Authorization was issued. Each MAH must appoint a Qualified Person Responsible for Pharmacovigilance (QPPV) responsible for pharmacovigilance. The MAH must submit information on the Qualified Person Responsible for Pharmacovigilance to the Roszdravnadzor (Federal Service for Surveillance in Healthcare). Information concerning the Registration Certificate Holder (its name and contact details) is included in the State Register of Medicinal Products, on the drug package, and in the Instructions for Medical Use, which should be followed precisely when using the respective medicinal product. In the event of a negative change in the risk-benefit ratio, use, or even marketing of such medicinal product in the Russian Federation is suspended. A suspension may be followed by a recall of the medicinal product from the pharmaceutical market. The responsibility for the safety of a medicinal product being developed for medical use in the Russian Federation lies with the organization receiving a clinical trial authorization (CTA)

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1 (1) / autumn 2017

from the Ministry of Health of the Russian Federation. This organization is either the drug developer (sponsor), or a different legal entity authorized by the drug developer (sponsor) (i. e. a Contract Research Organization). Information about the Contract Research Organization is also made available at the official web portal of the Ministry of Health of the Russian Federation. In the event of a negative change in the benefit - risk ratio, the Ministry of Health of the Russian Federation considers suspension or even withdrawal of the CTA, which is usually followed by discontinuation of the drug development process. The attending physician of the health centre or the Clinical Research Physician of the certified study site is responsible for the safety of patients or subjects participating in the clinical study. In case of self-administration of over-the-counter medicinal products for human use (responsible self-administration), the person deciding to use them is responsible for any consequences of such self-administration. This person is the patient himself / herself or his / her parents or other persons.

Pharmacovigilance Practices (GVP) for the Eurasian Economic Union member states. These GVP Guidelines were approved by EAEU Council Decision No. 87 dated November 03, 2016, and became effective on May 06, 2017. In the case of medicinal products under development (undergoing clinical trials), pharmacovigilance in Russia should also be carried out in accordance with the EAEU Guidelines on Good Clinical Practices (GCP Guidelines). These GCP Guidelines were approved by EAEU Council Decision No. 79 dated November 03, 2016, and also became effective on May 06, 2017. Other normative documents that regulate local pharmacovigilance on Russia include:  Federal Law No. 61-ФЗ “On the circulation of medicinal products” dated April 12, 2010 (pp. 64 - 66).  Order No. 200н of the Ministry of Health of the Russian Federation dated April 01, 2016 (effective from September 04, 2016), “On approval of the Guidelines on Good Clinical Practices.” Order No. 682н of the Ministry of Health of the Russian Federation dated September 07, 2016 (effective from January 01, 2017), “On approval of the form for the document containing results of efficacy and safety monitoring of medicinal products for human use.”

WHO MONITORS THE SAFETY OF MEDICINAL PRODUCTS IN RUSSIA? HOW DOES MEDICAL PHARMACOVIGILANCE Since the year 2010, the functions of IN RUSSIA WORK? monitoring and supervision in medical pharmacovigilance have been entrusted to the Federal Service for Surveillance in Health Care (Roszdravnadzor), and those in veterinary pharmacovigilance to the Federal Service for Veterinary and Phytosanitary Surveillance (Rosselkhoznadzor).

HOW IS PHARMACOVIGILANCE REGULATED IN RUSSIA? At present, pharmacovigilance during the post-marketing period should be performed in Russia in accordance with Executive Order No. 1071 of the Federal Service for Surveillance in Health Care (Roszdravnadzor) dated February 15, 2016 (effective from April 01, 2017), “On approval of the Pharmacovigilance Implementation Procedure,” and the Guidelines on Good

The “signal-oriented” pharmacovigilance system function model is currently used in Russia. This system is designed to detect, examine, confirm or disprove “signals” (new information concerning drug safety-related problems). Different methods are employed to obtain such new information. The two principal methods are spontaneous reporting (for registered medicinal products) and clinical studies (for medicinal products under development). Another utilized method is based on administrative decisions made by foreign regulatory authorities and on analysis of publications found in open sources of information (journals, Internet. Etc.). In 2016, Russia began switching to a new, “risk-oriented” function model for the pharmacovigilance system. This concept was based on prediction of potential risks and development and

implementation of a risk management plan (RMP). In Russia, preparation of an RMP is currently required for registration of medicinal products of biological origin (vaccines, sera, blood products, etc.). An RMP may also be requested by the Roszdravnadzor from any Registration Certificate Holder in accordance with the new regulatory requirements that have recently come into force. Failure to submit an RMP or a negative result of the Roszdravnadzor’s RMP review necessitates preparation of an administrative decision to recall the medicinal product from the pharmaceutical market of the Russian Federation (withdrawal of the Registration Certificate).

WHO PERFORMS MEDICAL PHARMACOVIGILANCE IN RUSSIA PROFESSIONALLY? A few thousand people occupy themselves with pharmacovigilance in Russia professionally:  Roszdravnadzor employees (central administration staff, workers of the territorial departments and the subordinate Centre for Monitoring of the Efficacy, Safety, and Rational Use of Medicinal Products); employees of the “Research Centre for Expert Examination of Health Care Products” (FSBFE RCEEHCP of the Ministry of Health of the Russian Federation) (experts and employees of the Centre for Expert Examination of the Safety of Medicinal Products); employees of pharmaceutical companies holding Marketing Authorizations (Qualified Persons Responsible for Pharmacovigilance, employees of medical and regulatory subdivisions, etc.; each MAH employee should receive basic pharmacovigilance training at the start and at regular intervals thereafter); employees of the Regional Drug Safety Monitoring Centres (functioning in each Region of the Russian Federation in accordance with local executive orders); employees of health centres for treatment and prevention (clinical pharmacologists and physicians of other specialties); employees of pharmacy organizations and pharmaceutical distributors (pharmacists and others); researchers and educators (employees of higher schools and research organizations, lecturers).

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HOW EFFECTIVE IS THE RUSSIAN PHARMACOVIGILANCE SYSTEM? Safety of medicinal products for human use undergoing clinical trials (pre-registration pharmacovigilance) is effectively controlled in Russia. All Russian and international drug developers follow the requirements for submission of Periodic Safety Update Reports and expedited safety reports for medicinal products being developed in an appropriate and standardized manner. As far as pharmacovigilance of registered medicinal products for human use (post-marketing pharmacovigilance) is concerned, Russia has been a member of the WHO Programme for International Drug Monitoring since 1997, and now all indicators of the Russian pharmacovigilance system meet established requirements. One of these indicators is the number of reports of adverse drug reactions per 1,000,000 of the country’s population per year that is received by the regulator; it should be not less than 100. The current Russian number is over 175 reports.

WHERE AND HOW TO GET TRAINED IN MEDICAL PHARMACOVIGILANCE? The Roszdravnadzor’s website (http://www.roszdravnadzor.ru/drugs/ monitpringlp/faq) contains answers to the most frequently asked pharmacovigilance-related questions, as well as the contact details (telephone numbers and e-mail addresses) of the responsible persons. It can also be used to obtain information from representatives of the competent authority. Training of QPPV’s (certified physicians, pharmacists, or biologists) is conducted within the framework of additional professional education – according to the advanced training programme “The basics of Good Pharmacovigilance Practice. Organization of the Qualified Person’s functions” at the FSBFE “Research Centre for Expert Examination of Health Care Products” of the Ministry of Health of the Russian Federation (http://www.regmed.ru/edu/education/ SeminarPlan). Lecturers participating in this programme can also teach pharmacovigilance at the courses organized by

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the “State Institute of Drugs and Good Practices” (FBI “SID&GP” of the Ministry of Industry and Trade of the Russian Federation) for pharmaceutical inspectors, as well as within internal training programmes conducted at organizations, including MAH’s and others. Information on topical problems in pharmacovigilance is published at the Roszdravnadzor’s website and in specialized quarterly peer-reviewed printed publications, both international (Uppsala reports etc.) and Russian (“Safety and Risks of Pharmacotherapy” Journal of the “Research Centre for Expert Examination of Health Care Products” of the Ministry of Health of the Russian Federation).

HOW SHOULD PHARMACOVIGILANCE ACTIVITIES OF REGISTRATION CERTIFICATE HOLDERS BE ORGANIZED? 1. Understanding and accepting the need for development and introduction of a quality management system and a pharmacovigilance system at the organization. 2. Appointment of a Qualified Person Responsible for Quality Control (quality management system based on the ISO standards) and a Qualified Person Responsible for Pharmacovigilance (QPPV), training for them and Notification of the Roszdravnadzor about the QPPV. Outsourced services may be used as well (though not necessarily). 3. Development (regulation) and introduction of a quality management system (QMS) and a pharmacovigilance system at the organization: preparation, approval, and implementation of a Policy and goals, quality guidelines (and other documents and records), and Standard Operating Procedures (SOP’s). 4. Pharmacovigilance work in accordance with the SOP’s, with documentation of results of these activities: Organization of a training system to give the QPPV and all other employees of the organization basic pharmacovigilance knowledge; Organization of the collection, retention, analysis, and reporting of drug safety-related information; Preparation and maintenance of a Pharmacovigilance System Master File; Proper expedited reporting and periodic reporting;

Preparation, maintenance, and control of Risk Management Plans; Preparation for audits (internal and external) and inspections of the pharmacovigilance system; Preparation of Development Safety Update Reports (DSUR) for medicinal products; Preparation of Periodic Safety Update Reports for medicinal products (PSUR).

HOW WILL THE RUSSIAN PHARMACOVIGILANCE SYSTEM DEVELOP FURTHER? In the nearest future, the development of the pharmacovigilance system in Russia will be determined by the development of the EAEU legislation and control of implementation. Principal vectors of this development may include expansion of the audience and specialization of pharmacovigilance training programmes, as well as a modernized approach to handling safety signals and plans for managing potential risks. These activities are on the agenda of the “Research Centre for Expert Examination of Health Care Products” of the Ministry of Health of the Russian Federation.

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1 (1) / autumn 2017 GMP Inspection Practice

One and a Half Years of Russian GMP Inspectorate: Yesterday, Today, Tomorrow

28 August 2017

Russian GMP Inspectorate exists for more than one and a half years: in December 2015, Federal Budgetary Institution “State Institute of Drugs and Good Practices” was authorized to inspect pharmaceutical producers that have production sites outside the Russian Federation territory on compliance with the requirements of GMP rules. Over the past period, a large number of inspections has been carried out, training and development programs for inspectors have been prepared, and Russian inspectorate itself achieved serious positions at the international level.

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INDICATORS OF 2016-2017 Letâ&#x20AC;&#x2122;s start from what inspections are generally organized for. During these activities, inspectors have to examine pharmaceutical production sites that supply medicinal products to Russia, find to what extent this information is corresponding with registration dossier, and the extent to which the production site complies with Russian standards of Good Manufacturing Practice. In fact, the first inspections of foreign manufacturing sites took place only in April 2016: some time was needed for applications from the manufacturers, approval of the inspections schedule, drawing up a plan of manufacturing sites, inspecting, and implementing all the necessary preparatory measures. A decent illustration of the Russian GMP inspectorate work is demonstrated by statistical indicators. In 2016, the Ministry of Industry and Trade of the Russian Federation received 620 applications for manufacturing site inspections.

465 of them were transferred to Federal State Institution "State Institute of Drugs and Good Practices" (FBI "SID & GP"), out of that number 188 inspections were conducted. For the first seven months of 2017, the number of applications sent to the inspectorate was 320, and 286 inspections were conducted (with the annual plan of more than 500 inspections). In 2016, 163 inspection reports out of conducted inspections were approved; in 2017 this figure increased to 241. During the first 7 months of the current year, 211 GMP compliance statements were issued (compared to 88 in 2016), as well as 41 refusals to issue GMP compliance statements (38 in the past year). Speaking about the geography of foreign inspections, 188 plants from manufacturers from over 40 different countries were inspected in total last year. Most of them were in India (31 inspections), Germany (14 inspections), Hungary (11 inspections), Slovenia (10); Poland, and France close the top five (8 inspections in each country).

2016 Number of applications for GMP inspection

465

Number of conducted inspections

188

Number of approved inspection reports

163

Number of issued GMP compliance statements

Number of refusals to issue GMP compliance statement

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2017 (For the first seven months)

320

286

241

211 38 41

The comparative analysis of data from inspections of foreign manufacturing plants

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A lot of time was needed to be able to confidently speak today about the professionalism of the GMP inspectorate of the Russian Federation. These specialists represent our country on foreign manufacturing sites today. It is encouraging to note that their work is highly appreciated by foreign colleagues. Our Institute is the advanced institution in domestic pharmacology. We are not only monitoring the observance of norms and rules - we train specialists, form the expert base, expand the competencies of market participants, and clearly demonstrate that Russia is the serious player in world pharmacology.

Vladislav Shestakov Director of FBI "SID & GP"

NONCONFORMITIES In total, according to the results of inspection of foreign manufacturing sites (2016), 1,801 nonconformities were identified, 126 of which (7%) were classified as critical, 770 (43%) as major, and 905 (50%) as others. On average therefore, following the results of one conducted inspection, 0.67 critical, 4.1 major, and 4.8 other nonconformities were detected. It is necessary to specifically note significant nonconformities - their percentage is large enough, indeed exactly these nonconformities may influence the quality of drugs (and consequently the life and health of a patient). There are five main categories of these nonconformities: procedures for the production release by an authorized person; measures to prevent cross contamination; procedures for quality control of finished products; risks of microbiological contamination and sterility assurance issues;

non-compliance with the requirements of registration dossier. In the first category, most often there are comments on the lack of proper interaction and traceability in the information exchange between the Authorized persons of different manufacturing sites (in case when these sites jointly participate in the drugs production) and the improper assignment of powers between Authorized persons in the relevant quality agreements. In the second category, inspectors most often encountered with the failure to comply with the requirements for toxicological assessment during equipment cleaning validation, as well as the non-use of all knowledge about the characteristics of the produced ingredients (e.g. solubility, adhesiveness); with the fact that during the validation of purification not all units of equipment involved in the technological process are evaluated, and after introduction of new products into the existing combined equipment production scheme, their impact on the validated status of

cleaning procedures is not evaluated. Comments on the third category related to drug production based on the control of products in bulk/unpackaged products in cases when the processes of primary and/or secondary packaging could have a negative impact on the quality indicators of the finished products; selection of archival/control samples in the amount insufficient for full double control in accordance with the registration dossier requirements; and the subsequent study of the finished pharmaceutical products stability with the use of unpackaged ("bulk") products. The fourth category concerns comments on absence or significant deviations in the system of continuous monitoring of particles in zones of A/B purity class, the failure to comply with the rules for the validation of aseptic filling (known as "media fill test") and the failure to comply with the rules for the division of production zones into classes of cleanliness while performing aseptic filling operations. The last, fifth category, includes the implementation of individual stages of

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Preparation for inspection should take place both within the walls of the Institute [FBI "SID & GP"], and at the manufacturing site itself. Special attention of the applicants should be paid to the correctness of application formation and the correctness of the products list to be inspected. Our experience has repeatedly shown us that this list is revised a number of times in the course of the preparation process - this helps to avoid unnecessary tension both during the inspection process, and the report preparation. Another essential point in "waiting for inspector" is a preliminary visit of manufacturing company representatives prior to the inspection to the manufacturing site. During this visit, they must independently verify the possibility and timeliness of the inspection - for example, to see that the manufacturing site is situated at the declared address, functioning, and is not closed for reconstruction.

Natalya Chadova Head of the Department of Drugs Manufacturing Inspection of FBI "SID & GP", a member of the State GMP Inspectorate

drug production at manufacturing sites which are not listed in the registration dossier, the use of quality control methods that do not meet the requirements of the registration dossier, the drugs release for sale in the Russian Federation without the full range of tests specified in regulatory documents to the drug.

PRIORITIES FOR THE DEVELOPMENT OF GMP INSPECTION At the very beginning of Russian inspectorate work, the insufficient preparation of manufacturing sites for the inspection procedure was observed. As a result, a lot of manufacturers received refusals in issuing GMP standards compliance statements. Currently the inspectors are observing more serious preparation of manufacturing sites. It is what affects the number of GMP compliance statements issued. This demonstrates the importance of inspections - if a manufacturer received a certificate of quality of the products confirmed by

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experts, it can be trusted, these products can be confidently purchased. Apart from the direct activities connected with inspections and preparation of reports on the results of foreign manufacturing sites inspections, inspectors of the Russian GMP Inspectorate are involved as the expert organization engaged by the Ministry of Industry and Trade of the Russian Federation in the GMP inspections of Russian manufacturers. They actively participate in discussions and deliberations on improving the system of state regulation of drugs circulation, as well as in organizing joint training programs for inspectors and representatives of the pharmaceutical industry of Russia and the countries of EAEU. The important part of the Russian GMP Inspectorate work is the integration of Russia into the world pharmaceutical community, participation in the formation of the regulatory framework of the united pharmaceutical market among the EAEU member countries, and the establishment of the international independent expert Council of

inspectorates. The latter project is the most interesting from the perspectives point of view: it involves the creation of the trust index to the inspectorate, and will also increase the level of inspection, make transparency in the mutual recognition of GMP, reduce the pressure on pharmaceutical manufacturers, and obviously improve the quality of manufacturing. GMP rules exist in the world since 1963; compliance to them guarantees that drugs will be produced and delivered to consumers with strict observance of all the necessary technologies, which means that these drugs will be of the guaranteed quality. However, even with a well-designed and carefully controlled system of quality rules, currently it is impossible to control 100% of all world pharmaceuticals productions. This means that there will always be a need for the work of the Russian GMP inspectors, which, firstly, facilitates providing people with safe medicines, and secondly, proves the seriousness of Russia's position on drugs effectiveness issues.

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1 (1) / autumn 2017 GMP Inspection Practice

GMP Inspection Practice: a Case for Global Benchmarking, Convergence and Mutual Reliance/Recognition 30 January 2017

EXECUTIVE SUMMARY In 1969, the global agreement on the Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce was proposed by WHO. The aim was to facilitate international trade in pharmaceuticals through mutual recognition of GMP inspection results. Today, almost 50 years later, up to one hundred countries conduct foreign inspections. As a result a manufacturing site well established, might be inspected many times in one year by local and different foreign authorities. This leads to duplication of work and waste of resources both by regulators and industry. Apart from political reasons several professional factors might explain this situation. The most obvious one is the sovereignty of countries and the lack of mutual confidence between national inspectorates. This may be related to regulatory and GMP differences, real or perceived, in expertise and/or resources. Also different legal approaches and local procedures in inspection practice may make results of foreign inspectorates less relevant in relation to the defined local requirements. Occasionally inadequate economic incentives for inspectorates may preclude work sharing. Better use of resources may be achieved through enhanced collaboration between regulators and reliance on inspection outcomes from trustworthy inspectorates. For this further convergence of similar national/regional GMP inspection practices a supporting legislation worldwide is needed. To this end a facts finding project on essential details of inspection process is suggested. It may be regarded as an extension of annual surveys conducted by EFPIA1. 1 S. Rönninger, J. Berberich, V. Davoust, P. Kitz, A. Pfenninger, Landscape of GMP/GDP inspections in research-based pharmaceutical industry – Part I: Data, Pharm. Tech. Europe, 2017, in press; Part II: Opportunities, Pharm. Tech. Europe, 2017, in press.

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Stephan Rönninger

Andrei Meshkovski

Amgen (Europe) GmbH

I.M. Sechenov First Moscow State Medical University

DEVELOPMENT OF GMP INSPECTION PRACTICE: A BRIEF HISTORICAL OVERVIEW Currently, GMP expectations and related standards are largely similar and so far harmonized on a global level. EU or PIC/S guides, which are almost identical, are recognized by some 50 member inspectorates of one or both organizations. Some other countries, forming sub-regional economic cooperation initiatives, may be added to the list, e.g. Russia, Belarus, and Kazakhstan, ASEAN, Gulf Cooperation Council (GCC). The WHO GMP, not much different from the above mentioned guides, is used in one way or another by a number of countries outside the two groups. The “pharmerging” markets in IMS Health terms: China, India, Venezuela, Viet Nam, Indonesia, Egypt, Pakistan, with their growing pharmaceutical production and exportation potential, may be mentioned in this context. Additionally ICH guidelines, such as ICH Q7, ICH Q9 and ICH Q10 are instrumental in bridging the gap between different GMP norms (EU – PIC/S, WHO, US FDA, ASEAN, GCC) and thus assist mutual reliance, or recognition.

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At the same time, the relevant assessment instruments, which is GMP inspection practices are lagging behind in formal local procedures as far as their international harmonization is concerned. Pharmaceutical inspection, that is official oversight of pharmacies, pharmaceutical laboratories, manufacturers and warehouses, existed in many parts of the world long before appearance of GMPs. Pharmaceutical inspection practices in the modern sense emerged in 1960-s in parallel with adoption of GMPs. Later the term was extended to also cover Good Distribution Practice (GDP) ispections, covering the importation of medicines as well. Originally, national GMP inspection practices differed because of differences in traditions, legislation/regulations, resources available, and institutional responsibility with health versus trade ministries. Harmonization efforts in the area of GMP inspection practice were initiated in 1960-es at sub-regional (Nordic countries), regional/interregional (European Community, PIC) and global (WHO) levels. As a result, in the following decades a certain consensus on common principles has been achieved. The role of pharmaceutical inspection in the overall sectoral

regulatory process was first emphasized by WHO. In the document “Guiding principles for small drug regulatory authorities” [1], licensing of medicinal products was identified as a pivotal function for “any system of drug control”. It was explained, however, that without a pharmaceutical inspectorate (supported by a QC lab) “licensing provisions cannot be effectively enforced2 ”. In the following years, WHO issued “Provisional guidelines on the inspection of pharmaceutical manufacturers” [2] highlighting essential elements of the inspection procedure:   Dual objective of the government pharmaceutical (GMP) inspectorate: to control and enforce general GMP standards and to verify that production and QC procedures employed in the manufacture of specific products are in 2 It may be noted that the role of a pharmaceutical inspectorate often goes beyond assessment of GMP/GDP compliance. In some cases, inspectors were those who drafted national GMP texts and took active part in training of industrial personnel in principles of GMP. Selfinspection teams at manufacturers, educators with academic training programmes, as well as commercial consultants, draw heavily on the experience of official inspectors.

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1 (1) / autumn 2017

accordance with the respective marketing applications/authorizations.   The primary responsibility of an inspector is to present a detailed factual report on standards of manufacture.   Different types of inspection: routine, concise, follow-up and special; quality system review. Announced vs. unannounced visits.   Frequency and durations of inspections: ideally annually; from a few days to two weeks or more.   Inspection planning and preparation.   Opening and final meetings of inspectors with company management.   Advice to follow production flow when visiting facilities. Company “escort” recommended.   Use of checklists: pro et contra.   Access of inspectors to self-inspection or internal quality audit reports.   Collecting samples.   Structure of the report.   Follow-up regulatory actions. Additional guidance by WHO included recommendations on inspection of manufacture of investigational products, on pre-approval inspections [3], on quality systems for national inspectorates, on inspection report and GMP certificate [3-6]. PIC-PIC/S and EU formulated a number of specific recommendations relevant for national inspection services [10-23]. The first version of the European guideline “Conduct of Inspections of Pharmaceutical Manufacturers or Importers” was issued in 1996. The current version of this document is included in the European Commission/EMA “Compilation of Community Procedures on Inspections and Exchange of Information” [21]. By early 1990s the following common principles were agreed upon on the international level, largely as a result of combined efforts by WHO, PIC and EEC:   The aim of inspection is to assess manufacture of finished pharmaceutical products for compliance with GMP standards. At that time only a few countries practiced GMP inspection of APIs manufacturers.   The principal outcome of the site inspection is an inspection report, not a GMP certificate.   Close relation of GMP inspection to other regulatory functions (product licensing, sampling on the market, and quality testing etc.)   Specialized administrative structure: inspectorate.

GMP inspectorate within the ambit of a national health system. Here the position of the PIC Convention (1970) should be stressed: “inspections made by national health authorities” (underlined for the purpose of the present text) [9]. Normally the GMP inspectorate is a part of a National Drug (Medicines) Regulatory Authority.   Official status of GMP inspections as opposed to “service in response to an application” concept. This status was confirmed by the mandatory character of inspections as well as by requirements for CAPA (in present day terms). In accordance with the official character of inspections, post-inspection regulatory actions against offenders were taken, when indicated. Inspections were typically funded from the regulators’ budget. As for imported pharmaceutical products, some countries like USA, EU, Australia practiced direct inspection of foreign manufacturers. However, in view of resource intensive foreign inspections and not-infrequent technical complications, bi-lateral and multi-lateral mutual recognition agreements (MRAs) were identified as the most promising approach to control the manufacturers in exporting countries. There is a very simple alternative: any state could issue a regulatory statute to accept inspections by specific countries (e.g. Columbia for US and many EU countries). In 1970, some ten European countries signed the Convention for the Mutual Recognition of Inspections in Respect of the inspection of manufactures of pharmaceutical products (Pharmaceutical Inspection Convention (PIC)) [9]. The Contracting States accepted and recognized inspections of pharmaceutical manufacturers carried out by the competent authorities of other Contracting States as equivalent to their own national inspections. In mid-1990s, the same principle of mutual recognition of inspections of pharmaceutical manufacturers was adopted by the European Community (presently EU). This Convention had a growing membership attaining an interregional dimension. As the EU was formed in 1995, PIC was hibernated and an alternative agreement was signed: involving more countries already b then: Pharmaceutical Inspections Cooperation Scheme (PIC/S). Under this mechanism, the exchange of inspection reports and company responses does not automatically lead to reducing the number of

inspections3. It is used as a preparation step for upcoming inspections. Currently over 50 states participate in the Scheme, including accession and pre-accession countries, which is one fourth of the UN list of Member States. Alongside the creation of PIC in 1969, WHO had recommended the Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce to importing and exporting Member States (World Health Assembly Resolution 22.50, 1969). The Scheme was developed with the view of facilitating international trade in pharmaceutical products on a global level through mutual recognition of GMP inspection results. However, no measures were foreseen for independent outside assessment of regulatory capacities of participating authorities. For this reason the credibility of certificates issued under the Scheme is unfortunately not widely recognized by importers. Over 140 countries participate in the Scheme. This arrangement is used for information exchange on imported finished medicinal products and APIs. There are opportunities. Presently, there is no international agreement regarding mutual recognition of GMP inspection results under the WHO umbrella on the global level.Recently, EMA published an overview of international cooperation initiatives related to medicines regulation [23]. According to this work, no global cooperation programme has convergence of GMP inspection practice on its agenda, at present.

EMERGENCE OF ALTERNATIVE APPROACHES Following appearance in 1987 of ISO International Standards on quality systems (ISO 9000 family standards), new approaches were adopted by GMP inspectorates. One should note in this context that certification under these standards, though aimed at the same goal as GMP inspection (assessment of the quality assurance potential of a manufacturer), differs from this activity in some important aspects. Since ISO 9000 certification is not a regulatory function, it has no mandatory character, is performed by private groups, at request of the applicant and at a time when the latter feels being prepared for the audit. The audit is focused 3 ВIndirectly PIC/S membership assists in reducing inspections number by forming a basis for MRAs.

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on the final result: the certificate, not on the report describing the state of affairs. The certificate is not related to quality of any particular product; there is no link to product file (dossier). The sole beneficiary is the applicant; the certificate gives him (or her) market advantage. In practical terms, certification is not primarily aimed at protection of public interests. The most important element “borrowed” by GMP inspection services from ISO certification practice is the internal Quality System of an inspectorate. International guidance on this issue was provided by PIC/S (seminars of 1994 and 1998), WHO and EU (guidelines of 2002 and 2003 respectively). According to these documents, a quality system of a GMP inspectorate is aimed at prevention and exclusion of conflict of interest of personnel. The system of obtaining fees should not improperly influence the inspection procedure and results. Independence and impartiality of inspectors should be assured by strict adherence to SOPs, procedures, rules, and codes of conduct. According to WHO text, they should not be under control of pharmaceutical manufacturers, and must be assessed and licensed. WHO further recommends that each inspection report be reviewed in accordance with the quality system of the inspectorate. This allows reports prepared by an individual inspector or by a small team of inspectors to be assessed by management, possibly assisted by their most experienced colleagues. In this process, the head of the inspectorate verifies that the inspection has been carried out in accordance with procedures, that recommendations are firmly based on observations and neither of them is biased. As a result the quality of reports is improved, conclusions are more objective and better grounded, and regulatory actions recommended are carefully thought through. With time, certain other approaches of the ISO 9000 certification practice were taken aboard by regulators in the pharmaceutical sector. Examples are: audits as a service at the requests of manufacturers, collection of user fees, emphasis on GMP certificates with little (if any) attention to inspection reports and CAPA. International organizations followed suit. The WHO Prequalification Programme (presently Prequalification Team), the Ph. Eur. Suitability Certificates, the practice of issuing GMP certificates to APIs’ manufacturers by EU regulatory agencies may be quoted in this context.

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RECENT TRENDS IN GMP INSPECTION PRACTICE As a result, the development of GMP inspection practices took an unusual path: from initial national differences to acceptance of common principles and then in the opposite direction: to alternative approaches, essentially non-harmonized. Presently, GMP inspection practice is only partly converged between countries and regions. National procedures differ in many important aspects. Some examples are listed below:   Position of the inspectorate within the regulatory system   Activities apart from GMP inspection (e.g. other types of inspection, licensing of manufacturers/distributors)   Work load in terms of number of manufacture license holders/manufacturing sites per one inspector   Financing method of the inspection function   Practice of audits as a service (at the request of manufacturers)   Unannounced inspections   Approaches to inspection of APIs manufacturers and to foreign inspections   Use of paper based inspections   Use of checklists in the course of site inspections   Access of inspectors to self-inspection/internal audit reports   Written information on the results for companies after inspection   Relations with registration (marketing authorizations) body and with QC lab(s)   Review of inspection reports within the inspectorate   Use of quality risk management principles by the inspectorate (see ICH Q9 and PIC/S guidelines)   Recognition of GMP certificates issued by stringent regulatory authorities   Use of WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce. Practice of GMP inspections as a service (at the request of manufacturers) and related financing of this function by user fees merits additional comments. The obvious advantage of this approach is independence of the inspection service from the state budget. It should be noted however, that the cost of inspection under this arrangement, though formally met by industry, is in fact transferred to the market price of medicines and thus to the consumer/patient. Also,

in certain national settings, the credibility of inspection function might be compromised if pharmaceutical sector professionals and general public regard issuance of GMP certificate as a commercial activity. In this context, a reference to the scandal with ISO 9000 certificates of 20014 can be made. Another point, which usually goes unnoticed, is that this approach tends to discourage international collaboration. When inspection function is financed through user fees only, information sharing and work sharing go against economic interests of inspectors. Most probably it is for this reason that there is no cooperation in the area of ISO 9000 certification.

FURTHER CONVERGENCE DESIRED The present state of harmonization of inspection practice and resulting mutual trust between inspectorates allows for functioning of certain international agreements and regulatory flexibility provided by local legislation. The outcome of inspections performed by an EU competent authority is accepted by all other EU authorities. Additionally, the European Union has operational MRAs which include GMP with Australia, Canada, Israel, Japan, New Zealand, and Switzerland. Australia has bilateral mutual recognition agreements with Canada, Japan, and Singapore. It was expected that the Eurasian Economic Union (Russia, Belarus, Kazakhstan, Kyrgyzstan, and Armenia) would be using the same approach in one way or another. At present, however, the principle of mutual recognition of inspections is not being implemented within the Union. Nonetheless, advantages of wider mutual reliance and recognition of GMP certificates are not used to their full potential. One of the reasons for this is lack of confidence between national inspectorates, which may be related to differences in regulatory capacities and/or proceedings and/or regulations/laws. 15 years ago, FIP Industrial Pharmacy Section (IPS) compared the stringency of GMP inspectorates of certain countries. Results shown below support the premise of nonequivalence. 4 On 30 November 2001 Lawrence D. Eicher, ISO Secretary-General has declared “We regularly receive complaints about certificates being awarded undeservedly to companies who have not been properly audited…” (ISO Press releases Ref.: 805).

CIS GMP news

1 (1) / autumn 2017

However, the past five years have seen major changes, essentially harmonizing the equivalence of many inspection agencies. The main stumbling block to total GMP equivalence is the different capabilities, and GMP emphasis by different national authorities. In recent years, important developments in GMP inspection are seen in Asia. Apart from Japan, mentioned above, countries such as Republic of Ko-

decisions without consideration of wider experience and global/regional trends. Lack of confidence in GMP inspectorates of other countries leads to repeated inspections of manufacturers (up to 9 inspections per site in a single year) resulting in duplication of efforts and additional expenses both for regulators and for industry. As stated above, additional resources are needed and respective costs are finally somehow transferred to patients. Multiple

GMP Inspection Thoroughness (in descending order) by Michael H. Anisfeld, Globpharm Consulting (US based) Presently President, FIP IPS Executive Committee. 1. 2. 3. 4.

USA, UK Northern Europe, Australia, Canada Southern Europe, Hungary, Japan Brazil, Saudi Arabia

rea (South Korea) and Republic of China (Taiwan) are active in overseas GMP inspections of adequate level with considerable attention to detail. Also the People’s Republic of China (Mainland China) conducts such inspections. The latter, however, so far are less demanding due to limited capacity and experience. An MRA between the European Union and the United States has been signed in 1999 with the chapter 6 on “Pharmaceutical Good Manufacturing Practices (GMPs)”. After performing several observed inspections, the FDA made proposal to have the MRA limited to some Member States only. As the set of observed inspections is finally about to be completed with all EU member states in 2017 and the MRA text was updated, it might become effective soon. There is the political agenda to do this independently from the Transatlantic Trade and Investment Partnership (TTIP) as the MRA covers public health and not a trade subject. Some countries with emerging regulatory capacities tend to copy and translate arrangements of stringent regulatory authorities, or of neighboring states in non-systematic ways.Some other countries, for example, among New Independent States, adopt unorthodox approaches, such as creating different structures for domestic and foreign inspections. It may be noted in this context, that WHO discourages copying national regulatory

GMP inspections also delay access of the needed medicines to patients, as GMP certificates are often mandatory to submit with regulatory filings. The international harmonization efforts in this area continue. The format of the inspection report recommended by WHO was recently revised [8]. All in all, the package of WHO guidelines on the pharmaceutical inspection is impressive (see selected references). It is, however, fragmented and not complete. Specific documents were published in between 1990 and 2016 and some are due for revision. In view of global trends and recent developments, additional efforts seem to be recommended. Possibly there is a case for WHO to revisit its recommendations in the area of updating and combining separate documents into one guide. The global atmosphere for such a move seems to be favorable. At the recent WHO sponsored 17th International Conference of Drug Regulatory Authorities (ICDRA), Cape Town, S. Africa, 27th November - 2nd December 2016, opportunities of closer cooperation between international harmonization initiatives on a global level were discussed. The revised MoU between WHO and PIC/S entered into force in February 2016. PIC/S strengthens its collaborative activities with EU (EMA, heads of Medicines Agencies), ICH, and International Coalition of Medicines Regulatory Authorities (ICM-

RA). Proposal to allow inspection units of partner organizations to join the Scheme as participating authorities is discussed.

EFPIA SURVEY The European Federation of Pharmaceutical Industry and Associations (EFPIA) representing research-based companies in EU conducts annual surveys on inspections among its member companies since 2003. According to data collected from some 660 manufacturing sites worldwide over the past 12 years, all in all, 64 countries performed foreign inspections. Here and below, the EU countries are counted as one country. It means that the real number of countries involved is approaching one hundred. Over the last few years (2011-2015), the largest number of foreign inspections was performed by countries with stringent regulatory systems: US (90) and EU (65). Countries with emerging regulatory capacity, such as South Korea, Brazil, Turkey, Kenya, and Japan, conducted between 20 and 60 overseas inspections each. The third group, consisting of countries with inspection services having limited experience (except for Australia and WHO Prequalification Team), is lagging behind with 1 to 20 foreign inspections. Interestingly, while countries of the first two groups in recent years reduced the number of inspections, those in the third group intensified their foreign inspection programmes. One example is China with 5 foreign inspections in 2011 against 16 in 2015. In the same years, Belarus quadrupled its results from 3 to 12 foreign inspections. In 2015, 640 manufacturing sites covered by the EFPIA survey received 1,495 domestic and foreign inspections. Overseas inspectors came from 34 countries. Most active were inspectors from US, EU, South Korea, Brazil, Turkey, Kenya, and Japan. Almost one half (46%) of inspections was performed by inspectorates that are members of PIC/S, in a country where the inspectorate is also a PIC/S member. Countries with limited capacities, such as Ivory Coast, Colombia, Kenya, Libya, Nigeria, Sudan, and Uganda were also active in inspecting manufacturers in many countries worldwide. Out of 1495 inspections, 167 (11%) were PAI. Out of these, 71 were domestic and 96 foreign. Among countries performing PAI those with different categories of inspectorates are found: PIC/S members (Canada, Japan, EU, US, S. Korea), PIC/S

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supported by INSPECTIONS BY EMERGING COUNTRIES A possible interpretation of the data

Number of sites covered Number of inspectors Number of inspections

Opportunity?!

time GMP/GDP requirements in law

Quality System in inspectorate

Reqirement for foreign inspections

Risc-based inspection approach

Reliance on other inspectorates

Reliance on other inspectorates allows knowledge of more sites with appropriate use of resources accession and pre-accession countries (Belarus, Brazil, Kazakhstan, Mexico), and others (China, Kenya). Five of 640 sites received 15 inspections each in 2015. Fifty two sites were inspected more than four times. 570 sites reported receiving between one and four inspections and 118 were not inspected in the course of that year. The average duration of foreign inspections is slightly over four days, and one day shorter for the domestic inspections. On the average, two inspectors are involved in one visit. Resources needed for one inspection in terms of inspectors/ days vary from country to country. For some countries these may be roughly estimated as follows. Equal, or over 10 inspectors/days for Taiwan, Mexico, China, US, Canada, Colombia, Saudi Arabia; between 5 and 10 inspectors/days for Canada, Turkey, Brazil, Belarus, S. Korea, EU, Japan and Kazakhstan, and less than 5 inspectors/days for Nigeria, Uganda, Australia, Russia, and Kenya. Available data suggests that inspected companies spend 10 times more resources for the preparation, conduct, and follow-up than regulators. In many cases companies are asked to submit documents prior to visits of inspectors. Involvement of industry’s personnel in the course and post-inspection is estimated as 70 person/days, on average.Average inspection fee is approximately €30,000.

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The 2015 oversight of EFPIA member companies cost regulators over 75,000 person/days and some €80,000,000 were the expenses of the industry. Following are conclusions and recommendations formulated by EFPIA on the basis of the survey merit consideration. The pharmaceutical industry has become increasingly global. Numerous manufacturing sites (from 6 to 30) located in multiple countries might be involved in the manufacture of one medicinal product. More than one site might need to be registered e.g. to mitigate risk of drug shortages. One site may have several manufacturing licenses which may call for several inspections. As a result not one regulatory agency can inspect all manufacturing sites in the supply chain. It follows that authorities should be aiming to rely on each other’s regulatory oversight where possible based on risk assessment and best use of own resources. In recent years the number of foreign inspections has stabilized at a high rate. Although cooperation between national/ regional regulatory authorities has been noted, there is still significant duplication of regulatory oversight at manufacturing sites. In view of the industry multiple inspections are not always risk driven. Inspections are resource intensive both for regulators and industry. In some cases the inspection fee is hard to justify. The added value of inspection activity

in general is not high. The results of the survey suggest that regulatory resources could be better balanced. The data available suggest that globally accepted GMP certification system would be beneficial. It may lead to reduced duplication of inspection efforts and would allow resources to be redirected towards higher risk segments of the medicines supply chain. To facilitate mutual recognition of inspections results and to reduce repeated audits GMP inspection procedures, operational principles of responsible authorities in different economies ought to be further converged. The slide (see figure) presented by Professor Rönninger, Amgen, Switzerland, at the 17th International Conference of Drug Regulatory Authorities (ICDRA), illustrates an important point: reliance on data received from other inspectorates may allow better use of resources with increased number of sites, on which information is available.

PROPOSED PROJECT FOR DATA COLLECTION The results of the EFPIA review data go a long way in exploring the global landscape regarding GMP inspection practices from the companies’ point of view. This data, however, being focused essentially on statistics of inspections

CIS GMP news

1 (1) / autumn 2017

and resources incurred, do not cover all aspects of practical interest. It is suggested that some form of a structured benchmarking with focus on the country's point of view under the stewardship of a competent global programmer, such as WHO Essential Medicines and Health Products (EMP). PIC/S obviously is a competent organization in this context. In view of its current membership, very impressive and growing, the support of the Scheme regarding advice on strengthening inspection systems might be of great value.

As a first step in this direction, a Survey on national GMP inspection practices is suggested. It may be regarded as a contribution to the global harmonization efforts in the area of regulation of Pharmaceutical industry. Such a facts-finding exercise, if successful, may provide background material for a publication, or an information paper. Eventually, the outcome of the project may be used in the preparation of a WHO working document to update the regulatory practices.

The proposed project would be complementary to the annual EFPIA surveys. It is seen as a one-time activity aimed at information at the country level and would automatically include the requirements for generic manufacturers. Therefore the questions focus on topics not covered by the EFPIA survey and data assessment. The questionnaire is addressed not to companies but, to individuals. Those people may have experience of working with industry, regulators, academia, or private consultancies.

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

11. 12.

13.

14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27.

Resolution adopted by the Twenty-Second World Health Assembly. WHA22.50. Quality Control of Drugs. S. Rönninger, J. Berberich, V. Davoust, P. Kitz, A. Pfenninger, Landscape of GMP/GDP inspections in research-based pharmaceutical industry – Part I: Data, Pharm. Tech. Europe, 2017, in press; Part II: Opportunities, Pharm. Tech. Europe, 2017, in press. Guiding principles for small national drug regulatory authorities. 1990. WHO TRS 790. “Provisional guidelines on the inspection of pharmaceutical manufacturers”. 1992. WHO TRS 823, Annex 2. Pre-approval inspections. 2002. WHO TRS 902, Annex 7. Quality systems requirements for national good manufacturing practice inspectorates. 2002. WHO TRS 902, Annex 8. Model certificate of good manufacturing practices. 2003. WHO TRS 908, Annex 5. Guidance on good manufacturing practices: inspection report. 2003. WHO TRS 908, Annex 6. Convention for the Mutual Recognition of Inspections in Respect of the Manufacture of Pharmaceutical Products. Geneva – October 1970. The Role of Inspection and Testing in Relation to the Marketing Authorization. The collected papers presented at a Seminar held in Louvain-la-Neuve from 15 to 17 September 1993. Published by the Secretariat to the Pharmaceutical Inspection Convention (PIC) and Pharmaceutical Inspection Co-operation Scheme (PIC/S). Manufacture and Inspection of Active Pharmaceutical Ingredients. The collected papers presented at a Seminar held in Naantali from 10 to 12 June 1997. Published by the Secretariat to the Pharmaceutical Inspection Convention (PIC) and Pharmaceutical Inspection Co-operation Scheme (PIC/S). Non-technical aspects of inspection. The collected papers from Civil Service College presented at a Seminar held in Oxford (United Kingdom) from 8 to 10 September 1999. Published by the Secretariat to the Pharmaceutical Inspection Convention (PIC) and Pharmaceutical Inspection Co-operation Scheme (PIC/S). The Inspection of Products Derived from Biotechnologies. The collected papers from the French Agency for the Safety of Health Products (AFSSAPS) presented at a Seminar held in Colmar (France) from 25 to 27 October 2000. Published by the Secretariat to the Pharmaceutical Inspection Convention (PIC) and Pharmaceutical Inspection Co-operation Scheme (PIC/S). Recommendation on Quality System Requirements for Pharmaceutical Inspectorates. Pharmaceutical Inspection Convention. Pharmaceutical Inspection Co-operation Scheme. PI 002-3. 25 September 2007. Aide-memoire. Inspection of pharmaceutical quality control laboratories. Pharmaceutical Inspection Convention. Pharmaceutical Inspection Co-operation Scheme. PI 023–2 25 September 2007. Aide-memoire. Inspection of utilities. Pharmaceutical Inspection Convention. Pharmaceutical Inspection Co-operation Scheme. PI 009-3 25 September 2007. Aide-memoire. Inspection of active pharmaceutical ingredients. Pharmaceutical Inspection Convention. Pharmaceutical Inspection Co-operation Scheme. PI 030-1 13 January 2009. A recommended model for risk-based inspection planning in the GMP environment. Pharmaceutical Inspection Convention. Pharmaceutical Inspection Cooperation Scheme. PI 037-1. 1 January 2012. PIC/S Assessment & Joint Reassessment Programme. Revised PIC/S audit checklist based on Evaluation Guide for GMP Regulatory Compliance Programme (by Health Canada). Pharmaceutical Inspection Convention. Pharmaceutical Inspection Co-operation Scheme. PS/W 1/2005 (Rev. 2) Annex 20 October 2014. Compilation of Community Procedures on Inspections and Exchange of Information. European Commission Health & Consumer Protection DirectorateGeneral. European Medicines Agency. EMA/572454/2014 Rev 17. 3 October 2014. Connecting the dots. Towards global knowledge of the international medicine regulatory landscape: mapping of international initiatives. EMA 2016. Dara Corrigan, The Mutual Reliance Initiative: A New Path for Pharmaceutical Inspections in Europe and Beyond. Guidance on good manufacturing practices: inspection report. 2016. WHO TRS 996, Annex 4. Peter J. Kitz. Opportunities for International Collaborations in inspections. FDA/PQRI Conference Sept 16 and 17, 2014. EFPIA Position Paper, Final, v8a – 19/05/2014. Enhanced Good Manufacturing and Good Distribution Practices (GMP/GDP) Inspection Efficiency. EFPIA. Annual Regulatory GMP/GDP) Inspection Survey 2015 Data. Stephan Rönninger, Amgen (Europe) GmbH. EFPIA. The GMP/GDP Inspection Landscape and opportunities for better use of resources: Industry view. 17th International Conference of Drug Regulatory Authorities (ICDRA), Cape Town, S. Africa, 27 November-2 December 2016.

ACKNOWLEDGMENTS Authors acknowledge with thanks valuable contribution made to the preparation of the article to:   Michael Anisfeld, Globepharm, USA;   Alan Chalmers, Pharma International, Switzerland;   Tor Graberg, AstraZeneca, Sweden;   Elizabeth Meyers, Amgen, Switzerland.

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CIS GMP news

1 (1) / autumn 2017 Analytics & Statistics

An Alternate Look at the Pharmaceutical World Revenues and Drug Affordability This article forms part of the CPhI 2017 Annual Report, which is released for the CPhI Worldwide event in Frankfurt (October 24-26, 2017)

W Girish Malhotra CPhI Expert and President, EPCOT International

orld Preview 2017, Outlook to 2022 [1] published by EvaluatePharma® is an interesting report. There are similar reports published every year. From a sales perspective these reports might be useful as to some, however, I have not seen a report that translates or equates sales numbers to number of patients served and/or affordability. Since developed countries (Haves) and developing countries (Have Nots) are two distinct customer bases, it would be useful to understand drug expenditure spending per person, per day for each market. The resulting numbers could be used to understand and develop plans to improve global sales and affordability of drugs. These numbers might also tell us “whether projected sales from other forecasters can be achieved, where the sales could come from and what steps need to be taken to achieve the projected sales and make the product affordable.” Numbers from Exhibit 1 that are in Table 1 demonstrate what is required to meet sales projections.

Exhibit 1: Page 8 [1]

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Sales, $ Billions

2017

2018

2019

2020

2021

2022

Differential Sales increase over the previous year, $ Billions Generic Orphan, (% of Total Sales)

123 (15.9)

11 (16.5)

17 (17.6)

18 (18.4)

20 (19.1)

20 (19.7)

Prescription Excl. Generic & Orphan

567

Total

774

811

860

920

990

1060

Differential $ gain over previous year, Billions

Table 1: Sales and Differential Sales

The numbers in Table 1 seem realistic and obtainable, however the projected sales increase for each year is equivalent [2] to the revenue of one or two of the top FIVE pharmaceutical companies for the next five years. Therefore, achieving these numbers is easier said than done. An earlier alternate study reviewing drug prices and number of patients might be of interest [3]. Table 2 has been created using the sales forecast from Table 1. The population of the developed and the developing countries and average sale per person per day in the developing countries [4] are used to determine the sales for the developed countries. Average sales per day per person for the developing countries including the rest of the world might be considered low, but using the available data [5,6] and extrapolating it, it is the best number I could derive. I am comfortable with the developed Year ->

numbers. In my travels and personal experiences, I have seen that prices for the prescription and generics in developing countries are significantly lower, than the prices for the same prescriptions in developed countries. However, even with low prices, people in developing countries have to decide between food for the family and drugs for the ill family member/s [7], as a result of low incomes. Based on the sales increase from 2008 to 2016 [Exhibit 1], one can speculate that the projected 2022 sales will mostly come from the developed countries, rather than the developing countries. Orphan drugs (less than 200,000 patients per disease) are going to be an ever-increasing source of revenue and as a result, Brand pharma have shifted their focus from drugs for the masses, to orphan drugs. It is well-known that orphan drugs increase revenue dramatically as they are very highly priced and also

highly profitable. New drugs are being introduced continuously, but most are only marginally [8] better than the drugs already on the market and are equally expensive. As a result, they are unaffordable to many and frowned upon even by physicians and healthcare systems. For example, PCSK9 is a class of drugs for cholesterol that will have a very limited market. In recent years there has been a focus on increasing the prices of drugs rather than developing affordable drugs. A recent observation [9] (â&#x20AC;&#x153;Rather than compete by lowering net prices, the drug companies compete by raising list pricesâ&#x20AC;? says Berman, the managing partner of Hagens Berman Sobol Shapiro LLP) makes an interesting point about how pharmaceutical companies raise revenue. Affordability in the developing countries is critical for sales. Merck [10] in 2008 had to significantly lower the

2017

2018

2019

2020

2021

Global Sales, $ Billions

774

811

860

920

990

1,060

Global population, Billions [5] Increase 1% per yr.

7.5

7.6

7.7

7.8

7.9

Population outside Developed Countries, Billions (~80% of total)

6.08

6.16

6.24

6.32

Total Drug spending in Developing Countries $ Billions, (basis $0.08 [5,6] per person per day)

175.2

177.5

179.9

182.2

184.5

1.5

1.52

1.54

1.56

1.58

598.8

633.5

680.1

740.1

807.8

875.5

1.09

1.14

1.21

1.32

1.42

1.52

3.42

3.57

3.78

4.11

4.43

4.74

Developed Countries population, Billions, Increase 1% per yr. Total Drug Sales in Developed Countries, $ Billions Total Drug $ spending Developed Countries per person per day Sales Multiple, Developed vs. Developing Countries

2022

Numbers are rounded Table 2: Global Sales for the Developed, Developing countries and Sales Per Capita per person

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1 (1) / autumn 2017

Sales Increase, Billions Year Sales Increase from One cent per person per day across the world, $ Billions $ Needed to meet revenue, Billions Shortfall, $ Billions

2017

2018

2019

2020

2021

2022

27.4

27.7

28.1

28.5

28.8

(-21.4)

6.3

20.9

31.9

41.5

41.2

Table 3: Value of One-Cent Price Increase vs. Global Sales Increas Needed per Year

price of Januvia in India, a country with the highest population of individuals with diabetes. Affordability forced patients to stay with metformin hydrochloride or other drugs over Januvia. HIV drugs were unaffordable to many in Asia and Africa till Cipla Inc. [11] intervened and Gates and Clinton Foundations supported the move, although they remain expensive in the United States. If some of the infectious diseases were not present in developed countries, it is possible that companies may not have developed the necessary drugs. HCV drug Sovaldi, sold in the US at $84,000, is sold in India [12] and other countries for less than 200 times the US sale price by Gilead, through its arrangements with the local pharmaceutical companies. Compulsory licensing [13] is part of the WTO agreement and has been used to lower drug prices in the developing countries, which is not ideal for branded drug companies. However, affordability is critical and branded companies occasionally forget that some of their customers cannot even afford food at times [7]. Another important fact that brand companies forget is that they have more patients in need of the drug in developing countries rather than in the developed countries. Economies of scale can lower costs and improve profits. Even with an excellent mutually subsidized healthcare system of the United States, it is well known that many patients do not take their drugs as prescribed [14,15,16]. Table 2 shows that the sales in the developed countries are going to stay at about four times the sales of the developing countries. This is very telling especially when the population of the developing countries is about four times of the developed countries. This lopsided arithmetic suggests that pharma companies have tremendous opportunities to increase their sales if drugs can become affordable.

POTENTIAL WAYS TO INCREASE SALES AND IMPROVE AFFORDABILITY With the current push to make drugs affordable in the United States and in other developed countries, pharmaceutical companies will be challenged to increase their revenue. Besides revenue increase through the sales of high-priced orphan drugs, affordability of the drugs to 80% of the population outside the developed countries is critical to driving sales. If this population cannot afford the necessary drugs, it is going to be a challenge to achieve the projected sales. Developed countries have the highest usage of drugs. Pharmaceutical sales in the United States are nearly half [17] of the developed country sales. Marginally better drugs are taking up significant financial and manpower resources and have less than expected return. For sales to increase new drugs have to be substantially better than the current drugs on the market, however affordability will always play a significant role. There are few ways sales can be improved and the options are discussed below, however these will not suit the business model of each company. Effort has to come from the companies rather than outside.

1) INCREASE PRICES This could be considered the easiest way, but it will have the highest negative publicity along with lawsuits [9]. Table 3 shows the net effect of such increase. Sales shortfall from the projected numbers will still be there even when the average price is increased by one cent per person per day.

2) LOWER COSTS [18] There are many different areas where costs can be lowered. They will come

from improvements in regulatory processes and manufacturing technologies and processes. Money saved will more than offset the investment costs necessary for such projects. Economies of scale can also significantly reduce costs and improve product quality. Lower prices could increase the patient base resulting in higher sales revenues.   Lower Regulatory Costs: FDA’s application, review and approval process of NDA and ANDA is based on analysis and re-analysis of the application, and this process is similar to a manufacturing process. FDA and regulators have suggested that companies should incorporate QbD (quality by design) practices in their manufacturing processes. May be the regulators should show the industry how incorporating QbD practices in their own workings will improve application approval quality leading to reduced approval time and associated costs. Recent efforts [19,20,21] have been made to shorten the filing and approval time. Continuous improvement effort is needed. Industry should not be told to improve their practices, the effort should come from within (quality by desire) as they reduce drug approval time.   Lower Manufacturing Costs: There are many excellent ways to lower manufacturing costs. Fundamentals of chemical engineering and chemistry that are judiciously practiced in the chemical and petrochemical industries have to be applied. Cross-fertilization is necessary. Unit processes and unit operations can be significantly improved. We have to exploit physical and chemical behavior [22, 23] of the chemicals along with existing commercially available equipment can be creatively exploited to simplify reactive and formulation processes. A simple example is to ensure that no more than two solvents, one being

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water, are used in the process. Multiple solvents suggests that the manufacturing process has not been optimized and is similar to the laboratory synthesis, that is generally expensive due to poor conversion yields and methodology. Exploiting melting point differences, mutual solubility and density differences can simplify processes. Most of the lab processes are dependent on measuring conversion and product quality during the reactive and formulation processes. Command of processes simplifies manufacturing and lowers costs while producing quality products from the start. As much as 25% savings [24] have been documented. There are other ways manufacturing costs can be lowered which are process and product volume dependent. An important issue, asset utilization, is overlooked. In the manufacture of active ingredients and formulations, asset utilization is generally less than 50% [25]. Even though this reference is old, not much has changed when it comes to pharma’s asset utilization. Poor asset

utilization raises product costs and is an opportunity to improve profits.   Supply Chain: Inventory turns better than pharma’s current 1-2 turns make a big difference on business, a well-known fact. They force better control of raw materials, work in process and finished goods inventories. Cash flow improvement has big financial impact on costs. A lot of the suggestions can be achieved if we have excellent economic processes.   Process Waste: Better processes have higher yield and thus lower costs. Command of processes produces quality products from the start rather than produce products through repeated analysis (aggravation). A better five step process with 95% yield at every step would have about 77% yield, compared to similar process having about 14% yield if each step had an initial yield of 67%. Higher yields reduce product cost and reduce environmental remediation burden.

There is another benefit of high yield. We have to remember that most of the drugs, even though they are fine/specialty chemicals, are highly toxic and they kill disease-causing bacteria to cure diseases. Thus, processes with low conversion yield and waste that is not properly disposed can have significant impact on aquatic, land, and human life. Making drugs affordable is the best long-term way to improve the total sales in the developing countries. Because of the income differences between developed and developing countries, the differences in drug process will remain for the foreseeable future. Economies of scale and better manufacturing technologies [26] can make drugs affordable and increase sales. However, to achieve all this will require business model review and change. It is not an easy task for an industry that has not aggressively embraced change and innovation. Their focus has always been on new drug development and marketing, drug affordability is an unknown area.

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26.

EvaluatePharma® World Preview 2017, Outlook to 2022, http://info.evaluategroup.com/rs/607-YGS-364/images/WP17.pdf Accessed June 22, 2017 Pharm Exec's Top 50 Companies 2017, Pharmaceutical Executive, Volume 37, Issue 6, Accessed June 23, 2017 Malhotra, Girish: Manufacturing technologies and their part to achieve future pharmaceutical sales, Chemica Oggi Chemistry- Today, September/October 2015 Vol. 33(5) pg. 28-31 The Global Use of Medicines: Outlook Through 2016 Accessed June 22, 2017 http://www.worldometers.info/world-population/ Accessed June 22, 2017 Hill, Raymond, Chui, Mandy: The Pharmerging Future, Pharmerging Executive, July 2009, Accessed October 10, 2016 Malhotra, Girish: Drug Prices: Food vs. Medicine - A Difficult Choice for Some https://pharmachemicalscoatings.blogspot.com/2011/06/drug-prices-food-vsmedicine-difficult.html Mullainathan, Sendhil: High Drug Prices are Bad. Cutting Them Could be Worse, The New York Times, June 30, 2017 Accessed June 30, 2017 Barrett, Paul and Langreth, Robert: The Crazy Math Behind Drug Prices, Bloomberg Businessweek, July 3, 2017 Accessed July 5, 2017 Merck Prices Diabetes Drug at Fifth of US Rate: http://www.livemint.com/Companies/bQMFNMPw2lUm49D0lOFEQI/Merck-prices-diabetes-drug-at-fifth-ofUS-rate.html Accessed June 26, 2017 Cipla, The New York Times, February 7, 2001, Accessed June 27, 2017 The same pill that costs $1,000 in the U.S. sells for $4 in India, Chicago Tribune, January 4, 2016 Accessed July 5, 2017 Compulsory licensing of pharmaceuticals and TRIPS: https://www.wto.org/english/tratop_e/trips_e/public_health_faq_e.htm Accessed June 26, 2017 As Drug Costs Soar, People Delay Or Skip Cancer Treatments http://www.npr.org/sections/health-shots/2017/03/15/520110742/as-drug-costs-soar-peopledelay-or-skip-cancer-treatments Accessed June 30, 2017 Patients Struggle With High Drug Prices, The Wall Street Journal, https://www.wsj.com/articles/patients-struggle-with-high-drug-prices-1451557981 Accessed June 30, 2017 Millions of adults skip medications due to their high cost, Harvard Health Publications, http://www.health.harvard.edu/blog/millions-skip-medications-dueto-their-high-cost-201501307673 June 30, 2017 2016 Top Markets Report Pharmaceuticals, http://trade.gov/topmarkets/pdf/Pharmaceuticals_Executive_Summary.pdf Accessed June 27, 2017 Malhotra, Girish: Chemical Process Simplification: Improving Productivity and Sustainability John Wiley & Sons, February 2011 Malhotra, Girish: Can Senate And House Bills S2615 And HR 4784 [Increasing Competition in Pharmaceuticals Act] Alter the Pharmaceutical Landscape? https://pharmachemicalscoatings.blogspot.com/2016/05/can-senate-and-house-bills-s2615-and-hr.html Accessed June 27, 2017 Malhotra, Girish: Can the Review and Approval Process for ANDA at USFDA be Reduced from Ten Months to Three Months? https://pharmachemicalscoatings. blogspot.com/2017/03/can-review-and-approval-process-for.html Accessed June 27, 2017 ANDA (Abbreviated New Drug Application) / NDA (New Drug Applications) Filing Simplification: Road Maps are a Must. https://pharmachemicalscoatings. blogspot.com/2017/05/road-maps-for-simplification-of-anda.html Accessed June 27, 2017 Malhotra, Girish: Focus on Physical Properties To Improve Processes: Chemical Engineering, Vol. 119 No. 4 April 2012, pgs 63-66 Malhotra, Girish: Process Simplification and The Art of Exploiting Physical Properties, Profitability through Simplicity, March 10, 2017 Accessed July 11, 2017 Cost of Poor Quality, www.juran.com/elifeline/elifefiles/2009/09/Cost-of-Poor-Quality.ppt, Pg 9, Accessed Feb 20, 2015 Benchmarking Shows Need to Improve Uptime, Capacity Utilization, Pharmaceutical Manufacturing, Sep 20, 2007 Accessed July 7, 2017 Malhotra, Girish: Batch, Continuous or "Fake/False" Continuous Processes in Pharmaceutical Manufacturing, Profitability through Simplicity, July 20, 2017

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CIS GMP news

1 (1) / autumn 2017 Analytics & Statistics

4 September 2017

his autumn seems to be promising for GMP professionals who have any relation to the Russian pharmaceutical market. There are two reasons for that. The first is the official launch of the Eurasian affiliate of the International Society for Pharmaceutical Engineering (ISPE)1 in October. ISPE is well known in the pharmaceutical world as a leading association of pharmaceutical professionals aimed to disseminate the best industry practices for medicinal product manufacturing. The second is the news that Russia applied for PIC/S pre-accession and it is expected to assign the official rapporteurs in September at the next PIC/S Committee meeting in Taipei, China2. Both events should, in theory, facilitate deployment of cutting edge industry standards for drug manufacturing, and make the country an equal member of the GMP world. The result will depend on different factors, but most importantly on the following: Creation of environment for free and open exchange of information and opinions between industry panelists and the authorities Sustainable efforts taken by the authorities to harmonize local policies and GMP mindset with international ones. Let’s have a closer look at these aspects. 1 https://ispe.org.ru/#contact 2 https://www.picscheme.org/en/news?itemid=43

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Is the Russian Pharmaceutical Industry Ready for Cooperation?

4 September 2017

Mikhail Khazanchuk Senior Quality & Compliance Manager

PHARMACEUTICAL ASSOCIATION The idea to open a pharmaceutical association focused on development of good pharmaceutical practices in Russia has been hanging in the air for a while. Despite the huge number of different non-profit organizations represented in the Russian pharmaceutical market, there is no one professional society specialized in drug manufacturing at the time. Note the fact that Iâ&#x20AC;&#x2122;m not talking about scientific institutions, or any commercial entities. There are such examples and they are dealing with quite different matters. I am talking about the professional society represented by different representatives of the industry, including educational institute graduates, employees from manufacturing companies, scientists, and regulators. And all of them are engaged in the

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development of policies defining the future of R&D and good manufacturing practices. Viability and attractiveness of such association is determined by some sort of interdependency of its members. For example, industry representatives are keen to understand the current thinking of regulators toward different GMP aspects; for regulators, feedback from the industry is an indicator showing whether an initiative is feasible or not, and most importantly - possible to implement; yesterdayâ&#x20AC;&#x2122;s student is interested in exposing himself to potential employers, taking part in conferences, and submitting papers in industrial journals sponsored by the association. This way one can see a kind of symbiosis that will define an association agenda and sustainability. In practice, those associations, which can perpetuate the described

cooperation between their members, are quite successful, expanding operations far outside of the geographical area where they were established originally. ISPE and PDA (Parenteral Drug Association) is quite unique example in this regard. Once again, Iâ&#x20AC;&#x2122;m not talking about industrial unions, which are plentiful in numbers, but about those professional associations, the mission of which is knowledge and best practices dissemination. On the contrary, the industrial unions express a consolidated opinion on different matters of organizations compiling the union. Obviously, the demand for professional association is determined by the big enough number of professionals interested in sharing opinions, participation in policy development activities, and publications. Considering the fact GMP became

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1 (1)Â / autumn 2017

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legally binding in the country less than four years ago, it’s understood why there have been almost no discussions about practical aspects of GMP deployment until recently. Now the situation is changing, therefore the decision to open an Eurasian branch of ISPE looks quite logical. At the same time, it’s important to not to forget that there should be bilateral communication flow between association management and its members who can and will express their personal opinion. This very format of cooperation within the association creates the conditions necessary for healthy polemics that in turn shape the association agenda, satisfying demands of the professional society.

to fulfill its expectations, extensively using conditional collocations as “if appropriate”, “if applicable”, “if necessary”, then we should understand why such discussion is in demand. Not to forget about many GMP inspection collisions originated by ambiguity of the situation in question when no direct guidance could be applied. It’s important to take in to account that open and comprehensive dialogue is impossible in an unbalanced environment. In other words, when not every opinion can be expressed. And here is again the case when the association can be a facilitator, if the association management is elected by the association members and is representing the industry structure, i.e. having

If we remember that GMP more often than not doesn’t give direct guidance on how to fulfill its expectations, extensively using conditional collocations as “if appropriate”, “if applicable”, “if necessary”, then we should understand why such discussion is in demand.

Is the Russian pharmaceutical industry ready for cooperation in such format? I’m not sure. Why? Let me share some observations. Taking part in different conferences devoted to GMP, inspections, I notice existence of several confronting groups: local and international drug manufacturers and regulators. Regulators are so sensitive to any criticism from the industry, local manufacturers carefully secure their modus operandi established in non-GMP era, foreign companies defend their right to be seen as GMP experts. Under such circumstances, it’s difficult to find a common ground for mutual dialogue. Nevertheless, it does exist. It is quality and safety of medicinal products, or better to say manufacturing practices to produce safe medicines of high quality. And the newly established ISPE branch should offer to the expert society such a format where it would be possible to look for solutions of multifaceted GMP challenges through open discussion. If we remember that GMP more often than not doesn’t give direct guidance on how

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members from local manufacturers, foreign manufacturers, scientific society. If we think about current economical context in Russia, then we should add that the membership in the association should not be too expensive. According to the available information3, the Management Committee of Eurasian ISPE branch will include the representatives of FBI SID&GP and mainly local manufacturing companies.

COOPERATION WITH PIC/S It’s difficult to predict now how Eurasian ISPE affiliate will be managed, and whether the initiative will be successful, but let’s hope it will, and it will facilitate distribution of the state of the art practices through industry and regulators. The latter is the most important in the light of recent news about the in3 https://gmpnews.net/2017/03/ispe-opened-itseurasian-affiliate/

tent of the Russian GMP inspectorate to join PIC/S. The mission of PIC/S is to lead “the international development, implementation and maintenance of harmonized GMP standards and quality systems of inspectorates in the field of medicinal products”. And the basis for achievement of that mission is common view and interpretation of GMP rules by inspectors from different inspectorates. The idea of Russia joining PIC/S is not new. The topic has been discussed earlier, and after GMP had been put in force, the discussion gained new energy. The view of FBI SID&GP on the matter is addressed in the December 2016 issue of Remedium journal4. The authors question what could be the role the Russian inspectorate be given among the other PIC/S members should the country decide to join this institution? In my opinion, the most important question is what are the goals the authorities have in mind applying for pre-accession? If the goal is to become the European inspectorate with mature quality management system and harmonized approaches to GMP inspections, then I would dare to assume that our inspectorate could be seen as an equal partner to cooperate with. So far in 2016 – 2017, the Russian inspectorate has been increasing the number of inspections abroad, being criticized for lengthy inspection procedures end to end, and for unconventional interpretation of GMPs. At the same time, as it can be seen based on experience of other inspectorates, the number of foreign inspections is decreasing after joining PIC/S5. The main driver for that is the desire to balance inspectorate resources, relying more on inspection results obtained by other inspectorate from country with PIC/S recognized regulatory environment. Is this paradigm acceptable for our inspectorate? At the “Modern tendencies of GMP inspections” workshop held in June this year in Moscow, the FBI SID&GP management announced it is aiming to join PIC/S in three years. Seems like the first step was made. Let’s wish our inspectorate good luck and wait for results.

4 Remedium, No12 / 2016 5 https://gmpnews.ru/2017/04/praktikainspektirovaniya-po-gmp/

CIS GMP news

1 (1)Â / autumn 2017 Analytics & Statistics

Russian Pharmaceutical Industry: Cooperation in Competition 50

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REFERENCE: DEPARTMENT OF ECONOMICS AND ANALYSIS OF FBI "SID & GP" The Department of Economics and Analysis of the Pharmaceutical and Medical Industry of the Federal State Institution "State Institute of Drugs and Good Practices" (FBI "SID & GP") collects and analyzes data on the production of drugs and medical devices on the territory of the Russian Federation, as well as product portfolio of Russian and foreign companies. The data provided by the Department is used in the preparation of informational and analytical materials; for providing reliable statistical information on the current production of drugs for treatment of socially significant diseases (such as diabetes, tuberculosis, hepatitis, HIV, etc.) for the Ministry of Industry and Trade of the Russian Federation; for assessing the margin level of pharmaceutical products from the Essential Drugs List. In addition, the employees of the Department participate in the development and implementation of Federal target programs for the industry development, carry out information support for sectoral events, and deal with research projects.

Stanislav Livanskiy Head of Economics and Analytics FBI "SID & GP" Center of Economics and Analysis of the Industry

hile analyzing the indicators of value and dynamics of the domestic pharmaceutical industry, manufacturers' data on the volumes of shipments, rather than physical production at actual selling prices, should be guided. This allows to conduct a comparative analysis with the data on sales in the market more correctly, especially when it comes to general trends and structural changes. The dynamics of production is actually three times higher than the corresponding growth rate for the entire pharmaceutical market. The rapid growth in production, which has been observed for the last several years, is being fairly logically transformed into an increase in the share of domestic products in the total volume of the

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pharmaceutical market: in 2016 this figure approached the 30% mark in terms of money, and on EDL included drugs even exceeded (31%). Production is growing due to new products market entry and reformatting of the current assortment towards more expensive products. A large contribution of “new products” is made by the state, implementing programs on import substitution in the sphere of public procurements, and stimulating localization at production facilities within the country. The structure of production compared with sales in the domestic pharmaceutical market is more focused on RX drugs and drugs from the EDL List by these criteria, the share of such products in manufacturing is higher than the average for the market. While only 26% of all production sites have Russian

GMP certificate, the products they produce have the share over 70% (in terms of value and volume). The important element of cooperation in modern conditions is contract manufacturing (on third-party capacities with stipulated terms of full compliance with technology and quality control of the customer's production). In the shipment prices it is about 68 billion rubles (17% of the total amount of drugs). At the same time, 80% are orders from the foreign companies for production at Russian sites. The remaining 20% account for the interaction of Russian companies with domestic players. This is logical enough - why invest in a production line, if neighbor has the same production capability? At the corporate level, 66 foreign companies in 2016 ordered production of their drugs in Russia at 30 sites. The share of the first five is 72% - a sufficient figure, but not as high as the similar level of companies that host contract production. It appears that the demand at the moment exceeds supply. However, there are alternatives: for example, buying a ready-made company, or green field construction. Almost 1/4 of the production volume in 2016 fell on localized products, a third part of them were manufactured at the companies’ own facilities in the Russian Federation. As it was mentioned above, high rates of production growth are the result of state policy aimed at supporting local manufacturing and import substitution. It includes a number of elements at once: the program for the industry development until 2020, the creation of special economic zones, and regulatory measures designed to improve the competitiveness of domestic companies. In the latter case, the introduction of a three-stage public procurement system where products based on domestic substance would receive additional benefits is under discussion. It could also lead to expansion of cooperation between different participants and, at the same time, to intensify competition at the level of producers of finished formulations participating in public procurement. What can local production offer the market? Currently, the structure of sales of biological products in Russia, as well as the structure of production to an even greater extent, differs substantially from the European one. We dominate by Interferons and products extracted from

CIS GMP news

1 (1)Â / autumn 2017

Russian Pharmaceutical Industry in 2016 The share of domestic products in the total volume of the pharmaceutical market

26%

of all production sites have

Analysis by FBI "SID & GP"

>31%

30%

of EDL included drugs

in monetary terms

Russian

GMP >70% certificate

of products are being manufactured by those sites

bio-sources, in Europe medication of tumor necrosis factor comes first. It can be assumed that as the health care system develops, the structure of consumption will shift towards the European. So far, this â&#x20AC;&#x153;gapâ&#x20AC;? is in fact a potential for all market participants and, first of all, for local producers that will develop competencies in the field of export of medicines. In Russia, the biology market is growing along with the rest of the market. The share of biological products in the sales structure is stable during recent years - about 17%. In the segment of budget purchases, the indicator approached 40%. Thus, the aggregate volume of the market that can fall under the influence of a three-tier system is 120 billion rubles.

The leaders of the segment are Microgen with the so-called traditional assortment, and "Biocad", which actively participates in import substitution. In general, more than 2/3 of biological preparations are produced by the Russian companies. About 1/3 of biologics produced in Russia are localized products; almost half of this volume has been transferred to own, newly constructed capacities, but so far the production stages have been transferred only for 1/3 of them all. In addition, a limitation of a threetier system implementation is actively discussed, only for large centralized purchases at the federal level. Based on these introductions, we can try to assess

the potential effect by choosing three socially significant nosologies (purchases for which are planned at the federal level) - HIV, hepatitis, and tuberculosis. In 2016, the aggregate market of these preparations in wholesale prices approached 29 billion rubles, in this segment, domestic substances are registered by 20 international nonproprietary names (INN). According to available data, another 13 APIs will be developed and approved for commercial output within next 5 years. Thus, even if the existing drug substances belonging to the target segment no longer appear on the market, the initiative under discussion will affect to some extent 3/4 of the combined market of these nosologies in monetary terms.

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Contract manufacturing 20%

Ru-Ru

17% 80% 66

of the total amount of drugs

International-Ru

Bio

Pharma

We are emerging from the recent crisis differently than eight years ago. Thus, according to official macroeconomic forecasts, the pharmaceutical market will operate in much more stringent conditions. After a failed 2009, the Russian economy “bounced back”, almost reaching pre-crisis levels. Obviously, it is not necessary to count on achieving comparable results in the economy in the near future. According to the baseline scenario, the Ministry of Economy and Development of the Russian Federation forecasts an increase of 2% of GDP, while the growth of real incomes of the population will be even lower - 1%. In addition, in the next three years, the growth of the economy will be

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foreign companies

120

The aggregate volume of the market of biological p reparations

billion rubles

sites

2/3 1/3 of them

limited to 1.5%, which, while preserving the budget deficit, will have a deterrent effect on the state expenditures, including in the health sector. What does it mean for the pharmaceutical market? The trends that we are currently observing, will have their logical development in the future, in particular, in the budget segment. It is expected that in the next 3-5 years the “resource constraint” model will prevail: the state will try to reduce the costs of public procurement provision in all ways. All other goals, including access to the market for new original products, will be made dependent on financial opportunities. Speaking about specific values, this is an 8% increase this year.

of biological preparations are produced by the Russian companies

are localized products

1/3

of the production stages have been transferred

If we rely on the theory of economic cycles, then we entered the period of low oil prices. Accordingly, when planning for 3-5 years, a combination of economic factors and regulatory initiatives clearly creates a favorable background for the further development of enterprises, which are primarily aimed at import substitution and / or the development of production in a full cycle. In general, production will continue outpacing the average market growth rate. However, growth can become more fragmented and concentrated (both from the point of view of therapeutic directions, and from the point of view of the main companies participating in the production process).

CIS GMP news

1 (1) / autumn 2017 Analytics & Statistics

Selected Indicators of the Russian Pharmaceutical Market Development in 2012-2016 and in the 1st and 2nd Quarters of 2017

Over the past five and a half years, the Russian pharmaceutical market has been considerably developed both in quantitative and structural terms. Furthermore, at the turn of 2014 and 2015, the industry weathered the economic crisis that became a catalyst for significant changes in the market. Let‘s look at the consequences of these events and at the current state of selected indicators of the Russian pharmaceutical market. 16 August 2017 Source: RNC Pharma - Research and consulting of the pharmaceutical market

IMPORT OF FINISHED MEDICINAL PRODUCTS AND IN-BULK The Russian pharmaceutical market still generates income mainly from imported products that account for 66.7% of total imports in the 1st and 2nd quarters of 2017. The situation is different depending on a specific segment. In particular, in the sphere of hospital procurements and in terms of so-called federal benefits the share of foreign products is much lower than average indicators of the industry. Here, the impact of import substitution is evident. Nevertheless, in 2016, there were 1.9 billion batches of finished pharmaceuticals (FP) for a total amount of 483.4

billion RUB (in monetary terms including customs clearance and VAT) (fig. 1). In 2015, shipment movements amounted to only 6.4% if calculating in RUB and natural growth rates were even worse (0.4%). In the 1st and 2nd quarters of 2017, foreign pharmaceutical supplies were stabilized, the ruble exchange rate was already 8.1%, and natural imports grew by 6%. Economic realities of the Russian pharmaceutical market, as well as processes of import substitution, have a considerable influence on the statistics of finished pharmaceutical supplies. In particular, after 2015, the Russian pharmaceutical manufacturers put a range of pharmaceuticals to the m arket, putting pressure on their foreign col-

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Nikolay Bespalov Development Director of the RNC Pharma analytical company

leagues. In addition, the localization of pharmaceutical manufacturing by foreign companies is being developed in Russia. The acquisition of Russian citizenship gives an opportunity to apply for preferences in the context of public procurements and almost all representatives of foreign businesses certainly take this opportunity. Some localize the

manufacturing independently, some seek assistance from Russian partners. Moreover, the localization processes often start with separate manufacturing stages, in particular, with in-bulk. The share of in-bulk pharmaceutical imports into Russia in the total amount of foreign pharmaceutical supplies has considerably risen in recent years. In

2012, supplies of pharmaceuticals in bulk accounted for 12.2% of total imports in monetary terms and, in 2016, they were already 18.7%. Moreover, the pharmaceutical supplies in bulk have been outgrowing bulk supplies throughout the years. For example, in 2016, in-bulk pharmaceuticals for a total amount of 110.8 billion RUB (in

Fig. 1. Imports of FP into Russia in monetary terms including customs clearance and VAT in 2012-2015 and in the Q1 - Q2 of 2017 Source: RNC PharmaÂŽ : ADB Import of FP into Russia

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1 (1) / autumn 2017

onetary terms including customs m clearance and VAT) were imported into Russia (fig. 2). The dynamics of supply volume in monetary terms was 27.2% in RUB at the turn of 2015, natural imports in bulk reached 4.3 billion minimum

in 2016, it grew by 3.3% (30.5%) and, finally, by the end of the first half of 2017, it reached 33.3%. It became possible due to active policy of import substitution that led to a considerable amount of new domes-

23.7% in monetary terms and 7.6% in terms of batches. However, the results of the first half of 2017 have been not so optimistic, as the dynamic was only 5.5% in monetary terms, but the natural shipment volume has risen by 1.7% over the year. To continue developing under the present conditions, domestic companies need additional incentives including accepting the multi-stage system of preferences in the context of public procurements.

IMPORT OF ACTIVE PHARMACEUTICAL INGREDIENTS (API)

Fig. 2 Imports of pharmaceuticals in bulk into Russia in monetary terms including customs clearance and VAT in 2012-2016 and in the Q1 and Q2 of 2017 Source: RNC Pharma® : ADB Import of Pharmaceuticals In-Bulk into Russia

dosage units (MDU1), and the dynamics amounted to 30.3%. However, in contrast to bulk pharmaceutical supplies stabilized in 2017, in-bulk products had an opposite effect. In the 1st and 2nd quarters of 2017, the dynamics of supplies in RUB were negative (-25.5%), but natural imports continued rising (9.2%).

PHARMACEUTICAL MANUFACTURING IN RUSSIA

tic pharmaceuticals including expensive ones brought to the market. The dynamics of the Russian manufacturing has been significantly outgrowing the rates of foreign product supplies since the beginning of the crisis. In 2016, domestic manufacturers shipped pharmaceuticals amounting to 314.5 billion RUB (in shipment costs including VAT) from their stocks (fig. 3). The dynamics of pharmaceutical shipments from stocks of domestic companies was

Despite objective achievements of Russian pharmaceutical manufacturers in the past few years, the factor of the hidden dependence of the industry’s imports on foreign equipment and raw material supplies should be also considered. The share of Russian active pharmaceutical ingredients (APIs) was almost 9.2% in a total amount of consumption by Russian enterprises in 2016 in monetary terms and, moreover, the share was considerably higher in physical units (tons) (almost 39.6%). Russian manufacturers of API mainly manufacture rather cheap products including a great amount of so-called medical gases, oxygen in particular. In 2016, 11.6 tons of API for a total amount of 61 billion RUB were imported into Russia in prices on release for free circulation including VAT (fig. 4). In 2015, the dynamic was only 2.9% in monetary terms, but natural API im-

Despite a relatively small group of Russian manufacturers (33.3% in the 1st and 2nd quarters of 2017), they have made the impossible possible in the past two and a half years. The number of domestic companies on the market had been declining until the crisis of 2014 and even if it increased, it was only by 0.5 - 1% per year. The crisis was a turning point. In 2015, the share of Russian products on the market grew by 4.2% (up to 27.2%) in monetary terms, 1 Minimum dosage unit (MDU) is a unit of measurement of natural volume of pharmaceutical import meaning an overall amount of individual dosages (pills, capsules, ampoules, etc.) of all pharmaceuticals released for a specific period

Fig. 3. Pharmaceutical manufacturing in shipment costs including VAT in Russia in 2012-2016 and in the Q1 and Q2 of 2017 Source: RNC Pharma® : Monitoring of Import Substitution and Localization in Russia

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ports have risen by 22.7% over the year. Moreover, in the 1st and 2nd quarters of 2017, foreign API imports continued rising: the supply volume in rubles increased by 30%, but the natural dynamics were not so optimistic and amounted only to 8.4%. Nonetheless, the situation will be different in the near future. At present, a number of projects aimed at API manufacturing in Russia are at different implementation stages: Active Component (St. Petersburg), Pharmoslavl (Yaroslavl Region), Pharmasyntez (Irkutsk Region), etc. The processes of import substitution will be primarily developed in terms of expensive API. At the same time, the volume of manufacturing of raw materials for Russian original pharmaceuticals is expected to rise. In particular, the representatives of the BIOCAD company have announced registrational clinical studies on specific pharmaceuticals in the sphere of immuno-oncology. They are expected to come to market in 2019.

EXPORT OF PHARMACEUTICALS FROM RUSSIA In 2014-2016, exports of pharmaceuticals from Russia showed the highest growth rates on the market. Suppliers showed the most outstanding results in 2015 when exports in rubles rose by almost 46%. The reason for such a rapid development in this direction was primarily the economic crisis that became a very important incentive to

raise the demand for domestic pharmaceuticals in response to the Russian currency devaluation. In fact, the impact of this factor wound down quite quickly as dependence on foreign API supplies makes the export development impos-

Fig. 4. Imports of API including equipment into Russia in monetary terms including customs clearance and VAT in 2012-2016 and in the Q1 and Q2 of 2017 Source: RNC Pharma® : ADB Import of API into Russia

sible. The same factor of the ruble devaluation in 2015 led to a sudden growth in the value of raw materials imported. Surprisingly, another export development factor was a political background, in particular, the ban on the import of different products including pharmaceuticals into unrecognized regions of the Lugansk People’s Republic and the Donetsk People’s Republic imposed by the Ukrainian authorities. There were not enough manufacturing

Fig. 5. Exports of pharmaceuticals from Russia in 2012-2016 and the 1st and 2nd quarters of 2017, except exports into countries of EEU Source: RNC Pharma® : Export of Pharmaceuticals from Russia

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facilities of local pharmaceutical enterprises to cover requirements in the region, so products began to be imported from Russia. The Ukrainian market has always been one of the most important directions of the Russian pharmaceu-

tical export, but supply volumes were reallocated in 2015. Only trace amounts of products had been imported into the territory of LPR and DNR until the political crisis, but in 2016, supplies into the region were already 72% of a total amount of export from Russia into Ukraine. In 2016, pharmaceutical exports from Russia were 27.2 billion RUB (fig. 5). They rose by 24.8% as compared to 2015. However, the 1st and 2nd quarters of 2017 have not been so optimistic – supplies have risen only by 2.5% in monetary terms. That is considerably less that inflation in that period. The activity of Russian exporters is expected to grow rapidly after putting the plants in foreign countries on the projected manufacturing volumes, in particular, Mechnikov in Nicaragua, R-Pharm plants in Turkey and Azerbaijan, and BIOCAD plant that is going to be constructed in Finland. Also, pharmaceutical supplies from foreign enterprises located in Russia are already rising, for example, products from such Russian enterprises as Stada, KRKA, and others, are already exported. Furthermore, in summer, Sanofi had announced the beginning of insulin shipments from its Russian enterprise.

CIS GMP news

1 (1)Â / autumn 2017 Analytics & Statistics

The Future of the Russian Pharmaceutical Industry is Closely Associated with Kaluga Region After an expert assessment performed in 2015 by the European Secretariat for Cluster Analysis (ESCA) among 750 clusters, only 5 Russian clusters received bronze certificates of Excellence. Among them â&#x20AC;&#x201C; the Kaluga Pharmaceutical Cluster that received The highest rating in the health and Medical science category.

Nearmedic Pharma The production of basic pharmaceutical products Kaluga region, Borovsky district, Malan'ino

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Alexander Toporkov Member of the Board of NP Kaluga Pharmaceutical Cluster, Director for Communications with Governmental Agencies at SC Nearmedic, academician RAMTS

20 Аugust 2017 Source: Vestnik Pharm Evolution 2017 Agency for Regional Development of Kaluga Region arrko.ru

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he cluster of pharmaceutics, biotechnologies and biomedicine created six years ago is currently one of the 11 national clusters included in the list of innovation leaders. It holds a bronze ESCA Cluster Excellence certificate. Its growth rate is much higher than that of the region’s other industries. Its successful development is driven by a balanced infrastructure created due to a systemic approach to current operations and strategic view of all processes evolving within the industry. I am certain that the future of the Russian pharmaceutical industry is closely associated with Kaluga Region. It has created a truly unique “ecosystem” that embraces all aspects of development and introduction of pharmaceutical and biomedical products: research centers, small research commissioning enterprises and engineering centers, major international and Russian pharmaceutical plants (including those of “Big Pharma”), clinical centers and educational facilities. NP KPC was established to coordinate all these processes and quickly resolve potential issues. It represents the interests of all cluster members. The cluster is currently developing cooperation links with all players of Kaluga Region’s pharmaceutical and biotechnological market. Cooperation efficiency is clearly demonstrated by Nearmedic Pharma, which used its proximity to the production complex of STADA, a major European pharmaceuti-

cal company, to build a highly efficient partnership. At design stages of its own plant, Nearmedic Pharma was contracting manufacturing to STADA facilities in Kaluga Region. This allowed it to increase production volumes of its products three-fold even before its plant was commissioned. Apart from that, Nearmedic specialists were undergoing training and qualification enhancement at the STADA Hemopharm plant. Today, Nearmedic cooperates with the BION group on joint research for development and synthesis of new products. BION itself is a great cooperation success story. Its joint research and development projects with international pharmaceutical company Bayer HealthCare led to development of an innovative pharmaceutical compound. After production scaling, the compound was integrated into manufacturing of Elastagen, and considerably enhanced the efficiency of Teraflex – a Bayer HealthCare product. Contractually, BION is Bayer HealthCare’s sole supplier of the compound. Each year brings new examples of long-term cooperation within the cluster, proving that scientific, technical, manufacturing and educational cooperation established within KPC allows all participants to achieve maximum efficiency, optimize costs, create new jobs and, most importantly, move towards import substitution in the pharmaceutical sector. All these efforts are effectively supported by Kaluga Region’s administration and designated development institutions.

CIS GMP news

1 (1) / autumn 2017

KPC. RESULTS FOR 2016

Irina Novikova Executive Director of NP Kaluga Pharmaceutical Cluster, Deputy General Director of the Agency for Innovation Development – Center for Cluster Development of Kaluga Region

2016 was a year of significant events and achievements. The most important of them was the success in the competition of the Russian Ministry of Economic Development that included the cluster into its list of participants for the priority project “Development of innovative clusters - leaders of world-level investment attractiveness”. At the end of the year, the region’s government and the ministry signed an agreement for support of the pharmaceutical cluster. Preparation of the tender application involved elaboration and approval of the Strategy for Development of the Pharmaceutical Cluster up to 2020, which defined unique cluster participant projects that would allow us to achieve international levels in the nearest future. The cluster is expected to manufacture 50 billion rubles worth of products each year. 2016 was also a year of actual commissioning of the synchrotron at the proton medical complex of the A. Tsyb Medical Radiological Research Center (MRRC), and opening of a “clean room” module at the Practical Training Center of the Institute of Nuclear Power Engineering of the National Research Nuclear University MEPhI. We participated in 19 nationwide and international events. The second international Pharm Evolution forum was a success. Three cooperation agreements were signed during a business mission to the Altai pharmaceutical cluster. As far as pharmaceutical resource training is concerned, we implemented 95 educational programs for retraining and qualification enhancement. Another important project – Healthy Heart Days - was implemented in cooperation with STADA. Residents of Obninsk, Maloyaroslavets, and Balabanovo were offered the opportunity to have their cardiovascular systems checked for free at a mobile medical center. Various deviations were identified for 54 of the 1,168 participants, two of which were urgently hospitalized for prevention of heart attacks. This socially significant project was implemented with support from KRAID and the Russian Federal Medical-Biological Agency (FMBA). Hopefully, such events will become a tradition.

Hemofarm (group of companies STADA CIS) The production of pharmaceuticals and materials Kaluga region, Obninsk

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AstraZeneca Industries The production of basic pharmaceutical products Kaluga region, Borovsky district, Dobrino

OUTLOOK FOR 2017 We have a clear plan, a “roadmap” of measures and projects for 2017. One of the primary directions is further development of infrastructural projects. This implies, first of all, creation of a laboratory for synthesis of active pharmaceutical substances at the Practical Training Center that will be used for development of finished pharmaceutical products and “carriers” for isotopes in radiopharmaceuticals, as well as construction of a control and analysis laboratory for sanitary and environmental measurements. Implementation of these major projects will require considerable financial investments. For this, we are relying of the federal subsidy allocated to support clusters selected for the “Development of innovative clusters - leaders of world-level investment attractiveness” project by the Russian Ministry of Economic Development. Successful completion of these projects will allow us

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to “close” the resource training cycle by equipping the Practical Training Center with facilities for all types of educational scientific work, including synthesis of active pharmaceutical compounds, development and design of finished dosage forms of pharmaceutical and radiopharmaceutical products, and finished pharmaceutical product quality control. It will also facilitate the process for allocation and approval of sanitary protection areas to existing and new cluster members, reduce research costs associated with scheduled inspections of operating production facilities. Cluster participants have plans for a number of important projects. Thus, Hemopharm and AstraZeneca will participate in a pilot project that involves marking of certain pharmaceutical products with control (identification) insignia. The project was initiated by the Russian Federal Service for Supervision in Healthcare acting on the assignment of the Russian Government’s First Deputy Chairman Igor Shuvalov.

Hemopharm will begin construction of an integrated laboratory complex for localization of its R&D division in Kaluga Region. Pharm-Synthesis plans to complete construction of a microbiological laboratory for pharmaceutical product manufacturing. Work will be continued on introduction and registration of new drugs and pharmaceutical products. There are plans to commission two new production facilities – the Pharm-Synthesis plant for manufacturing of finished pharmaceutical products and the SANATMETAL CIS plant for manufacturing of implants and medical products. There is yet another important event anticipated in 2017. NP KPC has applied for a field audit by the experts of the European Secretariat for Cluster Analysis with hopes to receive a silver Cluster Management Excellence certificate. A positive assessment will allow the cluster to remain the undisputed leader in the sector.

CIS GMP news

1 (1)Â / autumn 2017

STRUCTURE OF THE CLUSTER OF PHARMACEUTICS, BIOTECHNOLOGIES AND BIOMEDICINE 20 August 2017 Source: Vestnik Pharm Evolution 2017 Agency for Regional Development of Kaluga Region arrko.ru

70%

enterprises and organizations are part of the cluster

9,020

people employed by organizations participating in the cluster

3,626

of cluster products finished pharmaceutical products

OUTPUT VOLUME GROWTH

AstraZeneca Industries Berlin Pharma (BerlinChemie/Menarini)

Novo Nordisk Production Support RPG PharmVILLAR

Berachim

Partner-M

BION

Portioned Products

Iloks

Sphera-Pharm

SC Mir-Pharm (Mir-Pharm, OCPC)

Pharm-Synthesis Hemopharm (STADA CIS)

for cluster companies is significantly higher than the average growth rate of the Russian pharmaceutical product market and growth rates of other industries in Kaluga Region:

19.0

bln rubles

in 2015, 49.6% growth against 2014

small innovation and design companies

> 27.5

bln rubles in 2016

7.4

+ 38 62

> 80%

work at pharmaceutical plants

PRODUCTION COMPANIES

NEARMEDIC Plus

share of innovation companies

> 35.0

bln rubles

by the end of 2017

bln rubles in 2015

12.7

bln rubles

in 2014, 13% growth against 2013

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2.5

bln rubles

— value of research and development works and projects performed by cluster participants in 2016

SCIENCE AND EDUCATION Leypunsky Institute of Physics and Power Engineering Karpov Scientific Research Institute of Physics and Chemistry Scientific Research Company Medbiopharm

INFRASTRUCTURE

Institute of Nuclear Power Engineering of the National Research Nuclear University MEPhI

Agency for Innovation Development – Center for Cluster Development of Kaluga Region

Tsyb MRRC – branch of NMRC of the RF Ministry of Healthcare

Agency for Regional Development of Kaluga Region

Tsiolkovsky Kaluga State University

Regional Engineering Center (REC) for the pharmaceutical industry NP KPC

Nearly 1,000 people are currently undergoing training at medical faculties, departments of pharmaceutical and radiopharmaceutical chemistry, general and special chemistry, radionuclide medicine, biology, material engineering, nuclear physics and ecology to support the pharmaceutical cluster. Training is conducted under 90 specialized programs.

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> 600

employees of cluster companies completed training in 2016

Park of Active Molecules Alliance of Competences High Tech Technopark 12 industrial parks: built-to-suit / brownfields / greenfields Kaluga special economic zone: 2 sites with total area of 1,042 hectares

OUTPUT OF FINISHED PHARMACEUTICAL PRODUCTS

2013

2015

2016

109

139

varieties of pharmaceutical products

At registration stage of registration

varieties of pharmaceutical products

In long-term development

varieties of pharmaceutical products

CIS GMP news

1 (1)Â / autumn 2017 Contract Manufacturing

Contract Manufacture

Ensures Industrial Competition Today, in different discussion areas there is much talk about how Russian pharmaceutical industry has moved well beyond the stage of modernization and should now move to the next stage, i.e. launch export of its products. But it is rarely mentioned that our pharmacology has the potential not only in terms of export. Various pharmaceutical plants, both new and reconstructed, can become an authoritative platform for the development of contract manufacture.

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8 July 2017 The article was prepared by Elena Kalinovskaya, a journalist of the "Pharmvestnik" newspaper, commissioned by the Pharmcontract Group of Companies

COMPLETELY UNAWARE Russian discussion platforms may be of interest to foreign partners not only in terms of localization for the engagement in Government procurement, but in terms of production, too. The present economic situation in Russia has created favorable conditions for the production of different goods, including medicinal products. However, our pharmaceutical industry needs further work in order to give a boost to the contract drug manufacture. The main problem is that there is a regulatory barrier. Russian legislation does not allow production of medicinal drugs with the same INN (international non-proprietory name), but different trade names at a single manufacturing facility. According to Denis Shvetsov, Director General of Biokhimik OAO (Saransk), it is the only obstacle for development of contract manufacturing today. “As soon as legislation amend-

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ments are made, which can happen in summer 2017, as far as I know, it will become much easier for us to organize contract manufacture”, he says. Project Managing Director of R-Pharm, Kira Burma, agrees that this is the barrier that hinders the segment’s development. In the meantime, she reminds that we are already living in the Eurasian Economic Union. “There are already no restrictions on registration of the drugs with the same INN, but different trade names in the documents of Eurasian Economic Commission regulating the circulation of medicines within the framework of Eurasian Economic Union. Companies can register such drugs in compliance with the new Union rules since May 6th, 2017”, the expert reminds. Nevertheless, the presence of national legislation balanced with EEU rules and regulations will make Russian manufacturers more self-confident. According to Kira Burma, it would be

a good thing to introduce a separate definition for ‘contract manufacture’ into the Federal Law No. 61-FZ “On circulation of Medicines”. Under certain specific conditions, the absence of this definition can hamper the development of contract manufacture, including the process of its integration into international production chains.

IT’S ALL ABOUT TECHNOLOGY Another barrier that customers often encounter is the process capability of Russian industrial sites. “The choice of industrial facilities with modern production manufacturing equipment and highly qualified experienced stuff is limited in the RF”, Kira Burma says. “It is extremely difficult to find the site with identical equipment that would satisfy all the customer’s requirements. It is easier to re-equip the existing industrial site,

CIS GMP news

1 (1) / autumn 2017

though we should keep in mind that in this case it will affect the product price”. According to Development Director of ZAO MBNPK Cytomed, Sergey Pirogov, they make technological decisions on each particular contract: “First of all, we determine how heavily loaded our facility is now. When we have the time and space for additional work, we check if there is everything we need for the execution of the contract. Certainly, it is important for us to take into account the terms of the contracts: are they several months' worth of work, or are they long term projects? Will we be able to put this equipment to good use or not?” “The question of equipment is a routine issue, there is nothing exclusive about it, Denis Shvetsov says. As a rule, it is easy to agree on that; if not, the partners help us obtain additional machinery”. “There are many process equipment suppliers that can provide production facilities with their products on Russian market. One can choose whether to buy equipment from Europe, Asia or the Russian Federation. Difficulties may occur in the laboratory equipment supply”, Kira Burma adds. As noted by Sergey Pirogov, typically, when it comes to the production of finished dosage forms they need the equipment satisfying GMP require-

ments, which is mostly produced by manufacturers from abroad. As a rule, they assume another level of responsibility when producing the equipment; in addition, they always provide complementary servicing to their equipment.

THE QUESTION OF LAW Finally, there is one of the most important details of the contract manufacturing – the resolution of legal matters. As a rule, it is the holder of the registration dossier who remains the owner of the medicinal drug. The same person accepts full responsibility for the drug when it is released to the public. Therefore, when the dossier holder outsources the drug production to the contract site he has to be absolutely sure that the manufacturer will ensure adequate quality. Denis Shvetsov notes that, ultimately, the manufacturer does not need rights to the drug. Generally, we are talking about contract manufacture of generics, the core value of which is their trade name. The contract manufacturer produces the drug, and the registration dossier holder promotes it. In specific cases, the contract site will need to modify the license, if the technology of drug production requires it. But the main paperwork concerns the change of the manufacturer’s reg-

ulatory documents and introduction of amendments to the registration dossier in terms of adding a new production site in it. In fact, his process can take up to half a year. Domestic manufacturers who are ready to submit their facilities for contract drug manufacturing do not encounter the problem of competition between their own medicinal products and the partners’ ones. “Market competition should be natural. When there is a wide choice of medicinal drugs, health care centers, doctors, and patients should have an opportunity to make their choice independently”, Kira Burma says. She emphasizes that contract manufacture is a separate line of business. “Removal of the regulatory barrier that does not allow to obtain marketing authorization of the drugs produced within the context of contract manufacturing, with the same INN, but a different trade name, will facilitate the development of the pharmaceutical contract manufacturing market in Russia. It will let Russian pharmaceutical manufacturers produce medicinal drugs of other manufacturers along with their own. The development of drug contract manufacturing will provide the pharmaceutical market with competitive manufacturing expertise”, the specialist concludes.

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1 (1)Â / autumn 2017 Contract Manufacturing

Business Is Betting on High-Technology Enterprises

1 August 2017 The article was prepared by Elena Kalinovskaya, a journalist of the "Pharmvestnik" newspaper, commissioned by the Pharmcontract Group of Companies

Technical equipment for manufacturing sites is becoming a main issue for pharmaceutical companies existing in the era of GMP. Support tools developed by the Ministry of Industry and Trade give an opportunity not only to expand manufacturing, but also to examine prospects for export and contract manufacturing more closely. In addition, experts point out that when a partnership agreement is concluded, the process equipment that should meet international GMP requirements is thoroughly audited.

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BOOM OF LOCALIZATION According to the Ministry of Industry and Trade, there are more than 500 manufacturing sites in Russia today. The “boom of localization” reached a peak in 2013-2016 when more than 70 new manufacturing sites appeared in the country. The main reason for this was a pool of preferences that was developed by the government for local players, and therefore foreign companies revised their development strategies. Over the years, the number of acquisitions of the existing Russian plants has increased. Other players have chosen a strategy of transferring the technologies and concluding partnership agreements. One of the striking agreements was a partnership between the Skolkovo Foundation and biopharmaceutical company AstraZeneca concluded in 2017. This is about the company working with several start-ups of Skolkovo in such spheres as bioinformatics and drug development. Localization has stopped being just a regional issue for the Russian companies. The domestic pharmaceutical industry can offer the foreign partners favorable conditions for contract manufacturing. However, the contract manufacturing was just 17% overall in 2016. There are several reasons for this and one of them is complex preparation of manufacturing and of system of quality management to potential licensors’ requirements.

most every stage of modernization call the logic of the choice into question. The main issue Uzbek companies face is incompatibility of equipment of the manufacturing technology. As a consequence, it has to be replaced during the modernization process. This requires not only additional investments, but plenty of time as well. In Russia, the situation is different. The business leaders developing in the era of GMP realize that one of the key criteria of successful work is properly equipped manufacturing sites. “The technical equipment of our enterprise is a multi-stage process with many criteria. The quality of products manufactured is the basis of the company’s work and, of course, above all, we need to be sure that the equipment we buy meets modern quality and se-

curity requirements”, says Vyacheslav Kokeladze, Deputy Director General of Canonpharma Production JSC. The process equipment should meet productivity and application requirements based on the projected volume of manufacture, as well as meet function requirements. “If the customer’s manufacturing sites are equipped, Pharmcontract Group of Companies seeks to use a comprehensive “one-stop shop” approach based on joint work of builders, designers, process engineers and service technicians. Work of the team responsible for the project always starts with a detailed discussion of the implemented technology with an end user, with ascertaining of nuances and pitfalls and with finding proper solutions. The project leader coordinates the

SAVING IS EXPENSIVE Experts estimate that the average budget for the technology transfer is from €40,000 up to €300,000. The main criterion for selecting partners is high-quality equipment meeting national GMP requirements, at least. Most of the pharmaceutical companies are fully aware that it is impossible to attract partners without a site equipped with highly advanced facilities. An interesting case of modernization of manufacturing occurred in Uzbekistan. At present, the pharmaceutical industry is actively developing in the Republic. Despite this, local players are betting on low-end equipment. As experts note, it is really profitable if assessing the business model in terms of price. But those barriers arising at al-

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CIS GMP news

1 (1) / autumn 2017

The range of the process equipment is primarily determined by a range of medications, pharmaceutical manufacturing technology and manufacturing capacity

Veniamin Potashnikov,

a Chief Financial Officer of Biocom JSC

activities of the team providing continuous communication between departments and monitoring the dates of implementation of tasks under the single work plan”, Chief Process Engineer of the company Oleg Novozhilov explains. The EC type-examination certificate is also one of the key criteria. An opportunity to integrate the equipment into the IT system of the enterprise is compulsory. In addition, the companies carefully assess energy efficiency, an opportunity to reduce the labor costs and well-adjusted maintenance service of the equipment manufacturers.

THE CORRECT CHOICE OF SUPPLIER The first thing companies pay attention to when searching for potential equipment suppliers is the country of manufacture. The representative office in Russia, as well as reputation of the supplier as a business partner, plays an important role, too. “Suppliers are selected in accordance with the tendering system, in which such points, as the supplier’s reliability, the quality of service, flexibility in financing conditions and opportunities to retrofit the equipment are assessed. It is clear that economic conditions also play a significant role. However, it should be noted that price is not the most critical point, as an overwhelming part of our equipment is provided by the European manufacturers”, Vyacheslav Kokeladze explains.

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The level of equipment plays an essential role in the contract manufacturing, as it allows to implement manufacturing plans of different levels of complexity. “On the other hand, even the best-equipped manufacturing site will be useless without experienced staff, effective quality management system, and many other related processes”, Viatcheslav Kokeladze adds. In addition to that, ideally, the equipment for the contract site should be the same as the original manufacturers’ equipment (the same brand name, manufacturer and capacity). It guarantees the transfer of the manufacturing technology. “With its engineers and technologists’ experience and skills, Pharmcontract offers comprehensive solutions implying that already at the early development stages the supplied pieces of equipment are compatible with each other and that it can function during the future manufacturing process. Guaranteed equipment installation in rooms, necessary connection to facilities, commissioning, compliance with health and safety regulations and meeting requirements of the pharmaceutical

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industry are also important”, Oleg Novozhilov says. Medications of the customer reproduced without any disruptions in the technological stages, that is to say following the same manufacturing process as the customer has, should be an obligatory condition. “If the range of equipment is different from the customer’s equipment in brand name, manufacturer or capacity, the contact still may be concluded if deviations are set down in the working parameters of equipment, but not in the quality parameters of the medication”, Veniamin Potashnikov adds.

MODERNIZE IN TIME An issue of service maintenance of equipment also concerns the companies. Any fault may lead to disruptions in manufacturing plans or longer implementation of them. It may take 2-3 months to receive spare parts. Companies address these issues in different ways. There is even a system for preventing such incidents at enterprises. Replacement or modernization of equipment stem from a number of fac-

tors. “Increase in manufacturing, implementation of innovative manufacturing technology and extension of the range by creating new pharmaceutical forms require more powerful equipment, as well as additional laboratory equipment. Extension of the range often leads to appearance of new, more complicated medications or pharmaceutical forms, for instance, the technology of manufacturing of slow-release pellets in sachets. Obsolete manufacturing equipment is often not so secure and user-friendly as modern equipment, so we try to choose innovative technology-based solutions that will lead to further development of manufacturing”, Vyacheslav Kokeladze explains. Nowadays, the Russian pharmaceutical industry is under the influence of many factors, such as tightening of GMP requirements and changes in the legislation. So, companies planning to develop on both domestic and global market and having special requirements for manufacturing and quality control of medications should take all these factors into account within the framework of the modernization of manufacturing.

CIS GMP news

1 (1) / autumn 2017 Contract Manufacturing

Sotex + Rafarma:

New Pharmaceutical Synergy The PROTEK Group of Companies, a Russian pharmaceutical corporate group engaged in R&D, manufacturing, distribution and retails, acquired 100% of Rafarma Company assets in April 2017. With its advanced manufacturing facilities focused on production of antibiotics and oncology products Rafarma proves to be a solid contribution to the Group’s manufacturing segment, which has Sotex Pharmaceutical Company (“Sotex “PharmFirm”) at its core. Sotex is one of the few Russian companies holding EU GMP Certificate. It is an acknowledged national market leader with ambition to start exports of Russian ready formulations to European countries in the nearest future.

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Mr. Vadim Yatsuk, General Manager of Sotex, who has recently taken charge of the manufacturing segment of the PROTEK Group of Companies, shared the plans on further development of the segment and addressed the new targets set after acquisition of Rafarma. Sotex holds a solid portfolio of products and enjoys a strong position in the market standing with its own production site located in the Moscow region. What was the reason to acquire the manufacturing facilities of Rafarma? Sotex uses its own manufacturing facilities to produce injectable formulations. Any ampoule formulations, prefilled syringes, including syringes with passive needle safety device â&#x20AC;&#x201C; we manufacture all those products in compliance with EU GMP standards. Bayer, Sanofi, Novartis, Pierre Fabre, Takeda are among our long-standing partners in the field of contract manufacturing. With the practical experience and expertise gained, we were in need of manufacturing facilities complying with European standards to be used for production of solid forms of both our own products and the products of our partners. Rafarma became the strategic acquisition we required. As for unique competitive advantages of the site, we were interested in the R&D sector and clean rooms testing facilities that provide the

Vadim Yatsuk Head of PROTEK Groupâ&#x20AC;&#x2122;s manufacturing segment

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CIS GMP news

1 (1) / autumn 2017

PROTEK Group is one of the largest pharmaceutical companies of Russia. The Group has diversified business interests and operates in all major segments of the pharmaceutical industry such as medicine manufacturing, distribution and retail of pharmaceutical, health and beauty products. The Group employs over 14,000 specialists. Audited financial results for the 2016 accounted for 241.4 billion Rub. The Group has a vertically integrated structure, which enables it to set up a complete product supply chain – Production – Distribution - Retail. The key companies of the Group are CV «PROTEK», a national distributor of pharmaceutical, health and beauty products; Sotex Farm Firm, a medicine manufacturer; and Rigla Pharmacy Chain.

opportunities to develop preparations for clinical studies and pharmaceutical evaluation, to scaleup R&D projects, and to adjust the technology prior to manufacturing commercial batches of new products. Furthermore, Rafarma caught our interest from the viewpoint of manufacturing a wide range of oncology products in various dosage forms. We intend to further expand this therapeutic group both by developing our own portfolio and through cooperation with our contract manufacturing partners. In this regard Rafarma production capacities provide an undisputable competitive edge. How are you planning to develop contract manufacture now that Rafarma has been acquired? What competitive advantages of the new production facilities could attract new partners for contract manufacture? The manufacturing site in Lipetsk Region is recently built, conveniently located and designed in compliance with GMP guidelines. Rafarma’s manufacturing facilities enable production of antibiotics and oncology products in 15 various dosage forms and meet the most stringent requirements of both Russian and European regulatory authorities. Self-contained facilities fitted with isolated air handling and water treatment systems; manufacturing and laboratory equipment of the leading European brands; a strong team of highly qualified professionals with vast experience in technology transfers – all these features make Rafarma a very attractive production site for potential partners. Another competitive advantage is the expertise in the field of quality control accumulated by the manufacturing segment of the PROTEK Group. EU GMP certified production site of Sotex has an

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Sotex ÂŤPharmFirm is the core of the manufacturing segment which incorporates Rafarma JSC, Protein Contour Company Ltd., and AnviLab Company Ltd. as well. The Group business practice aims at the increase in the competitive ability, stability of the Group business as a whole, and at the maximum capitalization of each company in the respective market segments. PROTEK Group follows modern standards in the financial management. Its core elements include corporate financial reporting in compliance with the International Accounting Standards (IAS), international auditing, wellconsidered financial policy, and implementation of the Oracle E-Business Suite, an ERP system, in its segments.

exceptionally high level of organization of manufacturing processes, which is regularly confirmed by the findings of audits conducted by foreign pharmaceutical manufacturers. Our task is to ensure that Rafarma reaches the same level in the nearest future, so that its potential is fully exploited not only for localization and import substitution, but for manufacturing ready formulations for exports as well. Most importantly though, Rafarma acquisition opens vast new opportunities for the manufacturing segment of the PROTEK Group, providing for a truly unique package of services we can offer to our partners. Today we are able to perform the entirety of operations required to launch a new product in a market: development of a formulation from scratch in the R&D sector; implementation of the manufacturing process on an industrial scale; execution of all registration-related activities; production of the preparation in virtually any dosage form; marketing, promotion and distribution of the ready formulation.

Rafarma JSC is a multi-purpose research and development pharmaceutical facility focused on antibacterials and oncology products. At 5 self-contained GMP compliant sites (25,000 m2 of manufacturing facilities) with research, development and testing laboratory and in-house experimental base they manufacture preparations in 15 medical forms.

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Rafarma being a company that has just emerged on the market, do you think its resources are sufficient to achieve such ambitious goals? The pharmaceutical industry continues to face the lack of highly qualified staff. How do you intend to tackle this issue? As we have plans to expand our product portfolio, increase the output and build up our research capacity, we will need a lot of highly qualified professionals. Generally, our team is well staffed, with about 300 persons working at the manufacturing sites and in the laboratories, but we are actively recruiting new staff, hiring professionals from all over the country. The PROTEK Group employs over 14,000 people, so we have a huge experience in building professional and efficient teams. For example, Sotex ranks third among top Russian employers in terms of personnel engagement and seventh among the leaders of the pharmaceutical industry. What does it mean in real world terms? We are talking about highly professional personnel, continuity of expertise and ongoing improvement of internal procedures. Ensuring GMP compliance is a dynamic task, which is centered on and managed by people. Building a stable and dedicated team is a delicate work and a key to success for a modern pharmaceutical manufacturer.

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1 (1)Â / autumn 2017

JSC Rafarma Full Cycle Manufacture of Antibacterials, Oncology Products and other Preparations Partnership advantages:

local production and technology transfer experience

attractive priceoffer

April 2017, Rafarma merged with Protek Group's manufacturing segment, which has Sotex PharmFirm as its core element.

JSC Rafarma is a full cycle pharmaceutical enterprise designed and operating in accordance with GMP standards. Its multipurpose research and development facilities are located in Terbuny, Lipetsk Region, Russia. The company also maintains facilities for manufacturing small scale batches of APIs and solid forms based at the RAS Institute of Problems of Chemical Physics in Chernogolovka (Moscow Region).

Antibacterial and oncology products make up the bulk of the companyâ&#x20AC;&#x2122;s portfolio, which also includes oral hypoglycemic, cardiovascular, antituberculosis and other preparations. The full cycle manufacture of cephalosporin antibiotics, non-beta lactam antibiotics, cytostatic agents and formulations of other therapeutic classes is carried out at five self-contained sites.

distribution and promotion cycle

Annual Manufacturing Capacity:

1.5 billion

pills

180

million hard gelatin capsules

62.5

million injection vials

The facility includes a separate R&D laboratory for autonomous research activities and development of innovative medical products. Preparations are developed for clinical studies and pharmaceutical tests in our experimental cleanroom, where R&D scaling-up and technological fine-tuning take place before product rollout.

million suspension vials

Fitted with equipment from leading European suppliers, Rafarma JSC is capable of producing a wide range of ready formulations.

million sachets

7.5 18

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1 (1) / autumn 2017

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Key Facts and Figures:

@ @ @ @ @ @ @

Multi-purpose research and development pharmaceutical facility focused on antibacterials and oncology products 25,000 m2 of manufacturing facilities in Terbuny, Lipetsk Region, Russia R&D: research, development and testing laboratory, in-house experimental base Availability of equipment and a license to manufacture preparations in 15 medical forms Supplied with equipment from the world’s leading manufacturers: Bosch, GLATT, Kilian, Romaco Macofar, IMA, CAM, Fedegari, Tofflon etc. 24 hectares available for construction of additional manufacturing facilities

5 self-contained GMP compliant sites

Site No 1

R&D: research, development and testing laboratory, in-house experimental base Manufacturing of solid forms: pills, hard gelatin capsules, sachets, tubes

Site No 2

cephalosporins injections in vials, suspension vials

Site No 3

antineoplastics injections in vials, tablets and capsules

Site No 4

antibiotics non-β-lactam injections in vials tablets and capsules

Site No 5

antineoplastics injections in vials

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1 (1) / autumn 2017

Sotex PharmFirm - High-Tech EU GMP Certified Manufacturer

Partnership advantages:

European GMP certificate

ounded in 1999, Sotex PharmFirm is the manufacturing segment’s holding company. Sotex is a major domestic pharmaceutical manufacturer, one of Russia’s most high-tech and innovative pharmaceutical enterprises. The factory provides a full manufacturing cycle of injection solutions in ampoules and syringes. All processes are performed in strict compliance with international requirements using equipment supplied by Europe’s leading manufacturers. The company benefits from an in-house R&D unit. Using advanced equipment and first class human resources, the unit develops a wide product range including biotechnical formulations. The pipeline currently comprises

Extensive marketing support

over 50 products at various stages of development. Sotex takes pride in its unique experience of cooperation with world’s pharmaceutical industry leaders in the field of licensed manufacture and promotion of ready formulations. The company offers a full range of services, from registration, production, and distribution of medicines to retail sales. It also offers extensive marketing support and assistance.

Integrated business approach: production, distribution, and promotion of medicines

sible range of ready formulations, dosages and packages. This enables physicians to improve and modify medical treatment based on patient needs. Some dosages of the most high-demand formulations in the company’s portfolio are unique in the Russian market. The wide range and convenience of dosages help doctors establish individual treatment plans to improve patients’ health.

In 2016, Sotex received European GMP certificate for ampoule production, which broadened our opportunities to represent Russia adequately at the international market. Sotex marketing policy is focused on production of the widest pos-

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1 (1)Â / autumn 2017

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Key Facts and Figures:

Guaranteed sales volumes

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Minimized ROI risks

@ @ @ @ @ @ @ @

Rated 4th by IMS Health among Russian pharmaceutical manufacturers in 2016 in terms of output Portfolio includes 148 SKUs with 97 branded products (30.06.2017) Key therapeutic areas: oncology, neurology, rheumatology, nephrology, neuropsychiatry Manufacturing capacity: 140 million ampoules and 6 million prefilled syringes annually Unique line for manufacturing prefilled syringes with passive needle safety devices Annual audits from world leading pharmaceutical manufacturers R&D platform with competences of injectable and biotechnological product development Exports to more than 10 countries

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1 (1) / autumn 2017 Contract Manufacturing

PHARMACEUTICAL COMPANY SOLOPHARM

SOLOPHARM IS ONE OF THE LARGEST PHARMACEUTICAL COMPANIES, RUSSIAN LEADER IN LIQUIDS MANUFACTURING - meets GMP standards - optimal location of facilities in Saint-Petersburg on the territory of 3.7 ha - modern European up-to-date equipment - sophisticated manufacturing technologies Blow-Fill-Seal (BFS) and Bag-On-Valve (BOV) - full range of drug development – from the idea to the technology introduction - R&D laboratory - variety of manufactured products - unique dosage forms, preservative free - manufacturing capability of 1 billion product units per year

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AIR HANDLING SYSTEM

Total area of makeup air zone – 7 730 m2 Total capacity of AHUs – 743 374 m3/h

WATER TREATMENT SYSTEM

Water treatment capacity: water for injection (WFI) 12 000 l/h purified water 15 000 l/h water treatment consumption 1,1 Mio litres per day

CLEAN ROOMS

Total Clean Room area (production and laboratory zone) – 6 785 m2 Capacity of Clean Room air handling units – 606 140 m3/h

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1 (1)Â / autumn 2017

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Contract manufacturing is one of SOLOPHARM activities. SOLOPHARM is open to exploring new and different ways of collaborating at its site where all the conditions for the production of high-quality medicines are created in accordance with GMP. The facilities are equipped with a broad variety of up-to-date production equipment that allows producing various dosage forms. Production capacity - more than 1 billion units of products per year. SOLOPHARM offers a full range of services in the field of research and development, from concept and product development right up to registration and industrial production. The team of professionals ensures that customer requirements are thoroughly understood and met.

Contract manufacturing with SOLOPHARM is a quality guarantee and mutually beneficial collaboration. CONTACTS: Industrialny pr. 71, building 2, lit. A, St.Petersburg, Russia, 195279 Tel.: +7 (812) 385-47-87 ext. 560 / Fax: +7 (812) 385-47-88 contract@grotexmed.com www.solopharm.com

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1 (1) / autumn 2017 Contract Manufacturing

“Samson-Med” –

New Contract Manufacturing Horizons 29 August 2017

“Samson-Med” is an innovative pharmaceutical company with full cycle production. It actively realizes the localization strategy, national pharmaceutical segment development, and provides affordable and effective vital medicinal products.

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harmaceutical company “Samson-Med” is an innovative full cycle production manufacturer. The company realizes full variety of associated activities – from research and development of medicinal products to mass production and marketing thereof. From its foundation in 1937, the company has developed and implemented a number of unique production technologies of active pharmaceutical ingredients (API) and original endocrinal and enzymatic preparations. Today, “Samson-Med” actively cooperates with the most reputable and competent

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organizations in various areas. The company established partnerships with the following leading Russian scientific organizations: Mechnikov North-Western State Medical University, St. Petersburg Medical Academy of Postgraduate Studies, Saint-Petersburg I. I. Dzhanelidze Research Institute, Institute of Toxicology of Federal Medico-Biological Agency, A.N. Bakoulev Scientific Center for Cardiovascular Surgery, Saint-Petersburg State Chemical Pharmaceutical Academy, S. M. Kirov Military-Medical Academy, Pavlov First Saint-Petersburg State Medical University.

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1 (1) / autumn 2017

Besides own medicine production, the company performs contract manufacturing of API and finished dosage forms. “Samson-Med” maintains stable and effective partnership with Russian and International companies such as Stada (Germany), Petrovax Pharm (Russia), Geropharm (Russia) for more than 14 years. Nevertheless, the company is continuously looking for new strategic partnerships. Thus, on June 16th, 2016 Governor of Saint-Petersburg Georgy Poltavchenko and a CEO of “Samson-Med” Adlan Elikhanov signed an agreement of building a manufacturing plant for API and finished dosage form production in Pushkin District near Saint-Petersburg as cooperative strategic investment project. Also, Deputy Minister of Healthcare Sergey Krayevoy was present on the ceremony. Georgy Poltavchenko made a point that “Samson-Med” is proved itself as a trustworthy partner of the Saint-Petersburg City with long-established

good reputation. “The city actively supports this project. I am sure it will serve to the benefit of Saint-Petersburg and Russia,” concluded Georgy Poltavchenko. The company is a resident of the Import Substitution and Localization Center from 2016. The new production plant for the pharmaceutical manufacturing is designed and being built in Puskin on the area of 27,000 m2. The lot is allocated for the deployment of two production units for API and finished form manufacturing, 2,800 m2 laboratory building, warehouse and engineering units, sewage facility, boiler-house, etc. The facility of lyophilized injection form production and the aseptic ampule packaging line are of great interest for the contract manufacturing. The designed capacity of the lyophilized injection form production is 20 million vials per year (calculated for 2R, 4R types), and aseptic packaging line – 37 million vials per year.

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W 27,000 m area W lyophilized injection form production capacity – 20 millon vials/year W aseptic ampule filling line production capacity – 37 million ampules/year W state-of-the-art filling and packaging line from OPTIMA – 18,000 vials/hour W 100% In-process control W sublimation shelf area – 25 m W ampule filling line 2

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1 (1) / autumn 2017

State-of-the-art lyophilized injection form production line with packing, with the capacity of 18,000 vials/hour from “OPTIMA” company, meets the designed manufacturing criteria. The major vial types are 2R, 4R with an option to use vials of types 10R, 20R, 50R and 100R. The implemented dosage system allows to fill vials with high precision. There is a 100% in-process control that doesn’t impair production efficiency. The designed vial loading for lyophilization is automatic and implemented in line by line order. The filling line and loading system will be isolated under automatic environment monitoring system. Vial drying will be performed by

lyophilization on 25 m2 shelves. Filling solution preparation will be done on automatic preparation systems made by leading international manufacturers. Water preparation is performed by “Stilmas” systems ensuring the quality of the obtained filling solutions. Unloading of the dried vials will be performed automatically line after line, followed by transportation to the RABS packaging machine using “flip-off” caps with the possibility of additional marking on the cap. The company negotiates with such contractors as Dividella, Uhlmann, Seidenader, the purchase of the marking, inspection, and packaging equipment.

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The equipment planned for the aseptic ampule packaging line is considered from the world leading manufacturers: Bausch-Strőbel, Marchesini, Rota, and others. The designed line capacity is 24,000 ampules/hour. Ampule types are 1 ml, 2 ml and 5 ml. The filling process will be performed using syringe RABS system. Terminal ampule filled product sterilization will be performed using autoclaves from leading manufacturers, such as Fedegari, Getinge, LAST Technology. Investment project “Building a pharmaceutical production plant on Puskin District territory” is accepted as strategic Saint-Petersburg project according to the Government Decree of Saint-Petersburg No. 262 from 12.04.2016. The strategic investment project is realized during 2016-2019. According to the business magazine businesspuls.ru, the project of building a pharmaceutical production plant on Puskin District territory is one of the top rating largest investment projects of North-Eastern Federal District which has been started in 2015.

CONCLUSION Today, the pharmaceutical company “Samson-Med” is one of the most dynamically developing pharmaceutical productions in Russia. Positive feedback given by the Federal Government to the project makes it very appealing to investors. With the collected knowledge and the pharmaceutical market experience, long-term strategic partnership, governmental support, and customer credibility, the company future view is filled with confidence and that allows it to effectively overcome negative external economic factors.

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1 (1) / autumn 2017 Contract Manufacturing

Acticomp Company is a Leading Manufacturer of APIs in Russia Russian pharmaceutical market has been actively growing and developing in the last few years. The pharmaceutical industry of the country grows by 25% annually. Against this backdrop, the largest manufacturer of active pharmaceutical ingredients (APIs) in Russia – Acticomp CJSC – demonstrates record-breaking growth indicators of 50-60% per year. The company focuses on the industrial production of a wide range of generic APIs, and has an opportunity to develop customized APIs according to individual orders. The company delivers not only within Russia, but also to Europe.

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4 September 2017

oday, not many producers of finished pharmaceutical products (FPP), even large ones, have their own facilities, that can deliver necessary APIs. Opening of an ingredient-producing factory is a long-term and capital-intensive process. That’s why the majority of pharmaceutical companies use outsourcing, thus supporting the development of ingredient-producing industry. One more significant argument in favor of API manufacturers is state regulation of pricing for vital and essential medicines (VEM). In many countries of the world, authorities control the prices of the most important medicines and set their price limit at the minimum level, thus protecting their national interests. Outsourcing at the market of FPP production embraces a lot of opportunities for the growth of APIs production, as market players believe. However, the most important thing is that it can increase cost-effectiveness of the whole

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supply chain. Striving to cut costs, pharmaceutical manufacturers, that value their reputation, will try to purchase APIs from reliable manufacturers that can ensure stable quality, and deliveries in required volumes. About 45% of API manufacturers are located in Asian countries, which is connected with low labor cost and favorable legislation, first of all. 50% of the APIs and more than 70% of the generic pharmaceutical ingredients consumed in the world are produced in India and China. India and China also produce almost 80% of all antibiotic pharmaceutical ingredients – one of the most demanded groups, delivered to various regions of North America and Europe. However, the situation currently unfolding on the market can change the existing placement of forces in the future. Ambitious Russian companies, investing in the modernization and development of production facilities of APIs, can supply high quality products to the world market and compete with

the leading Indian, Chinese, and European suppliers. With current business environment, they stand a good chance to deprive competitors of their leadership, and expand the distribution area. China – a country that has been considered to be a leader of APIs production for a long time – is now experiencing serious systematic problems related to the environmental issues. Many chemical and pharmaceutical production facilities, that were opened in the 1970s-1980s, that are threatening the life and health of population, are being closed in the Celestial Empire. Restrictions are being imposed on the construction of new factories, and issue of new GMP certificates. According to some estimates, the export growth of pharmaceuticals from India may slow down by 8% on average in the nearest future due to the tightening of rules of operation at the markets of the USA, Russia, and Africa. Moreover, the Government of India is planning to implement a new state program of import substitution with preferences for

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1 (1) / autumn 2017

Acticomp Company has GMP certificate and manufactures APIs, complying with the quality standards of European and American pharmacopeia. We look forward to finding reliable partners in all countries of the world, and we are ready to supply APIs with a perfect price-quality ratio. Together with our partners, we can develop necessary active pharmaceutical ingredients within the shortest time possible.

Alexandr Semenov President of Acticomp CJSC

local FPP producers, which foresees the introduction of high customs duties for the shipments of all local APIs to the foreign markets. It is evident that when the program enters into force, the deliveries of Indian APIs to the world market will go down due to a significant price increase. Against this backdrop, Russian APIs, complying with the highest quality criteria, and even over-performing foreign equivalents in many respects, may become a worthy alternative to Chinese and Indian APIs, presence of which will decrease on the world market. As the President of Acticomp Company Alexandr Semenov says, Russian companies are ready to increase their production output not only to satisfy the demand at the Russian market, but also to replace Chinese and Indian competitors globally. “There is a myth at the pharmaceutical market, that it is impossible to compete with India and China in terms of APIs manufacturing. But it is only a myth. For example, we already supply our products to Serbia and Belarus. We negotiate with large FPP producers from Israel, Poland, Slovenia, Germany, and USA. When we finalize this process, we will be able to conclude new contracts. High demand for APIs allows us to make optimistic plans for the future. In 2020, we will commission a new factory producing APIs, which will become one of the most high-tech and innovative production facilities in Europe. The amount of investment into the project is about

35 million US dollars. The overall capacity of our production facilities will reach 140 tons per year. Anticancer drugs (cytostatic) and hormone substances of peptide synthesis will be produced at the new facility in addition to substances of classical synthesis, “ Alexandr Semenov says. Until very recently, Acticomp Company has exported about 5% of its overall API production. According to the results of 2017, the volume of deliveries to foreign pharmaceutical manufacturers will reach 10%. In three years, the company is intended to export more than one third of its overall production – more than 50 tons per year. “APIs manufacturers have a significantly lower entry threshold to the foreign markets than pharmaceutical manufacturers that have to pass a strict and multilevel registration process. Our product must only comply with the generally accepted and unified industry standards – GMP criteria, which means there are no obstacles to supply the APIs, as a matter of fact,” Alexandr Semenov notes. This year, Acticomp Company has completed the modernization of the existing production facility, having increased its capacity by 1.5 times. The amount of investment into the reconstruction, including that of the science and technology infrastructure, was 5 million US dollars. The introduction of innovative technologies allowed to speed-up the process of manufacturing. The increase of R&D basis by 5 times

provided more opportunities to introduce new APIs – up to 10 items per year – and gave additional advantage to the company on the market. R&D Department of 1,200 m2 is fitted with crucial equipment, which is necessary to develop synthetic routes and analysis methods for both generic APIs and APIs, term of patent protection of which will expire soon. The research team consists of the experienced specialists in the fields including those of organic and analytical chemistry. This team has access to the high-end laboratory equipment: highly efficient liquid chromatographs WatersAlliance, gas chromatographs with flame ionization detectors, mass-spectrometer detectors by Shimadzu, and many more. The researchers have access to modern information bases SciFinder and Reaxys, which allows them to be on the cutting edge of modern technologies. “Increasing range of manufactured products and cutting production cost represent the key trends at the pharmaceutical market. One of the advantages of Acticomp Company is an ability to develop and produce customized APIs according to an individual order at our own facilities. Today, we can produce about 50 types of different APIs, but the number of components will double in 5 years from now, Alexandr Semenov says. – We intend to take a noticeable share of the global API market. And we have all the reasons to do it.”

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THE MAIN APIS, PRODUCED BY ACTICOMP COMPANY: Azelaic acid

Flupirtine maleate НД ФС 000723-231013

Purified Micronized Flavanoid Fraction НД ФС-001049-300517

Azythromycin

Glycine

Ramipril

Betahistine hydrochloride

Indapamide

Ribavirin

ЛСР-000842/10-090210 ЛСР-005187/07-241207 ЛСР-000119/09-140109

Carvedilol

НД ФС 000358-020712

ЛСР-004369/08-070608

Keterolac tromethamine

ЛСР-010503/08-241208 ЛСР-001593/08-140308

Risperidone

ЛСР-002673/08-100408

ЛСР-002572/08-080408

НД ФС 000112-100611

Cetirizine dihydrochloride

Levofloxacin

Sildenafil citrate

Clarithromycin

Losartan potassium

Simvastatin

Clopidogrel hydrosulphate

Loratadine

Terbinafine hydrochloride

НД ФС 000135-230911

ЛСР-010389/08-231208 ЛСР-003766/08-160508

Desloratadine

ЛСР-001739/09-100309 ЛСР-003153/10-130410 ЛСР-002573/08-080408

НД ФС 000572-070513 ЛСР-006745/08-180808 ЛСР-002579/08-080408

НД ФС 000834-080514

НД ФС 000025-221210

Mebhydrolin

Tilorone

Diosmin

Meloxicam

Timolol maleate

Fenspiride hydrochloride

Naftifine hydrochloride НД ФС 001317-280116

ЛСР-003635/08-120508

Fluconazole

Perindopril erbumine

Troventolum

ЛСР-007705/09-011009 НД ФС 000440-191112

ЛСР-010212/08-151208

ЛСР-001760/09-100309

ЛСР-007011/08-020908

НД ФС 000139-280911 ЛСР-009874/08-101208

Trimetazidine dihydrochloride

НД ФС 000967-101114

CONTACTS: ACTICOMP, СJSC Aleksandr Salekh Leading foreign client manager Office 1101, Obukhov-Center business center, 271 Obukhovskoy Oborony Ave, St. Petersburg, Russia e-mail: asalekh@acticomp.ru tel/fax: +7 (812) 457-11-11

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1 (1) / autumn 2017 Contract Manufacturing

Research and Production Association PharmVILAR – 10 Years of Successful Contract Manufacturing in Russia 28 August 2017

PharmVILAR is a holding, which successfully works in 3 main areas of pharmaceutical business: distribution of pharmaceutical substances, development and production of proprietary therapeutic agents, and provision of the whole range of services for contract manufacturing.

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Inna Voskoboynikova

Kirill Kalinichenko

General Director Pharmaceutical and Industrial Company PharmVILAR

General Director Research and Production Association PharmVILAR

ince 1998, JSV Pharmaceutical Industrial Company PharmVILAR (the leading company of the holding) has gained a leadership position in supplies of state-to-art excipients to Russian/CIS pharmaceutical market, and represents products of business headliners like DFE Pharma (Germany), Evonik Industries (Germany), Shin-Etsu (Japan), Dr. Paul Lohmann (Germany), Calmags (Germany), Beneo (Germany), Standard Chem. and Pharm.Co. (Taiwan), as well as manufacturers of talc, starch, and many other pharmaceutical ingredients. Competent use of pharmaceutical excipients based on the latest achievement in the area is necessary for development of effective, safe, and high-quality medicines. At the same time, the range of pharmaceutical ingredients shows continuous quantitative and qualitative expansion with improvement of their technological possibilities. It opens

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excellent prospects for production of competitive therapeutic agents. Knowledge of the market, its tendencies and requirements, long-term experience of work and our own R&D activities allows us to offer the best multi-level, first of all technological solutions for manufacturers of pharmaceutical products. Of course, we pay special attention to development of our young production site – JSV Research and Production Association PharmVILAR. Its construction was launched in 2006, and already in 2008 we started contemporary production of final dosage form and substances, began production of our proprietary branded products, and first contract products. By this time, we had a sufficiently clear idea of the principles, which the production must fulfill in order to be interesting to potential customers for contract manufacturing. The plant must have a license and a GMP Certificate, necessary equipment, free facili-

ties (both production and warehouse), qualified personnel, and knowledge and experience in technology of pharmaceutical production. Manufacturer must be client-oriented, must quickly and accurately respond to customer’s requests, provide custom manufacturing service in a narrow profitability range, offer competitive price, must be able to provide service for procurement of active substances and excipients, including bulk volumes, and a strong Regulatory Department for registration of therapeutic agents is desirable. Adherence to strong confidentiality policy is also important. Why did we decide to become contract manufacturers? There were solid reasons for that. Though contract manufacturing of therapeutic agents is a rather new business model for Russia, it was actually our company, which contributed to its appearance and development, and we have gained more than 10 years’ experience of being customers

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1 (1) / autumn 2017

for c ontract manufacturing of our own branded products. We had vast experience of product development and registration. And one more reason – for many years, our company has been a leader in supplies of pharmaceutical excipients to Russian pharmaceutical manufacturers, and we can provide our production site with most up-to-date excipients (at a reasonable price) for organization of optimal technological process of final product manufacturing in the customers’ interests. It should be noted that contract manufacturing is a very demanding business, its development and implementation requires a very strong client-oriented position from the manufacturer, sometimes even at the expense of production of its own products. Of course, like any other business model, contract manufacturing has its pros and cons. Positive aspects include possibility of maximal use of the available equipment,

continuous challenge by new tasks and mastering of new technologies, possibility to gain profit without investments into marketing and promotion. Negative aspects include low profit margin of such production, and all risks related to the quality of produced materials are assigned to contract manufacturer. At present, Research and Production Association PharmVILAR Ltd. is a an actively developing enterprise, which produces final therapeutic agents in various forms - tablets (plain, film-coated, sugar-coated, effervescent, orally dispersible), capsules, oral powders (sachets), solutions, syrups, emulsions, extracts (liquid, soft, dry), liniments, creams, ointments, and other according to the production license of the Russian Ministry of Industry and Trade. In 2015, a new extended license was obtained, which expands our possibilities to produce different solid, soft and liquid pharmaceutical forms, as well as a wide range

of natural and synthetic pharmaceutical substances. A GMP Certificate was obtained the same year. We believe that our largest achievement during almost 10-year experience of contract manufacturing service is the trust of our customers and partners, which was gained, first of all, due to stable high quality of the manufactured products, speed, and creativity in solution of the appearing tasks. Our core values: We adhere to Russian legislation on each and every step of production, quality control, storage, and release of the manufactured products. We improve production infrastructure by technical renovation, modernization and update of the production facilities. We constantly analyze and improve the quality management system. We constantly improve the professional skills of the staff.

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We are ready to perform the full cycle of drug development, from formulation and technology development to production of final dosage form. The following quality systems have been implemented, and are used at the production site: Pharmaceutical quality system according to FMP principles; Quality Management Systems in line with ISO 9001-2011 requirements. The company is authorized to work with highly active and narcotic drugs. Research and Production Association PharmVILAR is the single Russian company, which has a GMP Certificate and a license for production of matrix tinctures for homeopathic products. The production facility consists of 2 workshops for production of final dosage forms and a workshop for production of galenic products (extracts and their active components). The company has qualified specialists, which know and fulfill the requirements of Good Manu-

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facturing Practice. The workshops are equipped by state-of-the-art, validated machines from well-known international manufacturers, which allow execution of the necessary technological operations. For example, workshops for production of final forms have high-speed mixers, which allow mixing and wet granulations, fluid bed dryers, multi-functional 3D-mixers with product loading by vacuum feeders. One of our tablet presses has a function of internal lubrication. We are ready to produce tablets of different diameter and shape, including oblong. Workshop for production of final forms has premises with controlled temperature/ humidity conditions, which are necessary for production of effervescent tablets. We also use capsule filling machines, coaters (both for film and sugar coating); we successfully introduce technology of 2-layer film coating. Machines for tablet and capsule packing into blisters have different tools, which allow packing even by 1 tablet per blister. Our strong capability is production of therapeutic products in sachet form.

We are one of the leaders among Russian pharmaceutical manufacturers by the volume of therapeutic agent production in this form. Packing zone is equipped with automatic line for product packing into cartoons. Galenic workshop is equipped to obtain liquid, soft and dry extracts from therapeutic herbal raw materials. It has extractors, percolators, equipment for syrup production (with a single batch volume up to 2,000 liters), filtration devices, vacuum evaporators, vacuum dryers. The workshop technologies have studied and consider all factors, which influence the process of herbal raw material extraction, including particle size, temperature mode, optimal extraction duration, etc. All substances and products, which are obtained in galenic workshop, are standardized, and their quality conforms to requirements of pharmaceutical monographs. By now, a new line for production of suspensions, o Â intments, and creams has been installed, including vacuum

CIS GMP news

1 (1) / autumn 2017

omogenizer, rotor-pulsation machine, h and tube filling machine. Quality control and technological laboratories are equipped with all devices, which are necessary for income control of raw materials, for pharmaceutical and chemical/technological testing of semi-finished products, and for quality control of final products, including high performance liquid chromatography (HPLC), gas chromatography (GC), etc. Laboratory analytical and pilot-scale technological equipment allows conductions of necessary studies for development of production processes and therapeutic products according to customer’s technical requirements, including development and validation of analytical methods, reference documentation, etc. The work is conducted in close cooperation with Regulatory Department. Upon customer’s request, we are ready to offer the whole range of services for registration of therapeutic products in Russia.

We can be interesting to foreign customers from the point of view of preferences, which Russian pharmaceutical manufacturers have in Russia over foreign companies. We can be also interesting as manufacturers of substances and premixes, including those based on foreign raw materials, which significantly simplifies the process of Russian registration of both pharmaceutical substance, and the final therapeutic product made from it. Before conclusion of contracts, our production facility regularly passes customers’ audits. As a rule, customers order “turn-key” product development, including production of therapeutic agents for preclinical and clinical studies. Sometimes, customers perform technology transfer to our production site. At present, large Russian pharmaceutical companies like Pharmaceutical Company Sotex, Canon Pharma Production, Valenta Pharm, NizhPharm, PharmStandard, Obolenskoye, etc. are

among our customers for development of formulations and technologies of final product manufacturing, and for contract manufacturing of substances and final products. Some of the products, which are manufactured by us according to contracts (cardiologic, anti-flu, anti-diabetic, anti-ulcer, etc.) are included into State program of import substitution. We closely cooperate with foreign pharmaceutical companies. Our production consistently develops, we increase our production and warehouse capabilities, and master most state-of-the-art technologies. As contract manufacturers, we are interested in long term and mutually beneficial cooperation.

We are being trusted and valued for quality and reliability! Turn to us, and we shall offer solution for any task!

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WE ARE CONTRACT MANUFACTURERS WE ARE TRUSTED AND VALUED FOR QUALITY AND RELIABILITY

FROM CONTEMPORARY KNOWLEDGE TO STATE-OF-ART TECHNOLOGY

Production facilities and experience of the company allow us to work successfully in the area of contract manufacturing of therapeutic agents and nutritional supplements. We perform the full production cycle. You order – we produce different pharmaceutical forms and substances according to contract: • • • • • • •

Tablets (including film-coated and effervescent) Capsules Sachets Solutions, syrups Herbal extracts (dry, liquid, soft) Soft forms (gels, creams, ointments) Premixes Upon your request, we are ready to develop formulation and technology for production of final therapeutic product, provide service for registration of your product in Russia.

Research and Production Association PharmVILAR Ltd., Maloyaroslavets www.gmpnews.net Contact in Moscow: tel/fax+7(499)372-13-23

CIS GMP news

1 (1) / autumn 2017 ИнтересыManufacturing Contract производителей

Canonpharma Production -

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a New Generation of Russian Pharmaceutical Manufacturers

27 August 2017

anonpharma production is a privately owned pharmaceutical company that is engaged in developing generic medicines for almost all therapeutic areas of public health service. The company has also developed and introduced a couple of original preparations. Canonpharma belongs to a new generation of Russian pharmaceutical manufacturers focused on extremely high standards of production quality and product care. We spoke to Viatcheslav Kokeladze, a deputy general director at the company, and asked him to share some information about the enterprise. Viatcheslav, could you please tell us about how it all began and what were the first steps for the company? Canonpharma production was founded in 1998. Speed of decision-making and implementation were at the heart of the companyâ&#x20AC;&#x2122;s philosophy and this approach helped in creating a modern manufacturing base in a relatively short timeframe. The first steps for Canonpharma in terms of development related to construction of a tablet packaging facility with capacity of 40 million blisters per year. Construction works were complete by October 1999, and shortly after that, the company was granted a manufacturing license for filling, packaging, storage, and sales of pharmaceuticals. After construction of the packaging plant, Canonopharma

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Effectiveness and safety of manufactured pharmaceuticals are literally a “Canon”

collaborated with manufacturers from Germany, Canada, Macedonia, and Latvia. In 2004, Canonpharma production constructed an advanced finished forms manufacturing facility, which was commissioned on a Greenfield site in Shchyolkovo, Moscow Region. Manufacturing activities officially began by March of the same year. What is Canonpharma production now? Today our enterprise remains fully committed to maintaining very high standards of quality for pharmaceutical products. This is clearly illustrated by almost non-existent product recalls, very low defect levels, and positive end-user feedback. Effectiveness and safety of manufactured pharmaceuticals are literally a “Canon” of Canonpharma. Nowadays, we manufacture more than 180 product SKUs, and the current capacity for manufacturing of solid pharmaceuticals is around 750 million tablets and 87 million capsules per year. In addition, we can also manufacture almost 11 million sachets per year. Currently, we are engaged in construction of a new production facility that is anticipated to be put in operation in 2018. After commissioning of this new manufacturing site, Canonpharma production capacity is going to double. With a skilled, motivated, and competent

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team, we are very certain that Canonpharma production is well positioned to capitalize on changing trends in the pharmaceutical market What about the company strategy? Canonpharma production has a clear goal of becoming a top ten Russian generics player with strong access to foreign markets, and we are making good progress towards that ambition. Our aim is to be able to respond to the needs of customers, and encourage progress in medicine and society by helping people live healthier and more fulfilling lives. The implementation of this strategy requires a strong pipeline with high-value products in development, operational efficiency, and solid presence in the Russian regions and neighboring countries. The strategy of the company also includes close cooperation with medical community to meet the needs for treatment with modern and available medications. The partnership with professional medical associations and representatives of scientific society allows the company to be aware of modern trends and methods of treatments for patients that, as a result, improve peopleâ&#x20AC;&#x2122;s health. Tell us a few words about the products manufactured by Canonpharma, please. The range of pharmaceutical products manufactured by Canonpharma production reflects the needs of the market for medications, disease patterns, and latest trends in drug therapy. Companyâ&#x20AC;&#x2122;s product portfolio includes over 180 product list items, including original preparations, as well as generic versions of famous products, which are only presented on the market by foreign producers. Our key product therapeutic classes are Cardiology, Neurology, Gastroenterology, Endocrinology, Psychiatry, Oncology, HIV, and Antimicrobial therapy. Majority of our preparations are included in the Vital and Essential Medicines List, as well as the reimbursement drug list. Some of our preparations do not have local analogues, and are a part of a list of priority medications for production in the Russian Federation. You are developing and introducing new generic preparation. Could you tell us about those? The company is constantly improving its manufacturing and research capacity to maintain introduction of new, safe, and affordable products, whilst maintaining the highest levels of quality. We focus our R&D efforts on developing a wide portfolio of products across different platforms. Canonpharma R&D department has a modern and well equipped lab to implement up-to-date technologies. We have developed, scaled-up, and introduced hundreds of new pharmaceuticals into

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manufacturing. At present, we have around 100 new products at different stages of development and registration. We will require all our efforts and experience in order to introduce these new preparations to the market. We also cooperate with several leading research centers in Russia to develop and carry out clinical and pre-clinical trials of our medications in order to confirm their effectiveness and safety. Which companies do you cooperate with, and in which countries, and what do you stand to gain from international cooperation? We have a partnership program that is based on a close and long-term cooperation with companies manufacturing active substances in such countries as Switzerland, Spain, Italy, India, Germany, Israel, China, and Japan. Vast majority of our suppliers have been audited by FDA or EDQM, which provides extra confidence in the quality our preparations. Canonpharma production is also deeply engaged in contract manufacturing with other pharmaceutical companies. Forming alliances with safe and reliable contract manufacturing sites in Russia and Belarus has allowed us to expand our product range and develop new pharmaceutical forms, such as suppositories, solutions for injections, infusions, suspensions, and lyophilized powders. In addition to that, Canonpharma manufacturing facility is currently performing contract-manufacturing services for some of its local and international partners. We are convinced that fruitful and long-term cooperation can only be accomplished if we offer full support to our partners, deliver on our promises, and reliably supply products that contribute to healthier living.

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Palladio BNM, a Pharmaceutical Packaging Plant, Opens in Obninsk

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We are located here because Kaluga region provided good conditions for us. Moreover, this is a very advantageous location for the plant, because Kaluga Pharmaceutical Cluster needs to have packaging manufactured nearby, as it will cut down the transportation costs. We hope that majority of pharmaceutical companies operating in Russia will become our customers. We will transfer the manufacturing practices and the experience gained by our European plants to Obninsk. The enterprise here will be exactly the same as in Europe, with the same strict quality control that plays a tremendous role in our manufacturing process.

Milomir Mijatovic

General Director, Palladio BNM Obninsk plant

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une 8, 2017 marked the official opening of Palladio BNM, a pharmaceutical and cosmetic packaging plant, in the city of Obninsk, Kaluga region. This is a joint Italian-Serbian enterprise. For 70 years, Palladio Group S.p.A., an Italian company, is engaged in manufacturing of pharmaceutical packaging, and it has become the European leader in this area. Palladio Group already has three plants in Italy, one in Ireland, and one in Serbia. Palladio BNM plant was designed to be built in three stages. The design and works have been performed by FormaPharm Engineering, a company specializing in the construction of pharmaceutical facilities. Stage 1 - construction of the 6,000 m2 surface area - is currently completed and required the investments amounting to 10 million euro. At Stage 3, the surface area of the plant will expand to 12,500 m2 and the amount of investments will reach 17 million euro. At that point, the plant will have about 180 employees and the production capacity of 500 million packages a year. This year, the plant will manufacture

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the packages and patient information leaflets for drugs, while the manufacturing of printed foil for blisters is expected to start in early 2018. The production facility will use the materials of foreign and Russian manufactures depending on the requirements of customers. Palladio Group has all the necessary quality certificates covering all plants of the Group. Since the company is specialized in working with the pharmaceutical industry, the manufacturing is organized in accordance with GMP standards. All internal procedures and standards are applied in a uniform way across all plants. In addition, their equipment can be used interchangeably, i.e. the orders of one plant can be fully manufactured at any other plant. The training of local personnel is performed by Serbian and Italian colleagues. The plant is located in the Kaluga Pharmaceutical Cluster, close to major pharmaceutical manufacturers, which will be the first to receive the offers of the plantâ&#x20AC;&#x2122;s services. The expansion of production capacity will extend the geography of product deliveries to other pharmaceutical clusters and regions of Russia.

The Russian plant, which is the sixth for Palladio Group, is also the largest in terms of its surface area and planned output, and this is not just a coincidence. The Serbian side of the founders, namely Mr. Miodrag Babic, the former President of Hemofarm Concern, has been collaborating with Russia for a long time; and he is well aware of great potential of the Russian market, which was evidenced by his successful past relationship with the great Yevgeny M. Primakov and local authorities headed by the Governor of Kaluga region Anatoly D. Artamonov. Both Mr. Babic and the Italian side represented by Marchi family closely follow the developments in the world of pharmaceuticals. They know about the Strategy for the Development of Pharmaceutical Industry until 2020 in the Russian Federation and see their chance in import substitution. The expansion of Russian drug manufacturing sets higher quality requirements not only for the products but also for their packaging. The Obninsk plant will also host a workshop and exhibition center with equipment for serialization.

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The pharmaceutical cluster of the region is one of the most promising in the Russian Federation; today it has 63 participants. Over the past year, the manufacturing of pharmaceutical products increased by 37%. Our goal is to overcome dependence on imports of medicines, and we are successfully moving towards it.

Anatoly Artamonov

Governor of the Kaluga Region

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Sebnem Avsar Tuna Vice President, Novo Nordisk for Russia and CIS

Novo Nordisk

Continues to Invest in Russia 20 August 2017 Source: Vestnik Pharm Evolution 2017 Agency for Regional Development of Kaluga Region arrko.ru

The Novo Nordisk plant is currently manufacturing the entire spectrum of modern insulins in the form of prefilled flexpen injection pens and penfill cartridges, and provides the required supply of such insulins to patients in Russia

Last year, Novo Nordisk and the government of Kaluga Region signed an agreement on implementation of another investment project in the region. What is the essence of this agreement and why was it decided to continue investments in Russia? That is correct. Last year, during the

St. Petersburg International Economic Forum, Kaluga Region’s Governor Anatoly Artamonov and Lars Rebien, who was at that time CEO of Novo Nordisk, signed an agreement on the intention to implement an investment project in Kaluga Region. The document details the parties’ agreement regarding

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construction of a new workshop for assembly of pre-filled FlexPen insulin injectors at the company’s plant in Kaluga Region – another step in the consistent investment policy implemented by Novo Nordisk on the strategically important Russian market. The investment project fully complies with the

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COMPANY DETAILS

MANUFACTURING:

In 2015, Novo Nordisk began manufacturing of modern insulins in Russia at a high-tech plant built from the “zero” cycle at the Grabtsevo industrial park in Kaluga Region.

Secondary packaging of a complete portfolio of modern insulins in Penfill cartridges and pre-filled disposable FlexPen syringe-pens since 2015.   Preparation for manufacturing of finished dosage forms of modern insulins in Penfill cartridges (production of the solution, filling and secondary packaging) in progress: filling line passed validation in 2016.

All manufacturing stages comply with GMP standards and international and Russian requirements to pharmaceutical manufacturing. The project applies energy conservation technologies. In 2016, the company announced the expansion of its investments in the Kaluga plant. Novo Nordisk’s investments in the region are in line with the Pharma-2020 Strategy and significantly contribute to the development of the Russian pharmaceutical industry, assurance of the country’s drug security, introduction of advanced technologies and improvement of the quality of treatment of pancreatic diabetes.

INVESTMENTS:   100 million USD   Plant area – 5 hectares   Total area – 13,000 m2   240 jobs (average employee age – 32)

ADVANCED TECHNOLOGIES:   compliance with international GMP standards, corporate standards and Russian legislation on pharmaceutical manufacturing   application of advance solutions in the field of safety, energy conservation and protection of the environment

Novo Nordisk The production of pharmaceuticals and materials Kaluga Region, Kaluga

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priorities and objectives defined in programs for socio-economic development of Russia, specifically, the objectives of the Strategy for Development of the Russian Pharmaceutical Industry up to 2020. We believe that it greatly contributes to the development of the Russian pharmaceutical sector, and to introduction of advanced technologies and improvement of treatment of pancreatic diabetes. But primarily, the project’s results will have a beneficial effect on the patients’ lives, making Novo Nordisk products more accessible to millions of Russians. What advantages will the new workshop bring to consumers? What products are in the current portfolio of Novo Nordisk’s plant in Kaluga? We want to be sure that we are doing all we can to help our patients, wherever they are. This is why we are here and why we are expanding our project for man-

ufacturing of modern insulins in Russia. The Novo Nordisk plant is currently manufacturing the entire spectrum of modern insulins in the form of pre-filled FlexPen injection pens and Penfill cartridges, and provides the required supply of such insulins to patients in Russia. The equipment for the new workshop has undergone certification and we are currently assembling and installing the filling line. Upon commissioning of the new workshop within the next few years the company will be able to cover the full manufacturing cycle of insulin (except for substances). This means that, in accordance with the Pharma-2020 strategy, there will be deeper localization of manufacturing in Russia of vital contemporary pharmaceuticals that do not have any analogues. If necessary, in the future the capacity of the plant can be further enhanced, and there is potential for export to EEU countries.

Import substitution is an important component of the strategy for development of the Russian pharmaceutical industry. Does this development vector hinder or contribute to the growth of your company? The impulse for localization of manufacturing in Russia comes from the Pharma-2020 program. Import substitution is practiced in many countries apart from Russia. Thus, Denmark implemented a similar program in the middle of the recent century. The main goals of this strategy are to create jobs and import technologies. However, localization of manufacturing generally leads to the locally produced product being more expensive than the imported one due to costs associated with setting up of production, import of source materials and assurance of the required quality standard. The cost of labor is also a very important aspect of the price.

Novo Nordisk The production of pharmaceuticals and materials Kaluga Region, Kaluga

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Novo Nordisk The production of pharmaceuticals and materials Kaluga Region, Kaluga

From the point of view of economy of scale, manufacturing of products in a single place is clearly more profitable and allows the company to offer products worldwide at competitive prices while assuring the highest level of quality. When our management was discussing the Pharma-2020 program with representatives of the Ministry of Industry and Trade at our corporate headquarters, it was said that we were capable of satisfying the Russian demand for insulin by importing it from Denmark, and that the price of the product manufactured in Russia could be higher. Obviously, the import substitution policy, on the one hand, helps the country to create jobs and acquire technologies. But on the other hand, it undermines the competitiveness on the specific market and leads to price increases. What is the scenario for Novo Nordisk’s collaboration with other participants of the Kaluga pharmaceutical cluster, or what should it be? There are two directions for development of Novo Nordisk’s collaboration within the

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pharmaceutical cluster. The first is to develop the system for training of specialists for Kaluga Region’s pharmaceutical industry. The second – collaboration on issues related to the pharmaceutical market, including manufacturing. As a Novo Nordisk manager in Russia and the CIS, how do you assess the business climate created in Kaluga Region, specifically, for implementation of pharmaceutical projects? Establishment of a pharmaceutical manufacturing plant from the “zero” cycle is a very ambitions and complex task even for a global company like Novo Nordisk that has 16 production facilities on 5 continents. I would like to thank the region’s administration and Anatoly Artamonov personally for creating and efficiently operating infrastructure for investment support, for their openness to dialogue, individual approach and expediency in making decisions. For us, as an investor, a constructive dialogue with authorities, transparency and clarity of all procedures, especially when dealing with state and regulatory structures, are very important.

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“The Hardest Period is Over…” JSC Berlin-Pharma has the capacity to manufacture 47 million packages of medication used in cardiology, neurology, gastroenterology and other fields of medicine annually. Our main product lines are Mezim Forte, Curantil and Prostamol Uno. We are planning to launch manufacturing of Siofors (3 products) that are intended for treatment of 2 type diabetes, and we are also preparing for registration of the widely-known bromhexine Berlin-Chemie

Berlin-Pharma The production of basic pharmaceutical products Kaluga, Grabtsevo Industrial Park

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Irina Braginskaya General Director JSC Berlin-Pharma

20 August 2017 Source: Vestnik Pharm Evolution 2017 Agency for Regional Development of Kaluga Region arrko.ru

After three years of JSC Berlin-Pharma’s operation, what specifics have you noted on the Russian market? What contributes to the company’s development and what, if anything, hinders it? Berlin-Pharma’s plant at the Grabtsevo industrial park is the first facility established by the Berlin-Chemie/Menarini international group in Russia. Today, it is a high-tech complex for manufacturing, control, and storage of pharmaceutical drugs. The company complies with GMP safety standards and has the capacity to manufacture 47 million packages of medication used in cardiology, neurology, gastroenterology and other fields of medicine annually. In the three years of its operation, Berlin-Pharma has been consistently and reliably manufacturing pharmaceutical products that are supplied to the Russian market. We have reg-

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istered 8 products so far, with 8 more undergoing registration with the Russian Ministry of Healthcare. What contributes to our development is the planning and support Berlin-Chemie/Menarini’s efforts to localize manufacturing in Russia. There is a lot of support from the administration of Kaluga Region, agencies for regional and innovation development on all stages of implementation of our investment project, with precise compliance with contractual obligations on their part. As for hindering factors – I guess “hinder” is not exactly the right word, but what prevents us from developing faster is the very lengthy registration procedure – around 2 years for one product. Naturally, we launch parallel projects. Last year, we obtained several registration certificates for full-cycle production.

What key products does Berlin-Pharma currently manufacture for the Russian market? Are you planning to expand the product portfolio or increase production volumes? Berlin-Chemie/Menarini products are well-known in Russia. They have long earned the trust of healthcare specialists and patients. The company has already registered more than 100 pharmaceutical drugs in Russia, in over 10 therapeutic categories. The concern always reacts quickly to Russian market demands and is invariably among the top three major manufacturers of pharmaceuticals that are of continuous demand in Russia. The Russian pharmaceutical market is extremely attractive. We carefully monitor all trends in the pharmaceutical industry, and strictly comply with the Russian government’s policy in the field of supply of Russian citizens with high-quality

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Berlin-Pharma The production of basic pharmaceutical products Kaluga, Grabtsevo Industrial Park

and affordable medicinal products. I am confident that Kaluga’s pharmaceutical cluster will be moving towards maximum substitution of imports and localization of pharmaceutical drug manufacturing. Our main product lines today are Mezim Forte, Curantil, and Prostamol Uno. We are planning to launch manufacturing of Siofors (3 products) that are intended for treatment of 2 type diabetes, and are preparing for registration of the widely-known Bromhexine Berlin-Chemie. We are planning to increase production volume, primarily, by expanding the product range, but also by expanding the market. Thus, we are considering the possibilities for exporting products to countries of the Eurasian Economic Union. What were the company’s results for 2016 and what are its plans for this year? In 2016, Berlin-Pharma manufactured and sold more than 28 million

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packages of finished pharmaceutical drugs. This was done in a single-shift mode, i.e. far from our full production capacity. The hardest period is over. It was the time when the plant was already built and equipment installed, but it could not begin production due to lengthy procedures for production licensing and registration of pharmaceutical products. We are now working with stability, and in 2.5 years have overcome the start-up period (inevitable for all new plants) when our costs were higher than our revenues, and managed to cover losses for 2013-2014. Berlin-Pharma has a cooperation project with Merz. What is the nature of this project? How is it developing? It is too early to speak about the project. I can only say that 3 innovation products that will be manufactured in Kaluga

are currently on the registration stage. Are there any partnership collaborations within the cluster? How do you think such cooperation should develop? So far, partnerships mostly relate to organizational issues. But there is practical assistance as well – in the form of resource training. We are currently considering collaboration in manufacturing as well. We were approached by an Obninsk-based Russian company regarding packaging of their pills in aluminium blisters. We have the technical capability to do that, and can help. However, such a project can only be implemented after appropriate registration with the Russian Ministry of Healthcare, so it’s a long-term prospect. I would say that at this point we are operating rather autonomously, but I do not exclude partnerships of any format. At least we are prepared for them on our part.

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COMPANY DETAILS JSC Berlin-Pharma is part of Menarini Group â&#x20AC;&#x201C; a major European pharmaceutical conglomerate. The group operates 9 pharmaceutical plants in different countries. Berlin-Chemie AG joined the group in 1992. Strategic goals of the consolidated Berlin-Chemie AG/A.Menarini are innovative research and internationalization of the healthcare market. The group has an impressive portfolio of products developed using its own resources, and a high potential for establishment of reliable partnerships with other pharmaceutical companies. In 2010, Berlin-Chemie AG/A.Menarini began the implementation of a major investment project to build a pharmaceutical plant in Kaluga Region. The project includes a plant for full-cycle production of non-sterile dosage forms, and office, laboratory, and warehouse complex. The total amount of investments is in excess 40 million euro. In February 2016, Kaluga Region and JSC Berlin-Pharma signed an agreement on implementation of the second phase of the Berlin-Chemie AG/A.Menarini investment project. The subject of the agreement is the construction of a logistics complex that will include warehouse and distribution centers. The complex will comply with global GDP (Good Distribution Practice) standards and will continue the pharmaceutical conglomerate's project for localization of manufacturing. Construction of a warehouse center next to the plant will create a highly efficient integrated logistics and production complex.

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In Line

with the Latest Technological Trends The Collost technology is implemented in the newly developed line of medical products for bone tissue regeneration

COMPANY DETAILS Nearmedic Pharma, the pharmaceutical company of state corporation Nearmedic, began operations at Obninsk industrial park in 2015. The area of the plant built with a 4-billion-ruble investment is 22,000 m2. Its capacity is up to 100 million packages of pharmaceutical drugs per year. The plant complies with GMP, ISO, and FDA requirements. The unique facility embraces the entire production cycle – from synthesis of primary substances to manufacturing of finished products. The entire line of the plant’s output is composed of proprietary products. Nearmedic’s portfolio includes nearly 20 products.

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Roman Bolgarin Project Development Director of NEARMEDIC PLUS LLC

20 August 2017 Source: Vestnik Pharm Evolution 2017 Agency for Regional Development of Kaluga Region arrko.ru

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Apart from finished pharmaceuticals, Nearmedic also manufactures medical products. What does the companyâ&#x20AC;&#x2122;s product portfolio include today? According to data provided by the IMS Health data analysis company, the Nearmedic Plus manufactured antiviral medication Kagocel has been holding the lead in sales (in natural volumes) for four years in a row. The drug is a three-time laureate of the Russian Pharma Awards (in 2014, 2015 and 2016) of Russiaâ&#x20AC;&#x2122;s practicing physicians, and was the winner of the international Green Cross pharmacistsâ&#x20AC;&#x2122; award in 2015. Growth in Kagocel sales volumes indicates that the drug has gained recognition not only among the specialists, but patients as well. The Nearmedic Group is currently introducing its range of type 1 native collagen-based medical products, Collost, to the Russian and international markets. Due to their unique qualities of a bio-resorbable implant with a retained native structure, this range of medical products has broad application in various fields of surgery, stomatology, and cosmetology. Collost products are used as a biode-

gradable material to fill up bone defects, for contour correction of soft tissue, and for securing non-infected wound surfaces. Applies to Nearmedic's products that are already known in Russia and abroad. As any other company that strives to develop and expand its horizons, we are also actively developing and introducing new pharmaceutical drugs, molecular and genetic test systems, medical products, and biomedical technologies in our own production and clinical practices. Thus, the mentioned Collost technology is implemented in the newly developed line of medical products for bone tissue regeneration. Original methods underlying these products allow us to produce bone implants with a high level of safety and efficiency in comparison with available analogues, and they will be used in surgical stomatology, orthodontics, traumatology, and orthopedics. In 2015, the company won a competition for support from the Industrial Development Funds. What pharmaceuticals and technologies participated in the competition?

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Nearmedic Pharma The production of basic pharmaceutical products Kaluga region, Borovsky district, Malan'ino

It was not exactly a competition. Companies submitted bids that were submitted to technological, industrial, and financial expert assessment, based on which a decision was made on whether to grant them loans. This is what happened with our project for creation of Russia’s first full-cycle production facility for manufacturing of agents used for personal identification and establish kinship. The project is currently at the stage of establishment of the production line at the Nearmedic Pharma plant in Obninsk. Is your company involved in any collaboration within the pharma cluster? Kaluga’s pharmaceutical cluster is a great example for formation and development of a classic-model cluster, which consolidates small, medium, and large research and production companies allowing the creation of a complete value chain within a single region. In other words, the pharmaceutical cluster is, first and foremost, a highly efficient cooperation network for all its participants. Several of our projects, including the project

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for introduction of the newest anti-tuberculosis drug, are implemented with participation of research and production companies that represent Obninsk’s small and medium businesses. We are actively collaborating with Kaluga Region’s leading medical centers on projects for introduction of advanced diagnostic test systems for socially significant diseases. Apart from that, Nearmedic Group is involved in governmental programs for development of regional and industrial clusters and collaborates with other cluster participant on R&D and production issues. In February 2017, two new Nearmedic representatives jointed the Kaluga pharmaceutical cluster: Nearmedic Pharma - the group’s production complex in Obninsk, and project company JoinTechCell. So, we are continuing to expand our cooperation. Can you say a few words about your long-term developments? As I have already said, the group’s project company JoinTechCell has become part of Kaluga’s pharmaceutical cluster. It intends to shortly introduce a

new medical product – a separator and centrifuge-shaker system for extraction of stromal-vascular fractions (SVF) from fatty tissue. The resulting product (set) will be sort of a mobile laboratory, convenient and easy to use. Throughout the world, cellular technologies in regenerative medicine aare a rapidly growing direction. SVF have been successfully used in treatment of all types of skin damage (burns, trophic ulcers), urogenital diseases, for restoration of damaged ligaments and articular cartilage (ruptures and fractures), as well as for enhancement of efficiency of traditional treatment methods, and improvement of the quality of life. SVF are used for treatment of diseases, for which there are no known effective methods of therapy, or when possibilities for therapy are limited. By advancing in this direction, Nearmedic follows its previously chosen development strategy: to be in line with the latest technological trends and to bring its own new products to the market that have to become brand names in their respective fields.

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The Kaluga Plant is Aiming for Full-Cycle Production The international Randstad Award 2016 named AstraZeneca the best employer in the healthcare industry in Russia.

Irina Panarina General Director of AstraZeneca Russia and Eurasia

20 August 2017 Source: Vestnik Pharm Evolution 2017 Agency for Regional Development of Kaluga Region arrko.ru

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he year 2016 was rather successful for AstraZeneca. According to our estimates, the companyâ&#x20AC;&#x2122;s growth in Russia was over 10% (in rubles). This is a good result, considering that many companies had no growth, or registered declines. Overall however, the figure is quite modest. In September, we introduced a pharmaceutical drug for treatment of ovarian carcinoma to the Russian market. This is one of the most common types of cancer with the highest mortality rate among all patients with oncological diseases of the female reproductive system â&#x20AC;&#x201C; not only in Russia, but worldwide. Also, in November of last year, we partnered with other pharmaceutical companies in signing of a memorandum on cooperation in the field of immuno-oncology with the Russian Society of Clinical Oncology. For 2017, we are planning to prepare our plant in Kaluga for full-cycle production. We are also planning to introduce two more pharmaceuticals to the Russian market: one is for treatment of lung cancer, the other is for treatment of type 2 diabetes. These are innovative drugs, which, I am certain, will help many Russian patients. We will also continue

our collaboration with the Skolkovo biomedical cluster; we are currently considering three potentially interesting molecules for application in oncology. We are always happy to support Russian science. Marking of pharmaceuticals is one of the most important projects that we are expecting to be implemented in 2017. I am happy to say that AstraZeneca is an official participant of the marking project. We believe this to be a very significant effort to counteract counterfeiting. This initiative raises the issue of the price of pharmaceuticals. We believe that if mandatory marking requirements are harmonized with European ones, this will not affect the cost of our products. Of course, market prices are formed by different parties, including distributors and pharmacies. But we will not be raising our prices. One of our areas of interest is investment contracts. We have moved forward from being interested in the matter to action. AstraZeneca submitted all documents required for execution of a special investment contract in November 2016. Under the special investment contract, we are offering manufacturing localization for several innovation drugs at our plant in Kaluga with investments of over 1 billion rubles. I hope the contract will be signed in 2017.

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1 (1) / autumn 2017 Интересы производителей Modernization & Localization

GEROPHARM: Insulin Market Imports Phase-Out 4 September 2017 Press Service of «GEROPHARM»

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was four years ago when GEROPHARM-Bio opened its manufacture, the only Russian full-cycle insulin production, supplying all types of products, from APIs to finished dosage form. Today the plant covers almost one third of the Russian demand for these vital products. After the second production line for genetically modified insulin API and analog insulin is put into operation in 2018, GEROPHARM will be able to fully cover demand for insulin in Russia. Dominant pharmaceutical market trends in 2016 are fuelled by the consistent implementation of federal import phase-out policy, according to the PHARMA-2020 program. Local manufac-

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turer products have been gaining larger share due to changes in regulation introduced in the past few years with aim to promote pharmaceutical industry, allowing domestic companies access to government contracts. The depth of localization is important: economic efficiency of GEROPHARM localized production will allow to cut finished product prices, helping to lower the cost of government contracts for insulin for the budget.

NATIONAL MANUFACTURER Today, the company supplies the market with Rinsuli® R and Rinsulin® NPH, high quality, efficient, and safe products, in all modern pharmaceutical forms: vials, cartridges, and injector

pens. Economic effectiveness of the technology gives Rinsulin products competitive advantage of lower prices compared to similar Western products of the same quality. Under federal contracts, the products are now supplied to most Russian regions, including the largest, such as Moscow, St. Petersburg, Moscow and Leningrad Regions, the Republics of Tatarstan, Bashkortostan, Khakasia, etc. In 2015, the company completed the project to increase the output of GM insulin products via a technology upgrade. Rinsulin API quality is confirmed by independent certified EU laboratories, such as Proteome Factory AG Berlin, Prolytic GmbH Frankfurt am Main, Labor L+S AG, and found to be in compliance with the relevant requirements

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of BP and USP. According to the requirements, maximum acceptable protein contaminant content in insulin API is no more than 2%. GEROPHARM insulin API contains about 1% of such contaminants, i.e., half of this limit.

IN ACCORDANCE WITH GMP GEROPHARM-Bio plant employs a Pharmaceutical Quality System based on two standards, namely GMP, and ISO 9001 Quality Management System. In 2015, the plant was inspected by the Russian Ministry of Industry and Trade and found it compliant with GMP. Another large-scale project by GEROPHARM Group, currently in progress, involves construction of a pharmaceutical plant in Pushkinskaya industrial zone. In 2018, the plant will launch full-cycle insulin and insulin analog production, as well as derivative APIs and medicinal products, with localization

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unparalleled in the Russian Federation. The launch of the new plant will help to satisfy demand of the Russian public health system for medical therapy of socially critical conditions prevalent in disease distribution in Russia, including diabetes, and to ensure Russian insulin market independence of foreign APIs, and to saturate the market with modern domestic high-efficiency products, demonstrating competitive high quality and lower prices compared to foreign analogs.

SCIENTIFIC INNOVATION FOR BETTER QUALITY OF LIFE Completion of the pharmaceutical plant investment project will make GEROPHARM Group one of the first companies in the world to market a complete range of insulin analogs, including

glargine, a top 10 global blockbuster product. The products are currently being developed in-house in a world-class R&D center in Strelna according to the highest international standards, ensuring high export potential of the project. All R&D in GEROPHARM is based on the cutting-edge know-how and recommendations, such as EMA and FDA guidance, building on the global best practices. Until recently, GEROPHARM was focused mostly on the domestic market. Today however, it starts a new era of export-oriented import phaseout, a time to build foundation for the manufacture of products with high export potential. Domestic production of vital medicinal products is currently among the priority federal projects targeted to ensure medicinal safety in the country. Import phase-out projects by GEROPHARM fall in line with the general federal policy for pharmaceutical development until 2020.

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1 (1) / autumn 2017 Интересы производителей Manufacturing & Localization

PJSC Biokhimik Will Provide Russia with Innovative Antibiotics PJSC Biokhimik is one the major pharmaceutical production companies in Russia, as well as one of the leading industrial enterprises of the Republic of Mordovia. The plant was founded back in 1959 under the decision of the the USSR Government, and since then has obtained great experience in pharmaceutical production with the emphasis on antibiotics. Nowadays the company is under process of the global modernization: it is enlarging its production capacity, reconstructing old production buildings – equipping them with modern production facilities.

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4 September 2017

ublic Joint Stock Company Biokhimik has for a long time been fulfilling key tasks on a national level, providing the country with safe antibiotic production. It is worth mentioning that as far back as the middle of the previous century, up to 80% percent of the patients in surgery died because of the staphylococcus and streptococcus infection contamination. And it was Biokhimik that produced the first Soviet penicillin which helped solve the problem. But in the 90s, the once legendary enterprise became degraded: the amount of customers reduced dramatically – as well as the working week hours. By the 2000s, the very existence of the plant was endangered. In 2015, PJSC Biokhimik got a new owner – Promomed Ltd. The managing company launched the full-scale

reconstruction and modernization process of the legendary enterprise. PJSC Biokhimik got a second chance; today it is a dynamically developing enterprise that is successfully participating in the innovation development programs. Today, the PJSC Biokhimik’s volume of production has increased by 162%, as compared to 2015; labor productivity has increased by 25.5%, and the export index – by 10%. The laboratory basis has enlarged, new personnel has been recruited. For the last two years, more than 5,000 m2 of the enterprise production facilities have been reconstructed and relaunched; the plant replaced 60% of its out-of-date equipment with new. A new factory shop was launched with a production capacity up to 400 million tablets a year. A department that specializes in gel and ointment production

is also under reconstruction. Launching the department that produces intracapsular drugs will be able to increase volume of production up to five times. It is also worth mentioning that a twolevel 16,000 m2 factory shop which is going to produce liquid pharmaceuticals is under construction now. It will include two lines of ampoule bottling with annual production capacity of 170 million; a division of nasal sprays’ production with capacity up to 5 million bottles per annum. All production shops are built strictly in accordance with the GMP criteria. PJSC Biokhimik’s key specialization is the production of antibiotics. But the enterprise’s production portfolio also includes anti-cancer, plasma-replacing preparations, as well as antiseptic, cardiovascular, antiviral pharmaceuticals, and tissues’ reparation stimulators.

Pharmaceutical manufacturing at PJSC Biokhimik

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Today PJSC Biokhimik produces more than 100 pharmaceutical labels within the range of the whole spectrum of forms, including injections, tablets, ampoules, ointments, gels, and bougies. More than 70% of its production is included in the National Medicines’ List of Vital Importance. Several months ago, the enterprise started building factory shop where the R&D laboratory will be located – as well as departments for chemical and microbiological synthesis of active pharmaceutical substances. It is right here where the innovative preparations will be created. The project’s second phase will include equipment adjustment & launching period, and personnel training. The project is to be concluded by the Q4 of 2017 – Q1 of 2018. Modern equipment has already been bought in Switzerland, Germany, and Italy. The total investments in the project are up to 550 million rubles (approx. 9.3 million dollars).

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In December 2016, the Minister of Health of Russian Federation Mrs. Veronika Skvortsova visited PJSC Biokhimik in the framework of her business trip to Mordovia. It was in her presence that the plant’s top managers signed a triple agreement that envisaged creating the pilot Russian Antibiotic Scientific & Production Center (SPC) on creating new antibiotic forms in Saransk city (the capital of Mordovia Republic – editor). The project office of the Antibiotic SPC is working to its utmost: personnel is recruited; lab and experimental & industrial period of producing first substances is concluded. The scientific base for the project is provided by Mordovia State University, and the production facilities are provided by PJSC Biokhimik. The RF Minister of Health Mrs. Veronika Skvortsova pointed out that Antibiotic SPC was to become the leading national production base for producing

antibiotics of the last generation. In his turn, the Head of Mordovia Republic Mr. Vladimir Volkov stressed the fact that the project is of strategic importance for the whole country and for the republic, that’s why the Government of the Republic of Mordovia became its third fullfledged participant. The Antibiotic SPC concept envisages the utmost combination of the high scientific level, perfect management skills that provide making quick and non-standard decisions, serious investments, and unique personnel qualification. It is worth mentioning that highly qualified personnel have always been a problem. But not for PJSC Biokhimik. The enterprise manages to solve the issue: students of the Mordovia Ogarev State University undergo probation period at the enterprise labs. Every year, the best trainees get higher personal scholarships from PJSC Biokhimik. After gradu-

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Minister of Healthcare of the Russian Federation visited the Biokhimik plant, December 2016

ating, they have the priority in getting job at the Antibiotic SPC, as well as at PJSC Biokhimik. The effective personnel and strategic politics has already yielded fruit. On August 4th, 2017 the Head of the Republic of Mordovia Mr. Vladimir Volkov was presented by the bottle No. 1 series No. 1 of the Vankomitzin antibiotic substance: the brand, from idea to a ready form, was worked out at the Antibiotic SPC. The preparation has a wide spectrum of application. Recently, Mr. Volkov presented the experimental sample to RF President Mr. Vladimir Putin. President forwarded his congratulations and gratitude to the SPC Antibiotic team. By the end of 2017, Antibiotic SPC is to launch on the basis of PJSC Biokhimik no less than four antibiotic substances. In the next three years, up to 20 new antibiotics of the 4th and 5th generations are to be launched. At present, in collaboration with Gause Scientific and Research Institute, Antibiotic SPC is busy working on several new last generation antibiotic brands;

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the partners also intend to start joint research on INA-5812 original lipoglycopeptide preparation. These antibiotics are to be used for curing tuberculosis, pneumonia, soft tissues and bones infections etc. Today PJSC Biokhimik is the only full-cycle enterprise in Russia that produces antibiotics – from an idea, substance production to a ready pharmaceutical form. Such approach makes sense economically: it is cheaper to use own raw materials; that is why PJSC Biokhimik medicines will be cheaper for the consumers in Russia. And, of course, the development of the enterprise, its innovative specialization will help to create new jobs at PJSC Biokhimik. And this is very important for the Republic of Mordovia. Today, a lot of contractors and potential partners are interested in building co-operation with PJSC Biokhimik. The enterprises’s list of offers is quite wide - from tablet, ampoule, and packing production to leasing plant facilities. Active and stable business ties have

been connecting PJSC Biokhimik with a whole range of companies in the field of tablet, ampoule, and packing production. After modernization period is over, the enterprise is to become a powerful contracting site. In its nearest plans is building co-operation not only with Russian companies, but with foreign ones as well; for instance, preliminary agreement was reached with partners from Iran and Africa. It is also possible that the plant will sign contracts on chemical and biological synthesis of substances. For the last year, the PJSC Biokhimik’s production export was 134 million rubles (approx. 2.7 million dollars). The company plans to seriously increase this figure. Pharmaceuticals that are produced by PJSC Biokhimik are now registered in Russia, In the CIS countries, and far abroad. The enterprise has been successfully co-operating with Kazakhstan, Kyrgyzia, Azerbaidjan, Uzbekistan, and Georgia. New markets – Armenia and Vietnam - are actively being developed, at the moment. Talks are held to export PJSC Biokhimik’s

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1 (1) / autumn 2017 production to Iran, Africa, and Yemen. As a matter of fact, the plant is co-operating with all the continents. The company has got ambitious plans – to launch approximately 170 new preparations in the near future. Major part of this future production will be antibiotics, and it is anticipated that production capacity of the enterprise will be increased three times. It is no secret that resistance towards antibiotic therapy has become a serious problem today. At the same time, it is also well known that quite often doctors are using out-of-date preparations. According to scientific research, economic damage from infection diseases in Russia in 2015 was 549 billion rubles (approx. 9 billion dollars). And the major part of all sick-lists goes for flu-like infections. Every fourth patient in Russia with pneumonia can’t be treated with antibiotic therapy – despite the fact that the annual growth of community-acquired form of pneumonia in 2015 was 24%. Besides that, Russia is also known for its high spread of a medicine-stable tuberculosis. PJSC Biokhimik believes its mission is providing Russia with the most modern pharmaceutical preparations, thus saving the country’s citizen from these dangers.

THE TASK According to the scientists’ prognosis, by 2050 about 10 million people will die annually from infections caused by resistant bacteria; and mortality from infection diseases will be higher than oncology death-rate. That is why production of the last generation antibiotics is considered the most important task for both Russian and foreign pharmaceutical industry.

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Servier Manufacturing Plant in Russia

ViiV Healthcare Localized the Manufacture of Dolutegravir in Russia 130

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16 August 2017

hree registration batches of dolutegravir, which were manufactured at Servier’s Russian manufacturing site (located in Moscow, until 2017 known as Serdix Pharmaceutical Plant of Servier Group), successfully passed stability tests and comparative tests of the dissolution kinetics. An updated dossier specifying the new Russian manufacturer was submitted to the Ministry of Health of Russia in order to introduce changes to the registration certificate.

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ViiV Healthcare successfully completed its project for technology transfer and localization of manufacture of the antiretroviral drug dolutegravir in Russia The localization project was designed to achieve a single-stage launch of a full manufacturing cycle (manufacture of a finished dosage form), without any intermediate stages, such as secondary packaging. Transfer of manufacturing technology and analytical procedures that was performed in 2016, now allows an appropriate control of manufacturing operations and quality. The substance manufacturing site Shionogi (Tokushima, Japan) has successfully passed a GMP inspection by Russian authorities.

According to estimates of the Ministry of Health of Russia, the epidemiological situation with HIV infection in Russia still remains unfavorable. According to the data of State Strategy to Combat the Spread of HIV in Russia through 2020 and beyond, since 2006 there was observed an annual increase in the number of new HIV cases of 10% on average. In 2016, the number of registered patients (i.e. patients with confirmed diagnosis) grew by 13% vs year 2015, and exceeded 658,000 persons. A greater coverage with t herapy is a key

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element of the strategy for improving the situation. Developed by ViiV Healthcare, dolutegravir is intended to be used for HIV treatment in combination with other

standing between the drug developer ViiV Healthcare and the Russian pharmaceutical manufacturer JSC Servier was signed in May 2016 in the presence of the Mayor of Moscow Mr. S. S. Sobyanin.

“The united team of ViiV Healthcare, GSK, and Servier has successfully completed another critical step of our largescale project of dolutegravir production localization in Russia. We exert every effort to make dolutegravir, recognized by the World Health Organization to be a significant progress in HIV treatment, available to Russian patients as soon as possible,” says Alexander Sokolov, General Director of ViiV Healthcare LLC.

antiretroviral drugs. The drug was approved for use in Russia in 2014. In 2015, ViiV Healthcare decided that a full cycle manufacture of the drug (i.e. manufacture of a finished dosage form) should be launched in Russia. Supported by the Government of Moscow, a memorandum of under-

The first pilot and registration batches of the drug were produced at the plant as early as September 2016. Currently, positive stability data are available, which were collected using the accelerated aging method, as well as the successful results of the comparative tests of the dissolution kinetics,

which confirm that the drug is identical to the control batches manufactured in the United Kingdom. An updated registration dossier specifying the new Russian manufacturer was submitted to the Ministry of Health of Russia. Dolutegravir proved to be efficient and safe in international multicenter clinical trials involving 16 Russian clinical sites. The trials demonstrated a rapid decrease in viral load, statistically higher virologic efficacy and a high resistance profile. The drug was included in the antiretroviral therapy recommended by the World Health Organization (WHO) and Russian and international clinical guidelines, and it is also included in the WHO Essential Medicines List; there is a successful experience of its use in Russia. The cost of a monthly treatment course, as offered by the manufacturer in Russia, is significantly lower than that of some other drugs used as a second line, or a third line HIV therapy, that, according to the company’s estimates, entails efficient spending of funds allocated for procurement of HIV drugs and considerable savings for the budget allowing further expansion of the coverage of HIV-positive persons with a modern and affordable therapy.

DOLUTEGRAVIR AND DAWNING STUDY DAWNING is a non-inferiority study conducted to compare second-line treatment of the protease inhibitor-sparing regimen of dolutegravir and 2 nucleoside reverse transcriptase inhibitors (NRTIs), with a current WHO-recommended regimen of lopinavir/ritonavir and 2 NRTIs in HIV1-infected adults. Results are being presented at the International AIDS Society congress in Paris. The study’s Independent Data Monitoring Committee (IDMC) noted significant and clinically-relevant differences between treatment arms in favour of dolutegravir and recommended that the boosted lopinavir treatment arm be discontinued. Participants receiving lopinavir/ritonavir were offered the opportunity to switch to a regimen with dolutegravir as the core agent, if considered appropriate by the investigator.

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Contract R&D Market is Developing in Russia NovaMedica has launched its R&D Center for development of new drug products in Moscow. The Center is going to become attractive R&D site for customized developments and contract manufacturing.

19 April 2017

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Sergei Sobyanin, Moscow Mayor, and Anatoly Chubais, Chairman of the Executive Board of the Managing Company Rusnano, took part in the Technology Center Opening Ceremony.

ovaMedica LLC, which was established in 2012 by Rusnano, Russian state corporation, and Domain Association, American venture capital foundation, opened its Technology Center for development and pilot production of innovative drug products in Moscow. It consists of an R&D laboratory and manufacturing areas with technological capabilities unique to the Russian pharmaceutical industry, and one of the best in Europe. The Center will prompt the locally-developed innovative drugs and drug formulations in solid forms for oral administration. The therapeutic areas including those to treat cardiovascular and gastroenterological diseases, central nervous system diseases as well as analgesics of the new generation will be developed. Sergei Sobyanin, Moscow Mayor, Anatoly Chubais, Chairman of the Executive Board of Rusnano Corporation, Oleg Bocharov, Deputy Minister of the Ministry of Industry and Trade, and others took part in the opening ceremony.

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Opening of such an R&D center in Moscow creates prospects for localization of drug products in Russia, which were extremely complicated and impossible to develop and manufacture in Russia earlier. Partnership with NovaMedica can be especially useful for localization in Russia of advanced solid forms having manufacturing peculiarities. Capacity of the R&D Laboratory and manufacturing areas is sufficient to meet both NovaMedica needs regarding implementation of own R&D projects, and to improve contract developments and manufacturing for customized projects. R&D Laboratory, as a part of the newly created complex, can support transfer of technologies and analytical methods during contract manufacturing.

R&D Laboratory of the Technology Center is already working on five projects of development program of NovaMedica. Four more projects will start during the year. These are drugs developed on innovative delivery platform ensuring improved bioavailability, or compatibility of active ingredients. Thanks to acquired functional properties, unique characteristics, and high quality of the produced drug products the Patients will benefit from more effective and safe medicines compared to equivalents that exist on the market. NovaMedica plans to develop scientific cooperation with the leading Russian and foreign pharmaceutical companies, scientific and technology centers, universities, and start-ups.

ABOUT COMPANY NovaMedica is a modern Russian pharmaceutical company founded in 2012 by Domain Associates LLC, leading U.S. venture capital firm, and RUSNANO, JSC (RUSNANO controls 50% of NovaMedica shares through the venture fund RusnanoMedInvest). NovaMedica's strategy is aimed at search, registration and localization in Russia of intellectual property rights for innovative pharmaceuticals products and technologies, as well as at development and implementation of own R&D projects. NovaMedica owns intellectual property rights within Russia and the CIS on innovative developments from the portfolio of the RusnanoMedInvest venture fund. Today NovaMedica’s pipeline already has 36 IP for preparations for antiviral and anti-inflammatory therapy, treatment of ophthalmic diseases and epilepsy, innovative technologies for detection of oncological and infectious diseases. Also, NovaMedica is working on creation of a number of its own products. R&D department of the company plans to develop about 15 innovative drugs until 2022. These are drugs for treatment of diseases in the field of gastroenterology, pain management, neurology, ophthalmology, and rheumatology.

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Today we are launching a facility, which without exaggeration can be associated with â&#x20AC;&#x153;Big Pharmaâ&#x20AC;?. State-of-theart equipment is installed here and this allows us to perform researches on the level previously unobtainable in Russia. Drug products to be produced here are developed by the major international producers. However, the fundamental difference of NovaMedica is that we are not going to produce just generics as many do, the Laboratory complex allows us to carry our own developments. In particular, I would like to note the role of the Moscow authorities. It would be much more complicated for us without their support and without the infrastructure complex created in the Technopolis.

Anatoly Chubais Chairman of the Executive Board of the Managing Company RUSNANO

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Russian Pharmaceutical Map Has a New Point of Convergence

The following people participated in the groundbreaking ceremony of NovaMedica plant (L-R): Sergey Tsyb, Deputy Minister of the MIT, Anatoly Chubais, Chairman of the Executive Board of the Managing Company Rusnano, Petra Danielsohn-Weil, Pfizer top-manager, Anatoly Artamonov, Governor of the Kaluga Region and Alexander Kuzin, General Director of NovaMedica.

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An interesting international pharmaceutical project has started in Russia. This project is a result of a convergence of interests of Rusnano, Russian state investment corporation, Domain Associates, an American venture capital foundation, and Pfizer, an American pharmaceutical corporation.

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30 May 2017

ovaMedica, pharmaceutical company established in 2012 by Rusnano JSC and Domain foundation, announced start of construction of the plant for sterile injectable manufacturing. Key partner and investor for this project is Pfizer – global pharmaceutical giant intends to localize about 30 EDL products at NovaMedica manufacturing site. Proprietary R&D products of NovaMedica will be manufactured at this plant as well. Moreover, there is a possibility to attract to the project other potential partners in order to localize complex injectable dosage forms. The plant will be constructed in the Industrial Park Vorsino in the Kaluga region which was recognized as the most attractive region for investors in Russia. The to-be-constructed plant will become the part of the Kaluga pharmaceutical cluster – the most powerful in the number of pharmaceutical production facilities and their manufacturing capacities in Russia. It includes facilities, which localize products for Big Phar-

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ma to serve the growing Russian market, such as AstaZeneca, Berlin-Chemie, NovoNordisk, Stada. NovaMedica plant will meet requirements of not only Russian, but also European and Eurasian Good Manufacturing Practice (GMP) for medical products, which together with world-class capabilities should bring high-quality products to Russian market. The launch of construction works was announced by Anatoly Chubais, the Chairman of the Management Board of Rusnano, Anatoly Artamonov, Governor of the Kaluga Region, Sergey Tsyb, Deputy Minister of the Ministry of Industry and Trade, Petra Danielsohn-Weil, Regional Head Europe Pfizer Essential Health, Leonid Melamed, Chairman of the Board of Directors of RMI Partners, Managing Company of NovaMedica, and others. Symbolic ceremony of construction start was an impressive, spectacular and unusual event. Distinguished guests took hand trowels and added stones into the missing puzzles of a mosaic which was made in the form of NovaMedica logo by local Vorsino craftsmen.

The engineering contractor firm “M+W Group” creates conceptual design of the plant. “M+W Group” is one of the global leaders in the market of the design, engineering and construction of high tech facilities and major complex projects. The plant has a projected capacity of more than 38.5 million units per year. The total area covered by production and auxiliary buildings and structures will be about 23,000 m2. The manufacturing facilities will be equipped with production lines assembled by the leading European manufacturers: Bosch, Ziel, GEA-lyophyl, Bausch+Ströbel, Belimed, Seidenader, Optima, Mediseal, Uhlmann, and others. The production facility will be represented by area for production of sterile injectable forms: lyophilizates and solutions in vials. There is also a possibility of further expansion of production for demanded forms of injectable products. The facility design includes creation of isolated blocks for production of standard and cytotoxic drugs. Construction of the plant is expected to be completed in 2020.

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Anatoly Chubais Anatoly Artamonov Governor of the Kaluga Region

“The pharmaceutical industry of the Kaluga region is the most dynamically developing direction in the regional economy. The cluster of pharmaceuticals, biotechnology and biomedicine, created six years ago, today unites 63 participants, has a “bronze status” of the best European cluster practices, is one of the pilot innovative territorial clusters. Enterprises located here produce more than 140 medicines and pharmaceutical substances. We relate further development with increased competitiveness of these products and expansion of its range. In this sense, plans of the NovaMedica company coincide with ours. It is planned to produce those medicines that are not produced yet at the to-be-created production site. We wish the company good speed in implementing of the project. For its part the region is ready to provide partners with the necessary assistance”.

Chairman of the Executive Board of MC “RUSNANO” and Chairman of the Board of Directors of NovaMedica

“NovaMedica is rapidly developing: in April 2017, the Technological Center with R&D laboratories and pilot production was launched, where innovative dosage forms are already being developed. A little more than a month has passed and we are opening a new page – we are launching the construction of the GMP plant in partnership with the giant of the world pharmaceutical industry, Pfizer. Moreover, the work on the creation of this plant is being carried out literally since the signing of the partnership agreement. On the part of Pfizer professionals with the vast experience from different countries of the world joined the project, so that the plant was designed flawlessly from all points of view. This joint work has already given the team of NovaMedica invaluable experience, and we obtained confidence that the project will be implemented successfully and with great efficiency”.

Petra Danielson-Vale Alexander Kuzin General Director of NovaMedica

“The start of construction of the plant is an important stage in the consistent strategy of NovaMedica to localize innovative products and technologies in Russia. This project would not be possible without conditions created by the state for the development of our industry. We thank the creators of the “Pharma 2020” program – the Ministry of Industry and Trade, as well as the Ministry of Health, and our shareholders: Rusnano and Domain Associates – for the consistent support, which helps to think on the large scale, build ambitious and long-term plans, and confidently implement them. We are grateful to our shareholders for the powerful intellectual contribution and comprehensive support motivating the team of NovaMedica for a breakthrough development. And, of course, we are inspired by the prospect of obtaining a unique experience in the process of working together with the leader of the world pharmaceutical industry, Pfizer”.

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Regional Head Europe Pfizer Essential Health and member of the Board of Directors of NovaMedica

“We are pleased with the new stage of our partnership with NovaMedica, which is aimed at providing Russian patients with access to locally produced high-quality vital drugs. It is important to note not only our joint efforts, but also the support we receive from the Kaluga Region Government in the implementation of the project. The upcoming stage is the construction of the modern production complex of NovaMedica, to which Pfizer will transfer production technologies of more than 30 sterile injectable products from the company's portfolio”.

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1 (1) / autumn 2017 Интересы производителей Modernization & Localization

Immunobiology:

From Modernization to International Cooperation 31 August 2017

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or a number of years the Russian authorities have paid close attention to health problems, and the state program for the modernization of the pharmaceutical industry was enacted designed for the period from 2013 to 2020. This is not only a matter of increasing the volume of domestic pharmaceutical production with the aim to replace imports but also to perform qualitative transformation of the industry, as which should make it one of the flagships of the country's innovative development. It is certainly not possible to accomplish this without international cooper-

ation: In order to create the pharmaceutical industry of the international level Russia needs both foreign technology and experience of its implementation and development. That's why localization of production of drugs produced abroad on sites of Russian companies accompaned by staged technology transfer became one of the main objectives of the state strategy of the pharmaceutical industry modernization At the same time, it cannot go unmentioned that in certain areas the domestic pharmaceutical industry can boast of a historically established priority, for which the necessary support is available: the well-functioning science

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school, skilled personnel and state of the art production facilities. The matter at issue, first and foremost, is immunobiological developments and vaccine production. It is here that efforts to modernize the pharmaceutical industry can produce and are already producing significant results in a relatively short term. One of the leading producers of vaccines in Russia is Chumakov Federal Scientific Center for Research and Development of Immune and Biological Drugs of the Russian Academy of Sciences. Not only does the enterprise have a significant position in the domestic vaccine market, but, what is equally important, it has a unique experience of international cooperation and export of its products to dozens of countries in the world. The dominant player in the Russian vaccine market is the state. About 90% of the sales in this segment come from state and municipal purchases, which in 2016 amounted to almost 15.45 billion rubles. At 2016 year-end, Chumakov Federal Scientific Center for Research and Development of Immune and Biological Products occupied 6.65% of the market for procurement of vaccines in packages and 8.26% in RUB*, but it should not be left unnoticed that the

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enterprise has enormous potential to further strengthen its positions. One of the main problems faced by the state employer in the procurement of vaccines is the disproportionately high price of several drugs imported from abroad or produced in Russia with the participation of foreign pharmaceutical companies. The textbook example is the Prevenar 13 vaccine, which alone took 31.59% of the market last year and cost the state nearly 4.9 billion rubles*. Another recent example is the emergency purchases of a vaccine with the polio-component, for purchases of which approximately 1.2 billion rubles from the State Reserve Fund were allocated in spring of 2017. In this situation, domestic market participants have a place to grow, especially since the National Immunization Schedule (the national calendar of preventive vaccinations) is still far from perfect: It doesn't provide for vaccinations against chicken pox, hepatitis A, rotavirus infections, papillomavirus infections, meningococcus, and vaccines against haemophilus infection and influenza are only made available to a limited group of people. Consequently, the need for affordable, safe and quality domestic vaccines will grow.

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It is clear that domestic vaccines will be cheaper for the state than the imported ones. As state-owned enterprises with a social function Russian producers are ready to sell their products at a cost cheaper even when the prime cost - even in those cases when they are the non-alternative drug suppliers. Chumakov Scientific Center already has successful examples of import replacement. In particular, the company developed and successfully produces the first vaccine in Russia for the prevention of tick-borne encephalitis Klesch-E-Vac intended for children from the age from 1 to 16. A drug that meets all domestic and international standards is much more affordable for the private consumer than the imported counterpart. Because of its high

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quality the vaccine is indispensable for emergency vaccination, and its liquid form greatly facilitates mass immunization campaigns. The main feature of the drug is the high efficiency of protection against all currently known subtypes of the tick-borne encephalitis virus. It is worth saying that vaccination against tick-borne encephalitis is not one of the mandatory immunizations in Russia, but is done in case of a significant risk of contamination free of charge. Another important activity of the Federal Scientific Centre for Research and Development of Immune and Biological Products within the import replacement program is the development of the Russian inactivated polio vaccine (IPV), which is a strategically significant drug for Russia. The relevance of

this development in the context of the global deficit of the inactivated polio vaccine, which has been observed since the beginning of the year 2017, is particularly evident. The World Health Organization's global plan for eradication of polio includes the inclusion of IPV in vaccination schemes in all countries of the world. The need for this product has increased dramatically and producers were not prepared to this. As a result, according to the Ministry of Helth of the RF the supply of inactivated polio vaccine to Russia has declined by more than 13 times, from 2.3 million to 169 thousand of doses ***. To prevent the collapse of the immunization plan, the state had to purchase an expensive pentavalent vaccine that includes the polio-component.

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As it already been noted the emergency purchase pf 1.74 million doses cost to the Reserve Fund nearly 1.2 billion rubles (more than 10 per cent of the value of all vaccines purchased under the National Immunization Schedule) ***. Development of Chumakov Scientific Center will allow avoiding the recurrence of similar situations in the future. The vaccine is currently undergoing clinical trials, after which it will be launched into mass production and will be able to replace foreign counterparts. "The production of inactivated poliomyelitis vaccine must be given special attention." The domestic vaccine will cost less than the foreign counterpart. In order to develop a high quality and safe vaccine our enterprise has the necessary equipment and highly qualified personnel", - Director of Chumakov Scentific Center Aidar Ishmukhametov says.

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In polio-free countries, which nevertheless retain the risk of the this infection, the World Health Organization recommends the use of a live polio vaccine, along with the inactivated one for revaccination. Currently, Chumakov Scientific Center is the largest producer of oral polio vaccine in Russia and the CIS countries. The technology developed for the production of the peroral polio vaccine has become the first technology for the production and control of polio vaccines certified by WHO. The very emergence of Chumakov Scientific Center and its production plant are closely linked to the control of polio: Another resurgence of the polio epidemic occurred in the middle of the XX century around the world, it started in 1954 in the Soviet Union and in a few years the incidence reached 10.7 cases per 100 thousand of population. It was decided by the country's leadership to

establish a special institute to study the virus and to find ways to control the disease. This struggle was crowned with tremendous success: a group of scientists led by virologists Mikhail Chumakov and Anatoly Smorodintsev developed their own vaccine on the basis of attenuated strains of the American scientist Albert Sabin. By 1960 the safety and efficacy of the vaccine were proved and since the onset of widespread immunization the country population's morbidity rate decreased by 200 times. In the history of modern medicine, there seems to be no second such example of successful cooperation between Russian and American scientists. In 1988, WHO endorsed the global polio eradication program, and Russia took a very active part in the combating the disease in many countries â&#x20AC;&#x201D; Japan, Brazil, Argentina, Greece, Bulgaria, India and a number of African States.

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Over many years of production of the polio vaccine over 7 billion doses of the vaccine were produced and supplied in more than 50 countries around the world in Chumakov Scientific Center. In fact, every 7th person on the planet is vaccinated with this vaccine. The Federal Scientific Center for Research and Development of Immune and Biological Products also has the authorization of the World Health Organization for the supply of vaccines against yellow fever for charitable programs implemented by UN agencies. Yellow fever is an acute viral disease, it is clinically manifested in haemorrhagic fever, often of fatal nature (20-50% of cases). The infection is a quarantine one and vaccination against yellow fever is mandatory in endemic regions. Accord-

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ing to WHO, 33 African countries and 10 South American countries are endemic by yellow fever. Serial production of the vaccine based in Chumakov Institute of Poliomyelitis and Viral Encephalites was launched in connection with the expansion of contacts between the USSR and the Ń ountries of Africa and Latin America. In 1974, the vaccine was introduced in medical practice as a result of successful trials carried out with the participation of WHO, and the vaccine was included in the list of drugs recommended for international use by WHO. The vaccine strain of the yellow fever 17D offered by M.Taylor is used to produce the drug. The virus is cultivated in the embryos of the chickens, free of pathogenic microflora (SPF-specific

pathogen free). The eggs used for the production of the vaccine have a SPF category compliance certificate and a quality control certificate from the manufacturer. Testing of the blood serum of the SPF-herd chickens for absence of 25 infectious pathogens is carried out twice per month. The yellow fever vaccine produced by Chumakov Federal Scientific Center for Research and Development of Immune and Biological Products, for several decades has been shipped to countries in South America and Africa that are endemic by yellow fever. There have been no cases of claims being reported in Russia and abroad during the whole period of the drug application. In 2005, production sites were reconstructed and the vaccine produc-

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tion facilities were equipped with the latest equipment in accordance with the international GMP requirements at the expense of Chumakov Scientific Center funds. In 2009, the WHO Expert Commission certified production of the yellow fever vaccine and included a Russian enterprise in the list of the four world producers of the drug for the needs of the organization. In recent years, WHO experts have conducted regular on-site inspections of the main production units, including the polio vaccines and yellow fever vaccines, water treatment, bottling and freeze-drying of products, quality control and assurance, hatcheries. Chumakov Scientific Center is currently the only Russian manufacturer of Immunobiological products certified by

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WHO. In addition to the polio vaccine and the yellow fever vaccine, the plant is producing an antirabicvaccine and a vaccine against tick-borne encephalitis, enteroviral diagnostic serums, virological and bacteriological nutritional media, solutions, test systems. In 2016, products of Chumakov Scientific Center were exported in nearly 50 countries around the world. Total deliveries amounted to 1,310,000 packages for the amount of 17.6 million rubles. In the first half of 2017, exports reached 1,084,000 packages of over 10.2 million dollars, thus showing a significant increase in y-o-y comparison. * At present, at the initiative of the Federal Agency for Scientific Organizations (FASO), a pilot implementation site is developed at the premises of Chuma-

kov Scientific Center of Development of Immune and Biological Products where scientific developments of other institutes will be fine-tuned i.e. launched into serial production. It is no secret that the transition from the discovery of the miracle drug to its mass production continues to be a serious problem, since implementation of the scientific idea into a commodity on the pharmacy shelf requires comparable and sometimes greater intellectual, financial, organizational resources than the scientific discovery itself. In fact, there is now a return to the Soviet practice of organizing scientific and production complexes, for which the enterprise has all the prerequisites: Production sites, high-end equipment, world-class specialists. Already, the Center is Â

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actively cooperating on a contractual basis with commercial companies, producing their drugs on its production lines. By the end of 2014, all production facilities of Chumakov Scientific Center were fully modernized and technical rearmament was completed in accordance with the international GMP standards. The enterprise was licensed by the State Institute of Drugs and Good Practices and received a certificate of compliance with the requirements of the Rules for the organization of production and quality control of drugs. A number of functional systems have also been introduced to provide training and professional upgrading of

staff, to audit suppliers of equipment, raw materials and consumables; and to provide feedback to customers and conduct post-marketing quality monitoring of produced vaccines and pharmacovigilance. The modernization of production not only increases output for the domestic market, but also Russia's share of vaccines for international charitable organizations such as WHO and UNICEF to 60 per cent. The enterprise has a special project with a finished production site where almost any vaccine can be produced. Relations with other institutions in the FASO system are built horizontally, on a contractual basis, and eventually a consortium of several scientific institutes

and production sites may emerge, where the Russian Academy of Sciences could play the role of the expert board, determining the capacity and the need to implement particular developments. The development of such a pool of enterprises - without a rigid structural formation - must be carried out in order to ensure national security, including protection against bio-terrorism, and the expansion and filling by domestic vaccines of the National Immunization Schedule. The synergy of efforts will help to scale up the production of drugs and expand the export potential of the immunobiological industry, Director of Chumakov Institute of Poliomyelitis and Viral Encephalites Aidar Ishmukhametov thinks.

REFERENCES * Cliphar data, www.cliphar.ru ** Budget allocations for the purchase of polio vaccine, press service of the RF government, http://m.government.ru/docs/27874/ *** Communication from the press service of the Ministry of Health of Russia, www.rosminzdrav.ru/news/2017/08/16/5960-soobschenie-press-sluzhby-minzdrava-rossii

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COMPANY INFO Federal State Budget Scientific Institution Chumakov Federal Scientific Center for Research and Development of Immune and Biological Products of the Russian Academy of Sciences (formerly the Institute of Poliomyelitis and Viral Encephalitis of the AMS) is one of the leading virological scientific research institutions in Russia and a well-known producer of medical products for prevention, diagnosis and treatment of viral diseases. The Institute for Polio Research was established in 1955 to address the practical challenge of combating the polio epidemic. In 1957, the Institute organized a production complex the tasks of which included development of a technology to produce and control the quality of the polio vaccine in order to combat a dangerous disease on the territory of the USSR and abroad. The enterprise developed technologies for the production of other vaccines, based on the Institute of

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Polio Research of the AMS of the USSR, and improved drug control techniques. Preventive vaccines against tick-borne encephalitis, measles, rabies, yellow fever, distemper, and a number of others were developed and introduced into health practices. The technologies for serial production of certain vaccines were transferred to other domestic producers of the immunobiological industry in Russia. In 1988, the enterprise became an active participant in the World Health Organization (WHO) program for polio eradication. In 2002, Russia received a certificate as a territory free of the wild polio viruses. The merits of the leaders and employees of the Enterprise were noted by WHO's awards, commemorative badges and the gratitude of Dr. M. Danzon, director of the WHO Regional Office for Europe, and the Ministry of Health and Social Development of the Russian Federation. During the life of one generation successful work was carried out to combat the infectious disease of poliomyelitis ("child paralysis"). The enterprise underwent a major renovation of the production facilities and technical retrofitting in accordance with the international GMP standards. In April 2009, the WHO Expert Commission certified the Russian production of a yellow fever vaccine. Products of Chumakov Federal Scientific Centre for Research and Development of Immune and Biological Products currently account for about 50 per cent of the strategic supply of yellow fever vaccine created at the initiative of WHO. Today, Chumakov Federal Scientific Center for Research and Development of Immune and Biological Products is a high-tech industry in the Russian chemical and pharmaceutical sector. The activities of the enterprise repeatedly won international, national, and regional awards.

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Nacimbio National Immunobiological Company 31 August 2017

acimbio was founded on October 29th, 2013 as a Holding Company within Rostec Corporation to operate in the area of immunobiological products development and production. Together with Russian and overseas manufacturers, the company works to supply the healthcare system with effective and accessible medicinal products.

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Nacimbio is a holding that develops, manufactures, and delivers essential medicines to ensure independence of Russia from the import of medical products. The company's product portfolio includes more than 350 medical products, including vaccines, antibiotics (including anti-TB drugs), bacteriophages, and blood derived products.

Influenza, hepatitis B, whooping cough, diphtheria, tetanus, measles, mumps, rubella and tuberculosis vaccines are successfully delivered to the regions by Nacimbio as the sole supplier of National Calendar of Preventive Vaccination (NCPV). The holding’s plant assets are:   NPO Microgen   LLC FORT   JSC Sintez

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NPO MICROGEN

LLC FORT

In May 2003, the country’s largest unitary state enterprises producing immunobiological products were united into Scientific and Production Association Microgen. The main objective of NPO Microgen was to create a competitive production unit in the sphere of biotechnologies, and to introduce new highly effective preparations to the healthcare practice. The establishment of the production association had a synergistic effect on the whole scientific and production potential of the country in the sphere of immunobiology, and allowed separate companies to strengthen their scientific potential, to exclude redundant developments, and to coordinate the production, sales, and logistics. The priority area of business is the production of vaccines for dangerous infectious diseases, including the vaccines from the National Calendar of Preventive Vaccination (NCPV). The company’s share in total sales of immunobiological preparations of Russian producers is 43%, net of supplies under the NCPV. The revenue from the sale of preparations in 2014 was over 7 billion rubles. Some companies included in NPO Microgen have more than 100 year history. They develop and produce vaccines and toxoids, blood products, bacteriophages, diagnostic preparations, growth media, and allergens. Leading production enterprises of NPO Microgen are:   Virion (Tomsk, Russia)   Immunopreparat (Ufa, Russia)   Allergen (Stavropol, Russia)   Biomed (Perm, Russia)   ImBio (Nizhny Novgorod, Russia)   Moscow Department of Bacterial Preparations   Irkutsk Enterprise of Bacterial Preparations

LLC FORT is a biopharmaceutical company specializing in development, manufacturing, and marketing of biological drugs. The main activities are focused on the creation and production of innovative essential drugs - vaccines for prevention of socially significant infectious diseases, as well as a number of unique products in therapeutic areas of high demand, in particular, immunology, rheumatology, nephrology, and oncology. FORT's manufacturing enterprises are represented by a modern large-scale biotech enterprise that manufactures drugs according to international standards. The new scientific-industrial complex was opened in April 2014 in the Ryazan Region. It enjoys modern infrastructure that ensures the full-cycle manufacturing, and is in line with international GMP requirements. With its own research and production division, FORT can carry out rational import substitution, operating at advanced levels of biotechnology, and concentrating efforts on the most important tasks: Russia's drug sovereignty, as well as granting the country's population with access to modern, high-quality drugs.

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JSC SINTEZ JSC Sintez, a manufacturer of medicines and medical supplies based in Kurgan, is one of the largest companies in Russian pharmaceutical industry that manufactures a wide spectrum of products. The company has been producing medicinal products since 1958. Today, JSC Sintez, which was initially founded to produce substances for medicines to be made by other plants, is an innovative company operating in accordance with international pharmaceutical standards, and manufacturing a wide range of high-quality products. It accounts for 3% of Russia’s medicines production in terms of production volumes, being among the Top-10 companies of domestic pharmaceutical industry. Every tenth package of domestic medicinal products is made by JSC Sintez.

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JSC Sintez produces its own substances for medicines, unlike many Russian companies. More than 30% of the JSC Sintez’s products, inter alia natural and semi-synthetic antibiotics, is manufactured using the substances of its own make. The product range comprises about 300 articles of medicines and medical supply. In 2015, JSC Sintez was recognized as the best company by growth rates in sales in the retail market. JSC Sintez accounts for 60% of the market of some types of antibiotics (cephalosporins). The products are exported to 14 countries. The company’s production site is a state-of-the-art pharmaceutical complex. It includes buildings with facilities for the production of medicinal products, research laboratories, finished goods warehouses, auxiliary premises, warehouses with raw materials and other materials, raw materials, and finished products quality control laboratories.

The quality system of JSC Sintez covers all stages of medicines production, ranging from thorough input control of substances, excipients, packaging materials, air, water, and other engineering media parameters, the staff uniforms, to finished product full quality control for all parameters. Raw materials and finished product quality control is carried out by chemical, pharmaceutical, microbiological laboratories within the JSC Sintez Quality Control Unit (CCU) certified by the Federal Service for Surveillance in Healthcare. Production activity goes hand-inhand with R&D to create new dosage forms. JSC Sintez Central Research Laboratory (TSL) is a research center capable of developing technologies to produce substances of antibiotics and finished dosage forms, register and protect the intellectual property, implement their designs into production.

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THE MOST IMPORTANT EVENTS RELATED TO THE COMPANY'S IMMUNOLOGICAL DEVELOPMENT IN THE FIRST HALF OF 2017:

1) Nacimbio cooperates with the most important Russian manufacturers of immunobiological products. In the first half of 2017, the company signed a number of cooperation agreements aimed at developing the vaccine market. Particularly in the context of the cooperation with Binnopharm, the production of a multi-component vaccine using the anti-hepatitis component developed by Binnopharm will be organized. The other agreement (with NANOLEK) sup-

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poses the combination of companies’ competencies and efforts in the development and organization of the full technological cycle for manufacturing immunobiological medicines at the facilities of both companies, including the technology transfer and joint research. 2) In 2017-2018, Nacimbio will supply more than 120.5 million doses of immunobiological drugs for the National Calendar of Prophylactic Immunization. This amount will exceed the last year’s supply by 20%. In 2017-2018 epidemiological season, the number of influenza vaccines will also increase compared to the previous period. 58.5 million doses are to be supplied. To provide the execution of the state order, Nacimbio collaborates with domestic pharmaceutical companies, producing drugs at all stages of the technological process in the country. Within the model of production cooperation, the holding is to supply medicinal products by seven companies: Binnopharm, Combiotech, MBA-group, Medgamal, SPbSRIVS, and two companies of the holding, Microgen and FORT. 3) In March, Microgen launched Phase 1 of clinical trials of the first domestic meningococcal polysaccharide vaccine against A and C serotypes. Preclinical trials have demonstrated that it is well tolerated, safe, and possesses a high immunogenic activity. Phase 1 of clinical trials is to be completed by the end of 2017. A controlled reactor method for cultivating the group A and C strains of meningococcal vaccine was implemented for the first time in Ufa branch of Microgen. The new vaccine will be produced in the reconstructed multicomponent vaccines plant at Ufa site of the company using BIOR reactors. 4) In April, Nacimbio introduced a technology of quality testing for antiTB vaccines, which shortens the testing period from one month to 1.5 hours. The technology is developed and approbated by the Stavropol branch of the Scientific and Production Association "Microgen", part of Nacimbio, and allows to increase the volume and speed of production of BCG and BCG-M vaccines. The technology is based on the bioluminescent analysis of the number of living tubercle bacilli in the preparation, which are detected by a special device — bioluminometer. It allows to measure the chemical energy released by living organisms — Mycobacterium bovis bacteria — as the result of oxidation reac-

tion under the effect of enzymes in the form of luminescence. 5) At the beginning of June, Microgen had developed a new method for manufacturing the inactivated split influenza vaccine. The new drug called Microsplit has been shown to be safe in successful phase I clinical trials. The drug Microsplit is an inactivated split vaccine containing both surface, and internal viral antigens, with the latter hardly ever undergoing mutations, unlike surface antigens. By containing two types of antigens, the vaccine provides cross-protective immunity, thus protecting against the annual types of the influenza virus, as well as new mutant strains. Trials to assess the safety and tolerability of the new vaccine were conducted at the St. Petersburg Influenza Research and Development Institute of Ministry of Healthcare of the Russian Federation, involving 30 healthy volunteers aged between 18 and 60 years. Microgen State Scientific Industrial Company plans to commence phase II clinical trials of the Microsplit vaccine by the end of this year. 6) At the end of July, Microgen confirmed, for the first time among Russian manufacturers, the stability of the vaccine strain of the virus, and the quality of production of domestic tick-borne encephalitis vaccines at the genetic level in accordance with WHO recommendations. Until today, no domestic tick-borne encephalitis vaccine has undergone similar molecular and biological trials. The works began in 2012, and were implemented jointly with the specialists of the Scientific Center for Expertise of Medical Applications of the Ministry of Health of Russia. The biological and genetic stability of the strain 205 (the Far Eastern subtype of the reference strain) of the tick-borne encephalitis virus was studied, and is used for the production of inactivated tick-borne encephalitis vaccines EnceVir (for vaccination of adults), and EnceVir Neo for children (for vaccinating children). The aim of the studies was to confirm the biological and genetic uniformity of the virus strain used in the production of vaccines in the course of their repeated passaging, and long-term storage in relation to the reference variant of the strain with high antigenic and immunogenic properties, which enable us to produce the stable immunity to the virus during vaccination.

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Dmitry Efimov CEO of JSC "Nizhpharm", Senior Vice President of STADA AG

STADA Arzneimittel AG is an international Group of companies, one of the leading manufactures of quality and affordable generic drugs, as well as well-known brand products. "Russia and CIS" cluster is one of the most important clusters for STADA. Dmitry Efimov, CEO of JSC "Nizhpharm", Senior Vice President of STADA AG kindly answered a few questions by "CIS GMP news".

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Dmitry Efimov: There is Still a Large Potential in Russian Pharmaceutical Market

31 August 2017

How long and in what quality has STADA been active in the Russian market? What were the goals of STADA’s leadership while entering the Russian market? STADA has historically grown through product presence expansion, mainly achieved through acquisitions of other pharmaceutical businesses and/or opening of representative offices across Europe and Asia. STADA’s transnational growth took off in 1986 with expansion to markets in Switzerland and Austria. STADA established representation in Eastern Europe and Pacific, becoming active in Hong Kong through a subsidiary in 1992. Year 1996 saw the takeover of ‘ Aliud Pharma’, a generics major in Germany. Consistent M&A policy lead to corporate sales growth over 1 billion Euro in 2006 for the first time. STADA kept increasing its worldwide presence. Russia’s pharmaceutical sector, booming at that

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time, naturally became a focal point. STADA launched active promotion of its portfolio on the Russian market in 2001. Having gauged its prospects, the leadership decided to further its business in the country. This could best be achieved through purchase of a local company with enough expertise and understanding of country specifics. ‘ Nizhpharm’ seemed the most attractive target at that time. The company’s ultimate commitment to product quality was among its core competences – ‘Nizhpharm’ had undergone GMP certification even before joining STADA. Besides modern production site and robust network of medical representatives, another big advantage of ‘Nizhpharm’ was its strong presence in CIS countries also targeted by STADA. Thus, the strategical investor took over more than just one of the largest national production sites; it also capitalized from the strong team deeply expe-

rienced in local business processes and highly adaptable to both internal and external change. What enterprises are currently active in Russia under STADA brand? If we talk about production sites, that would be ‘Nizhpharm’ in Nizhny Novgorod and ‘Hemofarm’ in Obninsk, Kaluga oblast. At the same time, our portfolio is much wider than what we produce. Around 2010 we realized clearly that STADA capacities, both locally and globally, are not enough for a successful growth in Russia. That’s why we actively engaged into attracting partner products. 60 percent of our current price list is our own production, while the remaining 40 is produced elsewhere, be it other STADA facilities around the globe or even capacities outside the group. If we look at sales structure, contract manufacturing will take up to 16 percent of earnings.

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What are your sales models for non-owned products? The models can vary. For instance, we purchase registration rights from the originator on an early stage. After that, we either assume ownership of the trademark or attribute our own and promote the product as a part of our portfolio. Our partners are usually small companies who don’t have financial capacities to market their produce. Overall, we find interesting items and offer patients modern and efficient products. What renovations had to be performed at Russian production sites in order for them to comply with international standards? ‘Hemofarm’ production site in Kaluga oblast was originally designed and built to comply with international standards of manufacturing management. It was a bit trickier with ‘Nizhpharm’. The plant building was constructed at the end of the 20th century, when there was no concept of GMP in Russia

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operational commissioning of the new section, corporate leadership managed to attract investments from European bank for reconstruction and development (EBRD). These funds were directed towards reconstructing morally obsolete ointment and suppository production complex and base preparation bay, as well as establishing a new substance preparation section. In 1999, ‘Nizhpharm’ contracted FAVEA to perform this project on turnkey basis, involving design, equipment procurement, construction and installation of these capacities; it saw successful completion in 2001. At the same time raw materials warehouse underwent redevelopment, accompanied by construction of a new modern finished goods storage facility. This marked completion of the first stage of reconstruction, and since 2001, the whole medical production on ‘Nizhpharm’ has been GMP compliant. In the following years, it became evident that production volume of

whatsoever. After privatization in 1995, despite evident economic problems, enterprise owners immediately decided to transform the site in accordance with GMP standards, which were known only to a scarce amount of professionals back then. They established a workgroup which underwent relevant training both in Russia and abroad. These people were ultimately tasked with further transformation of the plant and its production processes. Firstly, though, the decision was reached in favor of building a new section for solid-dosage items, which hadn’t been produced on ‘Nizhpharm’ before. In the beginning of 1997 we made deals with leading European producers who would supply us with cutting-edge equipment, and then we went on a lookout for a developer who could design and build a new section, taking the new equipment and full compliance to GMP into consideration. In 1998, the construction was successfully completed and subsequently certified in accordance with EU GMP requirements. This was the first GMP certificate issued for a production line in Russia. Due to ‘Nizhpharm’s success in Russia’s semi-solid dosage segment and

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‘Nizhpharm’ was not enough to satisfy high consumer demand. 2005 saw the kick-off of another capacities expansion project for ointments and suppositories, which was completed in 2007. New segments were certified, commissioned, and commenced industrial-grade production, which marked completion of stage two of ‘Nizhpharm’ reconstruction. As of today, every section of Nizhny Novgorod plant complies with EU GMP standards; both European and domestic inspectors have validated compliance on numerous occasions. We still keep our modernization effort. Pharmaceutical branch is in constant progress; new technologies emerge every day. As medical producers, we will just have to go along with these modern trends.

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To what extent is Russia’s pharma dependent on foreign technologies, substances, and so on? Are there any positive shifts noteworthy here? In Russia, there is no industrial production for pharmaceutical companies whatsoever. On the other hand, I can’t say there are dependencies from certain specific countries – we can always maneuver, buying either in Europe or, say, in China, where enterprises can offer quite a lot. Pharmaceutical business is a largely autonomous entity; we don’t have any specialized software which works globally. But, in terms of both equipment and active pharmaceutical substances, there is still large room for improvement in Russia. Business model of ‘N izhpharm’ foresees sales of both locally produced

items and imported goods, including those of sister companies within the global STADA. This has been our development scenario for the past ten years, and it has more than proven its sustainability. Ruble depreciation has prompted us to take a new look on localization of certain products which were formerly produced abroad, and to search for local substitutes for formerly imported medicines. If we see local suppliers ready to procure relevant services or quality goods at competitive pricing, we welcome such partnerships wholeheartedly. But there are certain peculiarities in pharma – we can’t, for example, just switch substances without undergoing painstaking bureaucratic processes of incorporating those changes into registration papers.

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Are there any products manufactured locally you would say you take pride in? We currently have around 400 positions in our price list; our goal is to develop our portfolio in such way as to assume leading positions in every segment. There are fields we historically excel in. For instance, we are strong in urology segment, where Nizhpharm’s Vitaprost has been the most frequently prescribed drug against prostate problems. We also have strong brands in rheumatology, where Chondroхid is one of the top ‘Nizhpharm’ products. We also have a large dermatological portfolio inherited from the Soviet times. On top of it is Levomecol, our best-known product that needs no marketing at all. It is a superb medication well known to everybody, it is 37 years old – and we still keep discovering new possibilities for its application. The ointment was designed

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in the late 70’s in Kharkov Pharmaceutical Institute, Gorky chemical and pharmaceutical plant (predecessor of today’s ‘Nizhpharm’) was the first one to adopt its production. Active components are broad-spectrum antibiotic levomycetin (chloramphenicol) and tissue regenerator methyluracil. The combination as a whole has a strong antibacterial, anti-inflammatory and wound-healing effect; it easily penetrates deep tissues without traumatizing cell membranes. This ointment’s recommended use is primarily during the most acute initial purulo-necrotic phase. This unique combination of active components with ointment base has enabled doctors to use Levomecol as treatment for children with bullous epidermolysis, so called butterfly children. How do Russian producers cope with production costs for certain medicines being higher than their selling price? This

discrepancy is due to harsh state control over vital and essential drug pricing. Do production sites have to suffer losses because of that? Not quite. Of course, profitability has taken a serious hit due to our dependence on imported components and raw materials, pricing of which has increased drastically over the last few years. At the same time, there are other portfolio segments where we can manage pricing policies more flexibly. If we look at market dynamics over the last decade, it will become evident that growth by volume is virtually nonexistent, but there is yearly growth by value. That means there is, on one hand, some sort of inflation component. On the other hand, since 2010 strict regulations in terms of vital and essential drug pricing have been in place. VED prices have been effectively frozen, and growth here can only be sanctioned by state.

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Hemofarm facility takes part in medicinal serialization pilot currently underway in Russia. What can you tell about this project? Why did STADA decide to participate? What do you expect from it? Quality and safety are two base principles when it comes to drug production and circulation. Even minor share of falsified or off-grade produce bring risk of dire consequences for patients. This is why every initiative in drug safety helps. At the beginning of this year Russia’s government initiated the Drug Quality and Safety project. Its implementation foresees placement of unique 2D code on every medicinal

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item package. This will provide for complete traceability of each item from production site to consumer. We strife to take as wide a part in this project as possible – both in terms of product portfolio and cooperation scale with all interested parties. New technologies always mean a lot of work, but taking part in this pilot will allow us to get ready for full-scale serialization system deployment. Automatic serialization equipment supplying each package item with unique ID markings is deployed on Hemofarm packaging lines. The system both applies DataMatrix code and controls the process in real-time mode,

which lowers error rate. At stage one we only serialize a pilot list of medications consisting of three items. As we undergo equipment modernization, the process will involve more and more STADA portfolio items. We used our global HQ expertise while deploying the technology – Germany’s serialization effort saw light eight years ago. Russian serialization system will be based on DataMatrix system in compliance with GS1 international standard. Marking will contain unique packaging unit ID, global trade item number (GTIN), and commodity code. Expiration date and batch number will also be mandatory components of such

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Maxim Khamet Chairman, FAVEA Group

code. Along with obligatory 2D mark, information can be presented numerically. Producers will have to use random number generators with negligibly low coincidence ratio to generate unique IDs. This will protect the code from counterfeit. Storage packaging, or so-called tertiary packaging, will also have its own marking system. When aggregated into tertiary packaging, every single unit’s unique ID will be linked to tertiary markings. These markings will provide tracking information when we move produce between logistical points. They will be scanned on every step along the way – from packaging line to cash reg-

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FAVEA has started working with NIZHPHARM in 1997 and it was our first project in Russia. Over the years, we can confidently say that the cooperation with NIZHPHARM was vital, as the market of Russia and CIS countries is the main sales area for FAVEA today. We especially remember the most ambitious project for NIZHFARM: "Production of sterile ointments, suppositories, and preparation sites for substances", which was implemented from 1999 to 2001. In connection with the use of European Bank funds for reconstruction and development, a group of international auditors inspected FAVEA before signing this contract in detail for the presence of required competencies. During that period, FAVEA specialists had accumulated a successful experience in carrying out such modernizations, since in the Czech Republic and in other Central European countries, the transition to GMP standards has been implemented between 1992 and 1996. Our advantage was the presence of own division, which was engaged in the development and production of dosage forms, as well as in research in the field of biopharmaceutics. Assistance of FAVEA’s specialists from research and development division allowed us to successfully implement the most modern technological developments, considering the

specifics of the Customers’ productions. FAVEA employees are proud of the fact that it was NIZHFARM who received the first certificate of GMP compliance in the entire Russian Federation. The last project FAVEA had recently finished for NIZHPHARM was a workshop for new suppositories production. In 2016, NIZPHARM commissioned a new production site section of suppositories with a maximum capacity of about 12 million packages per year. This enables the company to increase the production of suppositories facilities by 25%. Thanks to an integrated approach to creating a new production workshop as a single technological module, fencing structures were integrated together with all equipment and units of engineering systems and mounted elements of process equipment necessary for normal use in the production facility. FAVEA’s experience in arrangement of such module systems enabled construction works to finish in 6 months, perform personnel training, and to start new production site. This impressive result was achieved thanks to the professional work of the NIZHPHARM team, who during the 19 years of collaboration had been providing FAVEA with constructive and partner cooperation, which allowed the implementation of many successful projects!

ister or healthcare facility. Presently, the deadline is 2019 – after that, the industry will only be able to produce marked drugs. This will eliminate illegal and substandard goods from circulation. Every producer, importer, distributor, pharmacy, and healthcare facility will have to integrate serialization equipment into their frameworks. New data flow will demand additional enterprise IT expenses. They should not be considered idle, though – data exchange will advance logistics management schemes, which will ultimately streamline business processes and cut costs. Moreover, this will protect companies from direct counterfeit-related losses.

Expertise gathered in countries with successfully adopted serialization systems shows that businesses, as well as state and consumers, capitalize on them. For instance, you can quickly call back substandard batches. This also eliminates sale of expired drugs. States receive an efficient taxation management and control tool. By the time serialization system goes industry-grade, individual consumers will also have an opportunity to quickly verify drugs they purchase. All one will have to do is download a special mobile app and scan package DataMatrix code. This way, project’s results will become tangible for everyone.

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1 (1)Â / autumn 2017 Good Engineering Practice

Good Engineering Practice in Russia and CIS ĐĄountries 31 August 2017

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The transfer of the Russian pharmaceutical industry to the international GMP standards contributed to the rapid growth of the conducting of reconstructions and modernizations of pharmaceutical plants, as well as the construction of new production facilities. We asked the specialists of the Czech engineering company FAVEA Group to tell us about how popular is the field of pharmaceutical engineering in Russia and CIS countries.

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Christos Tsanaklis

Denis Kosianenko

Zdenek Pavelek

Technical Director FAVEA Group

Chief Project Engineer FAVEA Group

Quality Director FAVEA Group

Please tell us about your experience in implementing projects in Russia and CIS countries. How difficult were the challenges facing you in terms of their solution in accordance with international standards? The situation is very different for companies that have large, often international corporations behind them, unlike local companies that do not have a long history, or a strong engineering team. Christos: The first know the GMP standards very well, have their QA teams, are well-oriented in the subject, require a strict GMP implementation in the newly implemented projects. However, this does not mean that the others do not keep the main GMP principles in their projects, but here we have to explain more, to persuade customers to understand that these principles must be kept without looking for other, improper solutions. Here FAVEA is giving support to these companies, we first need to "train" the customer, to explain properly why the right approach to GMP requirements should be fully accepted. We consider every project as a unique one, and in each of our projects there are their own specific challenges and difficulties. For instance, we had project where the Client following market trends had to make modifications in the design during

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construction. This brought some difficulties for us, of course. As a result, FAVEAâ&#x20AC;&#x2122;s experts had to look for non-conventional solutions to implement changes in already built clean rooms and related engineering utilities aiming to minimize financial and time impact. Of course, that was performed keeping the quality and meeting GMP requirements. It is important to notice that despite all difficulties, the facility was built using the most modern technological solutions. Pharmaceutical companies in Russia and CIS countries behave similarly to other companies around the world. The problem here, however, is the level of knowledge that allows the introduction of new technologies, and the curZdenek: rent GMP requirements. There are a few high-level companies in these countries, mainly because they work with multinational corporations and follow their standards and technical solutions when making new investments and/or rebuilding. Unfortunately, there is a large part of the market-oriented companies in the CIS countries, and there is a general knowledge of current GMP requirements at a lower level, especially with a low level of knowledge of technical solutions for cross-contamination protection and ISPE recommendations for various technical areas.

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While implementing our project in addition to performing on-going regular (and sometimes non-regular) engineering tasks, we are often faced with absence of willingness to change mindset that had been created over the Denis: years. It is often the case when one is not ready to neglect momentary benefit in order to achieve better results in the future, reluctant to look “beyond the horizon”. This attitude, unfortunately, still quite frequent in Russia and CIS. However, the tendency is that sooner or later these problems will inevitably be a thing of the past. As there are European and International companies arriving on Russian and CIS market all players have to constantly increase the level of their people competence to be able to withstand competition at quality level. Also, overall corporate culture and business awareness need to keep being improved. This results in that more and more young specialists are being trained on international standards. We are glad that we can contribute to and actively participate in this process. We face challenges in almost every project. On one of the manufacturing plants of metered-dose inhalers (MDI), the designed section was multiproduct and provided for the possibility of simultaneous operation and production of finished products with different API.

To reduce the risk of cross-contamination, protection of corridors and adjacent rooms, we used a special system of locks and a corresponding concept of pressure differences, as well as developed a special procedure of cleaning and transferring of the materials to/from the working area. Design solutions have been engineered to ensure compliance with the requirements to the level of purity, protection of operators, environment, and finished products from cross-contamination, and to conform to a logical sequence of production operations according to GMP requirements. Since the beginning of 2015, the Ministry of industry and trade of Russia provides certificates of compliance for manufacturers of medicines with the GMP requirements. What can you say about Your Customers? Yes, this is certainly the right direction that helps raise the GMP level of pharmaceutical companies in Russia. However, it will be a long and challenging way for the ministry (to set and maintain the required GMP level), and Zdenek: especially for individual companies not only to reach this level, but also to compete with other companies, including foreign ones.

Сommissioning Karagandinskiy pharmatsevticheskiy Komplex Karaganda, Kazakhstan, August 2015

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Validation Tatchempharmpreparaty Kazan, Russia, June 2016

FAVEA provides training seminars and courses for manufacturers in the pharmaceutical industry in Russia, Ukraine, Kazakhstan, and Belarus. How well prepared are your listeners in the field of pharmaceutical engineering?

FAVEA is the organizer of international conferences GEP-Russia and GEP-Kiev. What kind of audience do you collect? Who are the speakers? What are the prospects of this conference?

Our seminars are attended by employees of different pharmaceutical companies. Some of these companies have their own training and engineering centers. The workers of such compaDenis: nies usually have good practical and theoretical knowledge. In this case, we prefer to conduct seminar not in a form of lecture, but in a form of discussion, which definitely has positive effect on the involvement of visitors into the learning process, and serves as reliable basis for exchange of experience. It is worth noting that most of the questions asked are about things not really related to the attendeesâ&#x20AC;&#x2122; daily operations, but still important questions of engineering, methodology of design, and construction process. People are interested in the expediency of implementation of the certain tasks at particular stages of project development. Questions are being raised about project planning, sequence of communication, and approach to coordination of all project participants. In relation to this, our company organizes a number of specific events, for example, GEP-Russia conference where we communicate main aspects of industrial engineering and share our practical knowledge.

FAVEA seeks to bring pharmaceutical companies in Russia and CIS countries closer to the new technical and organizational solutions to current GMP requirements. For this reason, FAVEA organizes the International GEP conference (Good Engineering Practice), Zdenek: where international experts (as lecturers) are working for major pharmaceutical corporations or supply companies. The aim of FAVEA's business is primarily to raise awareness of current technical solutions for pharmaceutical production, and to enable experts in Russia and the CIS countries to have a discussion with international experts.

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It has already been several years since we started to conduct annual conferences in Russia devoted to good engineering practice. This year, we have organized such a conference in Kiev, and the results inspired us to further continue doing it every year. These Denis: conferences are for quite a wide range of participants. Among our attendees are representatives of manufacturers of over the counter (OTC) and Prescription Only ready to consume drugs, equipment manufacturers, engineering and construction companies, as well as state authoritiesâ&#x20AC;&#x2122; representatives. The event is organized in a form of pool of prepared

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Zdenek Pavelek International Сonference GEP-Kiev 2017 March 2017

preliminary speeches and presentations, but also in the form of a round table discussion. This is great opportunity for each attendee to raise actual and hot topics and to get opinion from the representatives of different sides of industry. Beside this, each conference is dedicated to a certain subject, we consider interests and wishes of participants while organizing the conference and carefully select speakers and subjects of their presentations. Speakers from different countries, who have been working in different fields of pharmaceutical industry, and who have direct practical experience in science, production, design, and quality assurance take part in our conferences. Our own experts also permanently prepare reports on the most interesting topics considering interests of the audience. It already had become an honorable tradition for us. In the future, we hope that GEP will become main discussion platform for pharmaceutical industry. We clearly see all prerequisites for that, as the interest in the conference grows year after year.

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What can you say about cooperation with ISPE? Modern tendencies show us that ISPE actually becomes main industry standard. Therefore, it is even more pleasant to admit that we were one of the first companies on CIS markets who had been openly declaring support and compliance to ISPE recommendations. We had been taking actions on increasing awareness of market participants about main Denis: ISPE principles, and we were actively promoting their application. ISPE’s philosophy and spirit is close to us. We also put as of outmost importance the quality and its assurance at every stage of the project’s lifecycle. This year, with our support, ISPE opens its first branch in Russia. We plan to organize several mutual events, trainings, conferences. In particular, it will be the first time ISPE representative, vice president of European branch, Mr. Tomas Zimmer, visits GEP-Russia. This year, a great step was taken in cooperation between ISPE and state authorities, pharmaceutical, and engineering companies in Russia and CIS countries. Negotiations on establishing the ISPE Affiliation - EAEU (Eurasian Economic Union) had started. In October of this year, ISPE representatives will be in Moscow, signing access agreeZdenek: ments is expected if all entry conditions are met. ISPE Affiliation - EAEU should then significantly contribute to increasing the level of knowledge and experience, especially in the field of technical solutions to current GMP requirements, and to providing international cooperation of EAEU experts with pharmaceutical specialists from all over the world who operate within ISPE.

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Pharmaceutical Turnkey Solutions: - Design - Engineering - Clean rooms - Clean media systems - Service

Consulting: - DQ - Quality system upgrade - Preparation for GMP Inspections - Technical consultancy - Training

GMP Compliance Audits: - Drug manufacturers - API manufacturers - Distributors - Suppliers of raw materials, in-bulk - Suppliers of equipment and systems

Plan for the future with those who build it! About FAVEA FAVEA Group is a European pharmaceutical engineering company. We design and build pharmaceutical and biotechnological plants, and handle reconstructions of the existing pharmaceutical facilities according to GMP standards. For over 20 years, we have been successfully implementing dozens of turnkey projects. FAVEA also assists in qualification of production systems, providing audits, GMP consulting, and education.

Experience: over 20 years

Implemented projects: more than 50

Engineers: more than 80

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All FAVEAâ&#x20AC;&#x2122;s projects are designed and implemented in accordance with the EU GMP standard, current GEP requirements, ISPE and PDA recommendations, allowing to successfully pass national and international audits, and obtain GMP certificate

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Quality management system certificate ISO 9001: 2009 in the field of designing and engineering activities for building and reconstruction of pharmaceutical facilities

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1 (1)Â / autumn 2017 Active Pharmaceutical Ingredients

Bringing Solutions for CIS

21 August 2017Â

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IMCoPharma, a Czech company with a number of representative offices in the largest CIS countries and expert team engaged in distribution and consulting for over 20 years is a link between the EU and CIS pharmaceutical markets.

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We asked Mr. Ivan Mikes, General Director of IMCoPharma, to tell us about the company in more detail

Ivan Mikes General Director of IMCoPharma

Mr. Mikes, could you tell us about the interests you have in the markets of Russia and other countries of the former Soviet Union? IMCoPharma is a private pharmaceutical company with the headquarters and the central warehouse located in the Eastern part of the Czech Republic, in the town of Bilovec. Located in the very heart of Europe, we have an advantageous geographical position; however, it is not only the company’s geography that attracts all our partners working in the CIS markets, including Russian ones, but mainly opportunities of IMCoPharma. What can you offer your suppliers, on one hand, and to local pharmaceutical manufacturers, on the other? In what CIS countries do you have the representative offices? The company’s representative offices are located in Russia, Ukraine, Belarus, Uzbekistan, and Kazakhstan. Today, IMCoPharma is among the leading companies in pharmaceutical markets of all CIS countries, offering a portfolio with the best products and services in their categories. The strength of IMCoPharma is in its ability to work closely with our business partners, and supporting and developing pharmaceutical markets of the CIS using innovative projects.

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Thanks to our long-term cooperation with a number of European pharmaceutical producers of APIs and excipients, we have gradually gained a stable position on these markets and established strong partnerships, usually on exclusive basis. We also assist the companies with registering their dossiers in all indicated areas, or we can ensure any dossier based on customer‘s requirements. IMCoPharma offers a full range of regulatory expertise such as consultation services in connection with product development, in-licensing projects, regulatory assistance, and others. We operate a licenced warehouse near Moscow, which is suitable for storage and distribution of the goods that passed through customs. Thanks to the Eurasian Economic Union (EAEU) we can thus supply already cleared goods not only to our customers in the Russian Federation, but also to other member countries of EAEU. Beyond that, we also offer warehousing services in Ukraine and Kazakhstan. We are flexible in terms of supporting our customers with project financing and looking for the best options in order to find the most effective models of cooperation with each of our customers individually. Which European companies’ interests do you represent, and who are your business partners in CIS pharmaceutical markets? IMCoPharma runs its business in cooperation with such authorized, or exclusive partners as Roquette (France), F areva (France), EXCELLA GmbH & Co. KG. (Germany), F.I.S. (Italy), Serumwerk (Germany), Medichem (Spain), Pharmacosmos (Denmark), Salinen (Austria), Hovione (Portugal), Amino (Germany), Saneca (Slovakia), Trifarma (Italy), CFM-Group (Italy), Cayman Pharma (Czech Republic), and many others.

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Last year we established a cooperation with FAVEA Europe (Czech Republic), which became our engineering partner for CIS. How does your company manage to work in the CIS market with such a large range of pharmaceutical products from European partners? In support of the high standard of services we provide, IMCoPharma is certified in accordance with GDP, AEO (Authorized Economic Operator), ISO 9001, ISO 14001, OHSAS 18001. To ensure high quality of the financial and intermediary services, IMCoPharma insures all its receivables in the CIS countries. Over the years we have developed financial instruments, thanks to which we can take the complete responsibility for sales to our cus-

tomers, in the same time guaranteeing payments on time to our business partners. This way we are protected against insolvency or political risks that are usually connected with business activities in countries of CIS region. Where and how can one get information about the list of products supplied by you and your business partners? At present, IMCoPharma is at the final stage of introducing a new web portal designed primarily for the customers of the CIS countries – imcobuy, a unique online store with a mobile application for easy ordering. On this web portal you can find a list of products offered by our suppliers, which is available to all visitors of the website.

Registered users can get more information about specifications for the products, the manufacturer, the country of origin, valid registrations in the CIS countries, etc. Which exhibitions is it possible to meet your representatives at in order to get more information about your opportunities and offers, as well as about your business partners? IMCoPharma actively participates in major pharmaceutical exhibitions and international conferences around the world every year. Among them are CPhI Europe, GEP-Russia (Moscow), Pharmtech & Ingredients (Moscow), IPhEB & CPhI Russia (Moscow), PHTE (Kiev), TIHE (Tashkent), and others. You can always find out which event we are preparing for, and where can you find us in the very near future on our corporate website www.imcopharma.cоm. Could you reveal the future plans of IMCoPharma, or goals you would like to achieve in the coming years? The economic situation and legal business conditions in the CIS, and especially in the Russian Federation, are quite specific - notably in comparison with what we are used to in the EU. Particular countries of CIS generate basically similar forms of preferences and support of the development of local production, only under different names. The purpose of such activities is to support investments in the development of production and services. We do not take issue with particular decisions and their correctness, but in line with the global assessment of the CIS markets and, above all, the market of the Russian Federation as an emerging market, we are planning our further investments. Among them there are, for instance, expanding our own logistics and storage centre near Moscow, or further improvement of our services, so that we follow the local legislative conditions and thus meet requirements of the local pharmaceutical companies. Above all, thanks to the variety of our services, we are also becoming more trusted by our partners from the EU and other parts of the world who have decided to join us in the growing market of CIS. I dare to say that we have been doing a good job, and now the "IMCoPharma" brand has got a stable position on the pharmaceutical market of CIS.

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The second part of our interview was held with Mr. Lukas Adamec, Commercial Director of IMCoPharma, who has been working in the company for more than 10 years

Lukas Adamec Commercial Director of IMCoPharma

Manufacturing of APIs is an important part of the pharmaceutical industry, and you have probably analysed the market of active pharmaceutical ingredients in Russia and the former Soviet Union countries. How promising and interesting is this market to you? The market of Russia, as well as of all former Soviet Union countries, is interesting not only for us and our partners, but I dare to assume it is for all players in the pharmaceutical industry. Compared to other countries, we are witnessing a real boom in localization and development of pharmaceutical production in this market, which is confirmed by the percentage among the most dynamically developing territories. Is it possible to compete with pharmaceutical production from Asian markets, which is generally cheaper in comparison with Western Europe? What are the competitive advantages of your partners? We believe that it is the quality primarily that can help us to outdistance competitors, including Asian manufacturers, and by quality we mean not only the quality of the products supplied, but also the quality of the services provided. We always listen to our customers (manufacturers of drugs) and constantly increase the volume of services based on their requirements and wishes, in such a way as to ensure the customersâ&#x20AC;&#x2122; maximum comfort through our cooperation. This approach allows us to solve many problems on time (such as unforeseen situations at manufacturing site, inefficient supply planning) and deal with issues related, for example, to regulatory requirements, regulatory documents, etc. Our specialists and the specialists of our European partners

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are always ready to provide immediate assistance in coping with various problems that may arise at different stages of the project: during its introduction into the market (marketing, training), during registration, at the development and production stages, or during subsequent distribution. Could you tell us about the situation with the inspection and audit of European manufacturers of APIs by Russian authorities? How do you cope with such a situation? It is sometimes hard for local manufactures, so how are you able to support your business partners to meet these regulatory requirements? We are talking mainly about the Russian market. We are constantly monitoring this issue, as well as everything related thereto. We try to cover the situation to the full and recommend our partners that they should take steps that would simplify the task for our Russian customers, i.e. what I

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told you about in reply to your previous question. Our priority is to provide both maximum comfort and maximum support to the clients in terms of regulatory requirements, inspections and audits. It is one of many tools that help us to overcome competition and be successful in this complex market. Our regulatory specialists help customize all necessary regulatory support in line with customersâ&#x20AC;&#x2122; requests in the particular country. As for the audit, together with FAVEA Europe, our partner for engineering, we are able to prepare any of our partners for passing the inspection of the Russian authorities smoothly, and to meet all requirements for successful market performance. Please, tell us if your partners are interested in localizing the production of final dosage forms in Russia? We study such opportunities, and it should be noted that many of our partners, through our intermediation, held preliminary negotiations on this matter, and some projects are already in the process of registration. Localization processes are different, of course, and depend on the type and complexity of production. Such projects surely include the production of

simple generics, which are of interest particularly because of the duration of patent protection, but we also work with complex and expensive projects, where technology transfer is estimated not only in terms of time, but also in terms of start-up investments and personnel qualification. Despite the fact that we mostly represent European companies specializing in the production of raw materials, our portfolio includes a number of manufacturers from other parts of the world. So, what is the main goal of ÂIMCoPharma? We are an intermediator forming a bridge between Russian (or CIS) pharmaceutical market and the rest of the world. We understand the needs of this specific market and we try to find opportunities for our business partners. It is not a secret that the main opportunity in these countries is the localization of pharmaceutical production, and most of our activities are concentrated in this area. This means that we are ready to provide our customers from CIS with a full package of products and services to develop and localize their projects in their own country. Thus, we can introduce the products of our partners

from the rest of the world to the market, so that their products (APIs, excipients, etc.), know-how, or service are a part of these localized projects. Could you please describe your partners? Why are they attractive for the Russian pharmaceutical market? Among our partners there are different players in the pharmaceutical market, and first of all, they are the manufacturers of pharmaceutical substances (from the simplest to the most unique ones), ingredients, as well as development companies of new technologies, drugs, dossiers, etc. Together with us, I assume, they are attractive not only because of their product range, but also because of the above-mentioned service. It is not that important for us how big our partner is. In our (still growing) range of partners, we have players who are significant in the global pharmaceutical market as well as smaller partners who are able to offer some of their unique products to the CIS market. It is important for us that our partners trust us with what we are doing, and we are convinced that we are able to repay this trust by developing new opportunities that these partners could hardly reach without our know-how and experience.

IMCoPharma at GEP-Kiev 2017

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We are Close to Our Customers Interview with Mr. Lutz Thomas, Managing Director of Amino GmbH

Lutz Thomas Managing Director of Amino GmbH, Germany

Mr. Thomas, could you please briefly describe company´s history and your business focus on the world market? Amino GmbH is a manufacturer of amino acids and focuses exclusively on quality sensitive markets, i.e. in pharmaceutical applications and specialty nutritional uses such as medical nutrition products. We are regularly inspected and audited by our worldwide customers and the relevant authorities, and adhere to the strict rules and guidelines of cGMP. Which markets are the most interesting for Amino from the point of view of business potential? After restructuring the company ten years ago we have concentrated our marketing and sales efforts onto the European markets, and have enjoyed substantial growth in this territory. Today we are trying to expand our customer base to serve the entire world with our amino acids, and in parallel, develop our product portfolio to encompass non amino acid APIs by

CONTACT INFORMATION

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investing into R&D. For this purpose we have created a multifunctional platform of young scientists under the AminoVation brand. The AminoVation team is at our customers disposal for joint development projects. How is the market of CIS countries different from other markets Amino is present on? How did the cooperation with IMCoPharma influence your business achievements in Russia and other countries of CIS? The CIS market is geographically close to our home markets and therefore is a natural expansion target. Still, without IMCoPharma’s profound local knowledge and relationships that acted as a catalyst for our goals, the almost immediate success would not have been possible.

to be closer to our customers, to better understand the needs of the market, as well as of the specific customers. This way we can respond to and solve particular demands of the market. We meet our customers not only on local fairs, but together with IMCoPharma, we can organize common business trips to different territories. As a result, we can increase current business and develop new opportunities.

How do you reckon experience Amino has so far on CIS market? We have been here for several years already. With IMCoPharma, we are able

In what way do you find your cooperation with IMCoPharma helpful? We have understood that we should add a wide range of high quality service to our (what we believe) high quality of products. We, as a manufacturing company, focus on what we are good at, and we have found a partner that is able to assure this necessary service. In this way, we are able to offer a complex package of what is expected to our customer. This makes our product more attractive than that of our competitors.

Czech Republic IMCoPharma a.s. Budovatelska 1178/35 743 01 Bilovec Tel.: +420 556 778 411 Fax: +420 597 579 513 sales@imcopharma.com www.imcopharma.com

Russia IMCoPharma Vavilova St. Building 57A 117292 Moscow Tel./fax: +7 499 558 3515 Mobile.: +7 985 256 0097 moscow-office@imcopharma.com www.imcopharma.com

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1 (1)Â / autumn 2017 Pharmaceutical Quality System Founder and CEO of PQE, Gilda D'Incerti graduated with a degree in Economic Statistics from the University of Bocconi in Milan, Italy. Gilda has worked extensively in the field of Information Technology and specifically, IT Compliance on both a national and international level for companies such as Siemens Data (Milan) and Edicon (Montreal). Before founding PQE in 1998, Gilda was the IT Manager for The Menarini Group's Spanish affiliate in Barcelona, following this, Gilda became the Operations Manager for F&J Systems Italy and ultimately an Executive Consultant in Validation for M.I.S. She is globally recognized as an international expert in the field of Computer System Validation and Data Integrity Assurance due to her broad spectrum of project experience. As a Certified Tick-IT and PDA Auditor, Gilda has provided war room support and strategic consultancy for clients in order to comply with the FDA and other regulatory bodies during critical inspections. Most recently, Gilda collaborated with Cofepris in Mexico, creating the new documents for Mexican GMP guidelines.

Emerging Trends in Regulatory Expectations 174

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ULTIMATE TARGET Ensure the Patient Safety within the entire Product Life Cycle from R&D to Distriubution

GRP CLINICAL RESEARC

GLP DEVELOPMENT

GCP CLINICAL TRIALS

GMP REGULATORY APPROVAL FOR MARKET

MANUFACTURING

GDP LOGISTICS

9 July 2017

Gilda D'Incerti Founder and CEO, PQE

INTRODUCTION The ULTIMATE TARGET in the Pharmaceutical and Medical Device industries is to ensure Patient Safety within the entire Product Life Cycle, from R&D to Distribution. Quality of Medical Products (both drugs and devices) becomes a Social and Ethical Responsibility as products are developed, produced and distributed for preventing treating and reducing discomforts of diseases. The final User/Patient trusts the medical products efficacy and simply rely on them. A continuous commitment from manufacturing companies and from those involved in the product life-cycle is in need to continue gaining the Patient Confidence. Together with the principles and guidelines that the regulatory authorities are laying down for the industry (i.e. Regulatory Requirements) we can say that Quality of Medicines is not “only” mandatory by law, but also a Social and Ethical Responsibility. Responsibility implies the importance of the human factor when considering regulatory requirements: people are at the heart of doing, and it is the failures of people — often the combined failures of a number of people — which result in non-compliance in most of cases. Globalization has fundamentally altered the economic and security landscape and demands a major change in the way Regulators/Medical Products Manufacturers, Distributors and Suppliers fulfill their mission.

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Optimized Validation process for broadly used Lab and Production Control Systems

Specialists in Quality Management Systems

SOFTWARE Extended Knowledge of common SW Applications

OPERATING PROCEDURES AND PEOPLE

HARDWARE

Firmware Certified Auditors for Computer System Suppliers

COMPUTER SYSTEM (Controlling System)

Expertise on commonly used Laboratory Instruments and Production Equipment

Qualified Persons and Process Experts for Laboratory & Production Process

EQUIPMENT

CONTROLLED FUNCTION OR PROCESS

Certified Auditors for API manufactures / 3nd Party / Distributors

INFRASTRUCTURE (NETWORK) Experts on IT Infrastructure Design an Qualification

Globalization processes, characteri-zed by longer and more complex Supply Chains, and greater risk of Counterfeiting problems, have been forcing the industry and inspectorates/enforcement Agencies to challenge their current practices. Regulatory Expectations nowadays focus on Harmonization of global regulations in the sense of giving guidelines to address the following:   Overall Process Oriented approach. Since Quality should be built within the product, testing alone cannot be relied on to ensure product quality. Increasingly Validation of Computerized Systems is processes oriented, to ensure both the reliability of GxP/Business Processes and the Integrity of Data managed by each System, including Laboratory and Manufacturing. Many manufacturing sites have multiple systems from multiple vendors and different release versions: integration of manufacturing applications often takes 50% - 80% of a project cost. An effective integration of business logistics systems and manufacturing operations (production, maintenance, labo-

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COMPUTERIZED SYSTEM OPERATING ENVIRONMENT

ratories, material handling, storage etc.) suggest Corporate validation approach as a cost/effective opportunity.   Quality by Design (QbD) with an understanding of the product and the relevant development and manufacturing process along with a knowledge of the risks involved in manufacturing the product and how best to mitigate those risks. Quality by Design principles have been adopted recently by the regulatory authorities as the initiative attempts to provide guidance on pharmaceutical development to facilitate design of products and mitigate the risk through Design. Increased utilization of Risk Management and Change Management, that become paramount important for understanding where to buy, which supplier and sources need to be more controlled and how changes impact Product Registrations.   Increased Reliance on Suppliers and Outsourced processes. The rising complexity in controlling larger Supply Chains with raw materials, components,

sub-assemblies, Finish Goods and Packaging Materials coming from different sources from around the world. Businesses players need to be aware of the supply chains they participate in and to understand the roles they play. As the environment becomes more complex in terms of Products and Technology and due to the fact that Business Margins are more and more limited, companies are forced to rely more on Suppliers and Outsourced processes. Leveraging Suppliers Knowledge, sharing and applying it in supply chains can promote the business performance and efficiency.   Growing focus on Data Integrity as key evidence of Supply Chain reliability and ultimately of the Product Quality. In order to achieve these targets through a feasible and cost-effective strategy, a harmonized approach is required to create Validation Common Standards not only for the traditional owned IT applications, but also for stand-alone Laboratory and Production systems usually managed by the Engineering/Maintenance department.

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GLOBALIZATION IMPACT Globalization can be described as: rapid flows of goods, capital, services, labor and information around the world. Integration of national industries into global ones, is becoming a commonplace and it is increasingly unhindered. One of the strongest driving forces of this globalization is the revolution in Information and communication Technologies, which are now reaching some of the poorest and most remote locations in the world. A big concern for medical products companies occurs due to high costs for research and development, international competition, reduced life time of products and measures of health policy, cost saving, considerations. This pressure in pricing and competition leads to development and manufacture at lower cost, in innovative developing countries like India, China and Brazil. While the various functions of the industry were traditionally all located within the same company, now the vertically integrated supply chains are breaking apart into component activities that can be Outsourced.

The challenges for the Quality of medical products which are triggered by globalization include the assurance of Good Manufacturing & Distribution Practice compliance, new impurities in drug substances induced by alternative manufacturing routes, long lasting transports of medical products passing through various climatic zones, complex supply chains and product transfers. All these factors make the changes in Global Supply Chain inevitable. Regulatory systems of all kinds â&#x20AC;&#x201C; whether dealing with flows of finances, goods or information - find it difficult to keep up with the pace of change. WorldWide recognized Regulators (EU & US) together with other active Regulatory Authorities like (Japan, Brazil, Canada, Australia) have gradually evolved to respond to the increasingly global challenge of medical products development and distribution. Risk based approaches, Decision making techniques, Global Cooperation and Harmonization initiatives, Validation Common Standard are valuable tools to deal with the uprising challenges to ensure that safe, effective and high quality

medical products are developed, registered, manufactured and distributed in the most resource-efficient manner.

GLOBAL COMPLIANCE A model for Global Compliance is the challenge currently faced by all global regulated companies. In order to design an effective strategy and tactic, it is recommended to create teams including all the skills required to implement a feasible and scientifically sound approach. Such approach has to be supported by a centralized organization since a Regulated company shall ensure a uniform level of compliance across its sites and its suppliers. The best solution is to establish a central organization for Data Integrity in order to create standards and support the sites to assess, correct and monitor the Compliance level. This organization (termed Center Of Excellence) will create the Validation Common Standard (Golden Packages) to be provided to the sites in order to

COMPLIANCE CENTRAL TEAM

Centre of Excellence

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ISA 95 MODEL LEVEL

BUSINESS PLANNING & LOGISTICS Plant production scheduling, operational Management...

LEVEL MANUFACTURING OPERATION MANAGEMENT

LEVEL

Dispatching production, detailed production scheduling, reliability, assurance...

MANUFACTURING CONTROLL

LEVEL

Basic Controll, Supervisory Control, Process Sensing, Process Manipulation..

LEVEL

SCADA & DCS Laboratory and Production Equipment

IT Infrastructure

PRODUCTION PROCESSES

facilitate the creation of Validation documentation for the Computer Systems used at the site. The Global strategy of Regulated Manufacturers for Data Integrity shall be based upon the following key steps: Establish a central team to achieve   Common Quality Approach Preliminary Agreed with Global Team   Continuous Consistency between Central and Local Teams   Centralized Control of Validation Deliverables   A Tailored Team for Each Customer Need   Dedicated Local Teams to Specific Geographical Area   Allow a Timely Fashion Response Establish central of excellence (coe), assess current status and plan remediation   Implement a Sustainable Model to ensure Compliance across all company sites   Execute a feasible Assessment and Remediation based upon Global QA

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GLOBAL SYSTEM

SOP, Site Risk priority and Risk associated to each Computer System   Assessment to Verify the Validation Status of Site Control, Production and Computer Systems   Assessment Outputs to be Evaluated to Mitigate Bias for Consistent Results Across Customer Network   Remediation Plans to be Defined Centrally   Approach to Ensure that Sites will not Deviate Create and deploy validation golden standards  Develop documentation packages for each type of systems mostly used in the Laboratory and Manufacturing environment  Provide guidance and training to each site to create system specific  Ensure harmonized approach for systems across sites The rollout of this strategy allows Regulated Manufacturers to achieve sustainable and harmonized compliance of Computer Systems and, ulti-

mately, to ensure the Integrity of Data where the Product Quality is built upon. A Suppliers audit and monitoring program is another subject that receives great benefit from a centralized-tailored approach.

PROCESS ORIENTED APPROACH The classical company interpreta-tion model based on ISA95 implies the need of creating common standards consistent and integrated in all the levels. These standards provide defini-tions around people, materials and equipment, as well as procedural models on how these are combined to make products. Validation common standards and templates can be considered one of the milestones for the implementation of the ISA95 model not only for the traditional owned IT applications, but also for the systems, such as stand-alone Laboratory and Production systems,

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traditionally managed by the Engineering/Technical Services department. The relevance of assuring the validated status of compliance is emphasized not only in projects implementation, but also during the on-going phase. This new vision considers the medical product during its whole lifecycle, starting from development through technical transfer to routine manufacturing and decommissioning. Risk management tools and a robust Quality System are the pillars for building a more systematic approach to validation. All data and information should be secured, accurate, and reliable and only those personnel required viewing, adding, or updating a given piece of data are in fact allowed to access it. Reliable Data Collection shall be in place: any delay in releasing a batch of product is not only costly but cost of non-compliance consumes additional resources of the company. It is therefore crucial that during the manufacturing phase analytical data be collected, compiled, and submitted in a timely, accurate and reliable manner.

NEED FOR DATA INTEGRITY In the last 2-3 years, regulatory authorities became focused more on Software and Computerized Systems. The agencies detected problems in the Computer Compliance such as: incomplete or faulty recordkeeping; repeated and undetected errors in critical data; reduced capability to recall drugs and medical devices; release of contaminated blood and components. The numbers of US/FDA’s Warning Letters related to Data Integrity has strongly and consistently increased in the last twelve months. This Regulatory pressure together with the technology and environment complexity shall be counterbalanced by: Validation, Quality Risk Management, Record Management, and Supplier Management. Data Integrity became one of the highest priority and can be described as “The condition existing when data is unchanged from its source and has not been accidentally or maliciously modified, altered or destroyed”. [National Information Assurance Glossary] Reliability of Data defines consis-

tency also referred to as: repeatability, method precision or system precision. It is imperative to demonstrate that: Regulated data collected through Logistics, Laboratory, Production, Distribution and other systems have been generated and maintained with care, are technically and procedurally protected against manipulations. Documentation and Result Reporting have been done in real time (action), can be clearly identified, have been standardized, predefined, authorized (and Person who recorded must be clearly identifiable). Data integrity Control ensures the chain of evidences backward from the final documents; the Audit Trail Review process is required to ensure that data show no violation patterns. Each Regulated Company is required to assess the level of compliance to regulations (e.g. EU cGMP Annex 11) and to correct any deficiency in order to reach the required compliance level.

The System virtuous life cycle Controlled Retirement

NEED FOR BUSINESS IMPROVEMENT

Requirements Supplier Evaluation & System Selection

Operation

GO LIVE

Documentation Documentation

RETIREMENT

Specify & Design

REGULATED COMPANY

SYSTEM INTEGRATOR

Validation Testing

VALIDATION

Build Supplier Testing

REGULATED COMPANY

ACCEPTANCE

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REGULATORY REQUIREMENTS SET FORTH BY 21 CFR PART 11 & EU GMP ANNEX 11 ARE ORIENTED TO ENSURE DATA INTEGRITY

IF REGULATORY REQUIREMENTS ARE MET, DATA INTEGRITY IS ENSURED

SECURITY •

RELIABILITY•

REGULATORY REQUIREMENTS TRACEABILITY•

DATA INTEGRITY

ACCOUNTABILITY•

ENSURE COMPUTERS SYSTEMS VS REGULATORY REQUIREMENTS TO ENSURE CURRENT LEVEL OF DATA INTEGRITY

CONCLUSIONS Quality of Product (ind. raw materials, components, sub-assemblies, packaging materials) rely upon integrity of Laboratory and Production Records and is the ultimate responsibility for Market Authorization Holders (MAH) New Challenges are triggered by Global Supply Chain Process A number of different Enforcement

measures have been defined by Regulatory Bodies to mitigate Risk to Product Quality Compliance to new Regulatory Requirements is ultimately based upon Data Integrity Quality of Product (ind. raw ma-terials, components, sub-assemblies, packaging materials) rely upon integrity of Laboratory and Production Records and is the ultimate responsibility for Market

Authorization Holders (MAH) Outsourcing can be used by Regulated Companies provided that an effective Provider Qualification/Monitoring process is in place Validated Technology might be the only chance MAHs may have to face the current challenges for medical products industry (globalization, cost reduction, data integrity).

APPLICABLE RULES AND GUIDELINES Analysis described in this document has been executed according to the following rules and guidelines:   Rules: [1] [2] [3] [4] [5] [6]

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US Food & Drug Administration – Code of Federal Regulations, Title 21, part 210, “Current Good Manufacturing Practice in Manufacturing, Processing, Packaging, or Holding of Drugs; General” US Food & Drug Administration – Code of Federal Regulations, Title 21, part 211, “Current Good Manufacturing Practice (GMP) For Finished Pharmaceuticals” European Community – Guide to Good Manufacturing Practice for Medicinal Products (The Rules Governing Medicinal Products in the European Community, Volume IV) US Food & Drug Administration - Code of Federal Regulations, Title 21, part 820: “Medical Devices Current Good Manufacturing Practice” US FDA Code of Federal Regulations, Title 21, Part 803, “Medical Device Reporting” US Food & Drug Administration – Code of Federal Regulations, Title 21, part 11: “Electronic Records; Electronic Signatures; Final Rule”

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supported by [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17]

European Commission, The Rules Governing Medicinal Products in the European Union – Volume 4: Good Manufacturing Practices Medicinal Products for Human and Veterinary Use, Annex 11 – June 2011 European Commission – The Rules Governing Medicinal Products in the European Union – Volume 4 – Part III: Quality Risk Management – March 2008 (Adoption as ICH Q9 guideline Step 4) European Commission – The Rules Governing Medicinal Products in the European Union – Volume 4 – Part III: Pharmaceutical Quality System – June 2008 (Adoption as ICH Q10 guideline Step 4) Resolution – RDC N° 17, of 16/04/2010:Union Official Gazette Section 1 “Provides for the Good Practices of Medicament Manufacturing” (Anvisa) NOM-059-SSA1-2013, “Buenas prácticas de fabricación de medicamentos”, Mexican GMP Resolution - 2013019704, of 05/07/2013, “Por la cual se adopta el Sistema Integrado de Gestión de Calidad del Instituto Nacional de Vigilancia de Medicamientos y Alimentos INVIMA” Reglamento Sustitutivo del Reglamento de Buenas Prácticas de Manufactura (BPM) para Laboratorios Farmacéuticos - Acuerdo Ministerial 00000760 Registro Oficial 359 del 10 de enero del 20 RESOLUÇÃO - RDC Nº 59, DE 27 DE JUNHO DE 2000 - Agência Nacional de Vigilância Sanitária - BOAS PRÁTICAS DE FABRICAÇÃO DE PRODUTOS MÉDICOS DIGEMID (Direccion General Medicamentos, Insumos y Drogas) - Manual de Buenas Practicas de Fabricacion RM n° 055-99-SA/DM Russian Ministry Of Industry And Trade Of The Russian Federation – Appendix N 11 to Regulation Good Manufacturing Practices – June 2013 Chinese Annex 1 of Good Manufacturing Practice for Drugs – May 2015

Guidelines: [18] US Food & Drug Administration – Guidance for Industry Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations, September 2006 [19] US Food & Drug Administration – Guidance for Industry Process Validation: General Principles and Practices – Revision 1, January 2011 [20] US Food & Drug Administration – General Principles of Software Validation; Final Guidance for Industry and FDA Staff, January 2002 [21] US Food & Drug Administration – Guidance for Industry: 21 CFR Part 11 – Electronic Records and Electronic Signatures: Scope and Application, August 2003 [22] PIC/S Good Practices for Computerized systems in regulated “GxP” environment, Pharmaceutical Inspection Co-operation Scheme guidance, September 2007 [23] PIC/s Guidance Draft August 2016 PI-041-1 "Good Practices for Data Management and Integrity in Regulated GMP/GDP Environments" [24] GAMP Forum – GAMP Guide, A Risk-Based Approach to Compliant GxP Computerized Systems – Ver. 5.0 [25] GAMP Forum – GAMP Good Practice Guide: The Validation of Legacy Systems [26] GAMP Forum – GAMP Good Practice Guide, Testing of GxP Systems [27] GAMP Forum – GAMP Good Practice Guide, IT Infrastructure Control and Compliance [28] GAMP Forum – GAMP Good Practice Guide: Validation of Process Control Systems [29] GAMP Forum – GAMP Good Practice Guide, Global Information Systems Control and Compliance [30] GAMP Forum – GAMP Good Practice Guide, A Risk-Based Approach to Compliant Electronic Records and Signatures [31] GAMP Forum – GAMP Good Practice Guide, A Risk-Based Approach to Operation of GxP Computerized Systems [32] MHRA GMP Data Integrity Definitions and Guidance for Industry March 2015) [33] Agência Nacional de Vigilância Sanitária - Guia de Validação de Sistemas Computadorizados [34] WHO Annex 5 Guidance on Good Data and record management practices May 2016 [35] FDA-Data Integrity and compliance with CGMP (Draft, April 2016) [36] ICH E6(R2) Good Clinical Practice Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management (2014) [37] OECD Series On Principles Of Glp And Compliance Monitoring Number 17 Application of GLP Principles to Computerised Systems [38] SPE GAMP Guide Records and Data Integrity [39] CFDA Drug Data Management Standard

HEADQUARTERS Località Prulli, n°103/C • 50066 Reggello • (FI) • Italy Tel. +39 055 52 75 100 • Fax +39 055 52 75 142 www.pqe.eu • info@pqe.eu

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DATA INTEGRITY ASSURANCE

CONTACTS: Tel. +39 055 52 75 100 / +7 495 133 98 36 www.pqe.eu • info@pqe.eu

PQE is an ISO 9001 certified technology solutions and compliance consulting services company with global capabilities deliverable throughout the entire product quality life cycle, allowing us to offer services at a very competitive price.

IT INFRASTRUCTURE QUALIFICATION 182

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PQE supports customers in the implementation of a cost effective and feasible validation strategy. PQE's integrated approach enables client’s data integrity assurance and validation requirements through a scalable and fully regulatory compliant delivery model, based on a robust risk analysis.

COMPUTER SYSTEM VALIDATION

Computer System Validation has been PQE’s core business since its foundation in 1998. We have an unmatched track record of providing our clients with strategy and execution support with their FDA / EMA / WHO / TGA / SSA/ SFDA /ANVISA / INVIMA and other Local Regulatory Body compliance projects.

Our team with its extensive years of experience enables us to support our clients in "turnkey" validation projects for all types of computerized systems.

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1 (1)Â / autumn 2017 Exhibitions, Forums, Conferences

Key Comprehensive Pharma Event of the Spring

From March 28 to 30, the 75th pavilion of VDNH Moscow welcomed the 7th International Forum on Pharmaceuticals and Biotechnology and Exhibition for Producers and Distributors of Pharmaceutical Ingredients and Medicines IPhEB&CPhI Russia 2017 19 May 2017

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ver the past seven years, the event has become a traditional meeting place for the pharmaceutical industry professionals. Deputy Minister of Industry and Trade of the Russian Federation Sergey Tsyb in his welcoming message to the participants and guests of the exhibition noted that IPhEB&CPhI Russia was a business platform for innovations, modern technologies, and new approaches that could change the Russian pharmaceutical market. This year, more than 150 participants from 19 countries, including India, China, the Czech Republic, Greece, Sweden, Italy, the United States, Russia, and etc demonstrated their products and solutions at the exhibition area. The exposition of the Ministry of Industry and Trade of the Russian Federation was one of the event's most important. The collective exposition covered the production of pharmaceutical substances. The increase of production vol-

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umes, and the expansion of the range of substances manufactured in Russia is an important step allowing to establish the national full-cycle pharmaceutical production of drugs. At the Minpromtorg’s exposition, the domestic companies, such as NPO Petrovax Pharm, Perm Chemical Company, Berahim, INPTS Peptogen, Usolie Siberian Chemical Pharmaceutical Plant, and Pharmstandard companies demonstrated their latest achievements and products. ZAO Retinoids demonstrated substances and drugs for the treatment of skin diseases. Nacimbio presented drugs and developments in the field of immunology, produced and supplied by its subsidiaries: Sovigripp and Ultrix vaccines, the domestic botulinum toxin preparation Relatox, tick-borne encephalitis vaccines EnceVir and EnceVir NEO, probiotics, bacteriophages, and a wide range of drugs. FSUE Moscow Endocrine Plant announced an import substitution project

focused on the introduction of proprietary pharmaceutical substances. The exposition of the Cluster of Medical and Pharmaceutical Industries and Radiation Technologies of St. Petersburg attracted the attention of many visitors and guests at the exhibition. Farmproekt, WERTEKS, Polysan, ActiComp, Generium, Nanolek, Geropharm Group, SamsonMed, Houm of Pharmacy, NP Medical and Pharmaceutical Projects of the 21st Century presented their achievements and latest developments. Key moments from companies’ lives could be found in gallery the of Cluster. Dmitry Chagin, CEO of the Association of Pharmaceutical Manufacturers of the Eurasian Economic Union, says that St. Petersburg’s pharmaceutical industry is actively developing. In the city’s economic development concept for 2030, the pharmaceutical industry ranks second after tourism. Companies that offer equipment for full-cycle production of soft gelatin capsules also participated at the

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IPhEB&CPhI Russia. Among them was Pharmcontract GC, the largest national distributor of technological and analytical equipment together with its Korean partner Sky Softgel Co LTD. Sky Softgel is well-known its production of blister machines, and counting-filling lines of the highest quality, and its patented technologies. During three exhibition days, the show was attended by 3,119 visitors from 54 countries. The efficient work of attendees and successful negotiations were greatly facilitated by Matchmaking program. This is a powerful, effective, and intuitive online matchmaking tool, which allows you to search for and arrange meetings with exhibitors. This year, 936 companies were registered, and 421 meetings were held. X7 Research became one of the most active users of Matchmaking service. Pavel Fedorov, Business Development Director of X7 Research, points out that company achieved their planned business goals with Matchmaking program, and continues to participate in the event. “We successfully held all planned meetings and negotiations with partners thanks to the convenient system of registration and appointment of meetings,” he said. “At the same time, productive cooperation with exhibitors of IPhEB&CPhI Russia helped us find new business contacts outside the planned meetings. I am convinced that the com-

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bination of Matchmaking with the exhibition is the most comfortable and effective format of business communication.” The specialists and experts were welcomed to take part in the extensive Business programme of the IPhEB&CPhI Forum. In 2017, the Business Programme included more than 5 discussions of different formats on acute and interesting topics. Among them - the work of the domestic inspectorate system, the prospects for development of the Russian pharmaceutical market, the aspects of storage and transportation of medicines, labelling and global trends in the field of pharmaceutical packaging. At the Business program, the Ministry of Industry and Trade of the Russian Federation arranged a round table discussion on the production of substances in Russia as an important factor in the development of the national pharmaceutical market. The round table was moderated by Lilia Titova, Executive Director of the Union of Professional Pharmaceutical Organizations. The discussion centred around the registration and use of substances in proprietary production of medicines, the economy of production of substances intended for sale; the interaction of science and business in this field, the company’s long-term specialization in the production of pharmaceutical substances, the prospects for opening a new production of this type in Russia, and export poten-

tial of the industry. The round table was attended by leading domestic and international manufacturers and suppliers of substances. Among them - S amson-Med, ActiComp, Indukern-Rus, Polysan, and others. At the Forum, NC Pharm Logistic signed a cooperation agreement with the Samara pharmacy chain Vita. NC Pharm will act as a stable and reliable partner for further geographical expansion of the Vita chain. NC Pharm’s warehouses in the Moscow region and Nizhny Novgorod will provide responsible storage, and order processing services for Vita. They will also perform cross-docking operations, ensuring not only the consolidation of medicines coming in from various pharmaceutical manufacturers, but also the delivery of orders to pharmacies. The signing ceremony was attended by the director of NC Pharm Logistic Harold Vlasov, and the director of the pharmacy chain Igor Borovikov. The official opening ceremony of IPhEB&CPhI Russia was attended by the director of FBI “State Institute of Drugs and Good Practices” Vladislav Shestakov, CEO of the Association of Pharmaceutical Manufacturers of the Eurasian Economic Union Dmitry Chagin, President of Unosource Prashant Patak, Brand Director CPhI Russia Orhan Caglayan, and General Director of RESTEC® Exhibition Company Igor Kirsanov.

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1 (1) / autumn 2017 In his welcoming speech, Vladislav Shestakov accentuated that over the past few years, Russia has become a full-fledged global player of the pharmaceutical industry. Trends seen in the country’s pharmaceutical industry indicate an increase of the international companies’ interest in entering the Russian market. Dmitry Chagin agrees: “Today, the domestic pharmaceutical industry ranks second in terms of growth rates, giving way only to the tourism sector. The Russian pharmaceutical market continues to grow, having reached 16 billion rubles a year for the first time.” Once again, IPhEB&CPhI Russia proves the importance of issues listed above. In his welcoming speech, Orhan Caglayan said: “One cannot fail to note the qualitative breakthrough in the way this event has been organised and held this year. The Forum has turned into an international discussion platform for issues related to interregional and international aspects of development of industry.” The event was organised by RESTEC® Exhibition Company and UBM, with active support of the Ministry of Industry and Trade of the Russian Federation and the Union of Professional Pharmaceutical Organizations (SPFO). In 2017, the Unosourse Pharma Ltd acted as the platinum sponsor of IPhEB&CPhI Russia, Pharmcontract GC was the sponsor of the registration area and ROID translation agency was the language support partner. The next International Exhibition and Forum IPhEB will be held in April 2018 in St. Petersburg.

PLANS FOR 2018

АBОUT ІPHЕB RUSSIA

From 2018, IPhEB will not be а CPhІ brаndеd еvеnt in Russia. UBM wіll cоncеntrаtе оn strеngthеnіng іts glоbаl phаrmа pоrtfоlіо grоwth, wіth а fоcus оn bеttеr sеrvіng custоmеr nееds. Thе cоmpаny іs еxpаndіng sаlеs іn еіght оthеr CPhІ brаnds glоbаlly, іncludіng а nеw еvеnt іn thе Mіddlе Еаst & Аfrіcа fоr 2018, аnd thrее еdіtіоns wіth mоrе thаn 40,000 аttеndееs еаch yеаr (CPhІ Wоrldwіdе, CPhІ Іndіа, аnd CPhІ Chіnа). Five years of cooperation with a strong international company with well-established brand with a long history, allowed the Restec team to receive the important experience. Focusing on high-quality service, innovative promotional tools, Restec continues to conduct and develop the pharmaceutical event fоr Russіа аnd CІS countries under the stаnd-аlоnе IPhEB Russia brand name. We invite pharmaceutical companies to participate in the event on 11-13 April 2018 in St. Petersburg, Russia.

Thе fіrst Іntеrnаtіоnаl Fоrum оn Phаrmаcеutіcаls Еngіnееrіng аnd Bіоtеchnоlоgy (ІPhЕB) wаs hеld іn 2011 іn St. Pеtеrsburg аnd was оrgаnіzеd by RЕSTЕC Еxhіbіtіоn Cоmpаny. Thе ІPhЕB іs thе оnly spеcіаlіsеd еvеnt fоr АPІ аnd Fіnіshеd Fоrmulаtіоns sеrvіng thе Russіаn mаrkеt. Thе ІPhЕB іs а mееtіng plаcе fоr prоfеssіоnаls frоm аcrоss thе еntіrе Russіаn phаrmаcеutіcаl іndustry. It fеаturеs еxpеrt оpіnіоns, аnаlysіs, аnd dеbаtеs оn hоw tо drіvе fоrwаrd busіnеss іn thе rеgіоn.

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Fоr mоrе іnfоrmаtіоn vіsіt: gotoіphеb.com

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Pharma contract services Pharma contract services

contract services

1 (1) / autumn 2017

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contract services

Co-located with:

24 - 26 October 2017

Messe Frankfurt, Germany

REGI STER NOW gotoc phi.c

om/re

giste

CPhI Worldwide:

The world's leading pharmaceutical exhibition Bringing every aspect of the pharmaceutical supply chain together in one location

“Big pharma, small pharma, specialty pharma and packaging.. everyone is here!”

“You have to be here to be a big player in the industry!”

Cedric Roesler CEO, Diffway

WHAT VISITORS SAID ABOUT THE 2016 SHOW*

Cosmas Mukaratirwa Managing Director, Cospharm

WHY ATTEND CPhI?  Cost Effective: 42,000 pharma professionals from 150+ countries in one location

81%

rate CPhI Worldwide as the leading global gathering of the pharmaceutical industry

 Entire pharma supply chain: 2,500+ exhibitors covering ingredients, APIs, excipients, finished dosage, contract services, packaging, machinery and more

80%

agree that CPhI Worldwide is the most important show in the pharmaceutical industry’s calendar

 Industry developments: stay up-to-date on market news and trends during the Pre-Connect Congress, CPhI Pharma Innovation Awards and Pharma Insight Briefings

81%

believe that CPhI Worldwide is a great show to find new business opportunities

 Free access: 1 ticket, 5 shows, 150 free seminars, innovation tours, innovation gallery and matchmaking

* post show survey 2016

2017 EXHIBITORS INCLUDE:

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1 (1) / autumn 2017 Exhibitions, Forums, Conferences

Welcome

to the 28th CPhI Worldwide!

Mix with the world of pharma, products, people & solutions

CPhI Worldwide - one of the biggest pharmaceutical industry exhibitions - will take place on 24 – 26 October 2017 in Frankfurt, Germany. GMP news is the media partner of this event and will take part in it. Please visit our stand KH12

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™

PhI Worldwide will take place on 24 – 26 October 2017 at the Messe Frankfurt, Germany. After last year’s record-breaking event, the world’s most prominent pharma executives are ready to gather again for three days of collaboration, information dissemination, and discussions that will define the future of the industry. Running concurrently with the pharmaceutical ingredients halls are four other nearby brands, helping visitors quickly identify the right event for their business’s needs: ICSE is an outsourcing focused event designed to connect the pharmaceutical community with contract providers from clinical trials, CROs, logistics providers, data management firms and CMOs.

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InnoPack connects buyers and specifiers from the packaging and pharmaceutical industries. P-MEC Europe features exhibitors from traditional largescale capital equipment to companies focused on instrumental analysis, measuring and testing technologies, materials testing, laboratory and quality control. Finished Dosage Formulation for every aspect of the finished dosage supply chain. Beyond the exhibition, the Pharma Forum includes access to media publications; the latest innovative products and services in the Innovation Gallery; free high value content at the Pharma Insight Briefings and Exhibitor Showcases; and the chance to share your experiences and recharge your batteries in the Pharma Insight Lounge. This year’s CPhI Pre-Connect Congress will take place on the 23rd of October, the day prior to CPhI Worldwide, and offers its most exciting and comprehensive agenda to date. This platform gathers experts and thought leaders from the entire pharmaceutical supply chain to provide insights into the latest developments.

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Emphasizing that CPhI Worldwide is also a key opportunity to learn about new trends, business insights and prospects, the revered CPhI Annual Report launches its 5th edition. This eagerly anticipated collection of essays will provide thought leadership on the industry’s hottest topics and issues. Finally, in recognition of pharma excellence, the vastly expanded CPhI Pharma Awards returns to the show for its 14th year, with eight new categories – awarding an impressive 20 commendations in celebration of the most successful and innovative pharma achievements. Held in the heart of Europe’s largest pharma market, this year’s event is an unmissable opportunity to network with existing contacts, learn, and engage vital new customers that will be invaluable in moving your business to the next level. Register now for CPhI Worldwide 2017 at: www.cphi.com/europe/ Please note that free registration for CPhI Worldwide closes on the 15th October 2017.

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CPhI Worldwide: "Our Goal is to Be the Vital Conduit Connecting the Industry" Interview with CPhI executives

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CPhI is one of the biggest pharmaceutical industry exhibitions in the world. What are the main figures can such a large-scale industry event be characterized by? (Analytics and statistics, number of visitors, number of countries etc.) CPhI Worldwide, as the world’s largest pharmaceutical trade show, is not only seen as a bellwether of global pharma’s current strength, it also a key indicator of future trends and prospects. A strong show is indicative of a prosperous industry and in the last five years attendee numbers have risen by 50%. The 2016 CPhI Worldwide event in Barcelona saw an all-time record attendance of over 42,000 people, with 2,550+ exhibitors from 156 countries. Building on this success, CPhI Worldwide 2017 will host over 20 dedicated zones covering ingredients, APIs, excipients, contract services, packaging, biopharma, machinery, and many more. What are the main goals of the exhibition and what are the main milestones you are aiming to achieve? Our goal at CPhI is to be the vital conduit connecting the industry, to ensure we facilitate greater supply chain integration and encourage global partners to work together. This is why each year we continue to add new zones and events to CPhI Worldwide, to enable companies and people to meet. It's a global industry, with many players and sometimes a chance encounter is all the catalyst needed to reimagine what is possible. It’s the one place you can meet one-to-one with hundreds of providers and see first hand the different services and products. But it’s more than just a platform to score suppliers and meet contacts; it’s about interacting with other creative minds to envisage new approaches and better learnings. An inevitability of gathering this many people together for a focused week is that each year vital new methods emerge and there is a cross pollination of ideas and approaches. This principle is why each year we continue to add new zones and events to CPhI Worldwide, to help encourage new partnerships and help different parts of the industry to work closer together. Where else can you meet scientists, business development executives and CEOs to talk through a potential formulation challenge, a flexible sourcing need,

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an outsourcing contract and ingredients provider? And all in the same day.

ber of logistical challenges – so it’s very much horses for courses.

What is the regional division of the CPhI exhibition? What is the main train of thought behind the creation of each of the exhibition divisions? CPhI has events in all of the major global pharma markets that have the biggest growth potential, but we also tailor each event to cater for the specific needs of the region. For example, in China and India they have large domestic manufacturing markets and so these events are jointly branded with P-MEC to support the industry’s need for the latest pharmaceutical machinery. Similarly, at CPhI India – a market with a huge finished dosage and generics industry – there is a larger presence of Chinese API manufacturers (as well as Indian). In contrast, North America has the most advanced and prosperous market – and so the event isn’t just catered to ingredients or manufacturing, it has a far broader scope with a big focus on innovation and content. Or in South East Asia, where we bring in distributors as this region has a num-

There are many other exhibitions taking place within the CPhI exhibition. What are the essential requirements for becoming one of the exhibition events under your "roof"? What started as an event that just covered ingredients many years ago has now become the one event that covers the entire global pharmaceutical industry supply chain, from drug discovery and development to commercialization, and from API to finished dosage form. But we also cater for all of the adjacent industries from pharma packaging to pharma machinery and contract services, and each year our bio pharmaceuticals audiences grow as well. The event breaks down its co-located events in zones for different parts of the industry and features country pavilions for those looking for country specific suppliers. The zones include ICSE, P-MEC, InnoPack, Finished Dosage Formulations (FDF), Excipients, Fine Chemicals & Intermediates, Cleanroom Technology and CRO & Clinical Trials Zone, amongst others.

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