Express Pharma (Vol.13, No.20) August 16-31, 2018 by Indian Express

VOL. 13 NO. 20 PAGES 72

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Market

Dr Michel Pairet, Member of the Board of Managing Directors, Innovation Unit, Boehringer Ingelheim

16-31 AUGUST 2018, ` 40

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CONTENTS Vol.13 No.20 August 16-31, 2018

HEALING BEYOND BOUNDARIES,AGAINSTALL ODDS

MARKET

Chairman of the Board Viveck Goenka

In Part Two of our Independence Day coverage, we identify trade and non-trade barriers faced by India Pharma Inc as it seeks to serve patients beyond boundaries by delivering cost effective quality medicines | P18

Sr. Vice President-BPD Neil Viegas Asst. Vice President-BPD Harit Mohanty Editor Viveka Roychowdhury* BUREAUS Mumbai Usha Sharma, Raelene Kambli, Lakshmipriya Nair, Sanjiv Das, Swati Rana, Tanuvi Joe New Delhi Prathiba Raju DESIGN Asst. Art Director Pravin Temble Chief Designer Prasad Tate

MANAGEMENT

RESEARCH

PHARMA TECHNOLOGY REVIEW

P10: INTERVIEW Dr Michel Pairet Member of the Board of Managing Directors, Innovation Unit, Boehringer Ingelheim

ANGLE TRAINING FORUM HOSTS FIRST EVER ‘KUMBH MELA’ OF PHARMA TRAINERS

ANALYTICA ANACON INDIA, INDIA LAB EXPO TO BE HELD IN HYDERABAD

Senior Designer Rekha Bisht Graphics Designer Gauri Deorukhkar Senior Artist Rakesh Sharma

Digital Team Viraj Mehta (Head of Internet ) Dhaval Das (Web Developer) Photo Editor Sandeep Patil Marketing Team Rajesh Bhatkal Ambuj Kumar Debnarayan Dutta Ajanta Sengupta E Mujahid Nirav Mistry PRODUCTION General Manager BR Tipnis

DIRECT TO CONSUMER ADVERTISING OF MEDICINES AND MEDICAL DEVICES A CALL FOR ACTION!

CUSTOMER VOICE – IT MEANS BUSINESS!

PLAYERS IN GLOBAL CANCER SUPPORTIVE CARE PRODUCTS MARKET FOCUS ON GETTING APPROVALS FROM GOVERNING BODIES

IND AS 115 - KEY IMPACT FOR LIFE SCIENCES ENTITIES

APTAMERS IN CANCER THERAPEUTICS

P32 INTERVIEW Sajiv Nath MD, Yokogawa India

30 31

GENOME EDITING USING CRISPR-CAS9 SYSTEM SHOWS TREMENDOUS PROMISE EISAI/BIOGEN TO ADVANCE ALZHEIMER’S DRUG, PROVIDE FRESH HOPE

Automation solutions for PHARMA industry www.br-automation.com

P35 INTERVIEW Virendra Chaudhary Director, Algor Logistics

Manager Bhadresh Valia

Express Pharma® Scheduling & Coordination Santosh Lokare CIRCULATION Circulation Team Mohan Varadkar

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EXPRESS PHARMA

August 16-31, 2018

EDITOR’S NOTE

Playing for global stakes

ndia has a very visible presence in the global pharmaceutical sweepstakes. For instance, while Sun Pharmaceutical Industries (Sun Pharma) is reportedly the fifth largest speciality generic pharma company in the world, Lupin bags the eighth rank in terms of global generic pharma companies in terms of revenues in FY2018-19 (Bloomberg). India is expected to rank among top 3 pharma markets in terms of incremental growth by 2020, with a 20-22 per cent share of of global export volume. But as a popular ad jingle goes, ‘yeh dil mange more.’ Unfortunately, it won’t be a cakewalk. Pharma exporters are reportedly facing a push back. Therefore if the first part of our Independence Day special coverage, (issue dated August 1-15, 2018), examined how the three ‘Is’ — Indigenisation, Innovation and Information — could be leveraged to help India achieve true independence in the pharma sector, the second part (issue dated August 16-31, 2018) examines how trade and non-trade barriers are threatening free and independent trade of medicines, not just ‘Made in India’ medicines, across boundaries. Though companies quoted in the cover story readily admit that global regulations are common to all pharma exporters irrespective of nationality, it is clear that the next quantum of growth in exports will not be as easy as it was in the last decade. The MSME sector in particular is feeling the pinch as the low hanging fruit has been picked and most do not have the resources to stretch to clear the higher regulatory bar. The common refrain is that most of these regulations are actually export barriers and protectionist measures. Government of India, through the Department of Pharmaceuticals (DoP), Ministry of Chemicals & Fertilisers, has stepped up efforts to resolve these issues. Indian pharma exporters have been requested to report country-specific export issues to DoP Joint Secretary Shri Navdeep Rinwa. According to a notice in the weekly bulletin of India Drug Manufacturers’ Association (IDMA) dated July 22-30, 2018, such inputs will ‘strengthen the Department with appropriate material for discussion in various bilateral and multilateral fora under the provisions of various Trade Agreements.’ IDMA has said that they will compile these communications from members on a weekly basis and submit a consolidated report to the Joint Secretary. Most bigger pharma companies have moved to the next level of exports: the trade of intellectual

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August 16-31, 2018

Most bigger pharma companies have moved to the next level of exports: the trade of intellectual property, in the form of clinical stage assets in return for milestone payments and local clinical expertise

property, in the form of clinical stage assets in return for milestone payments and local clinical expertise. Take for instance the most recent example: Glenmark’s recent licencing deal with China’s Harbour BioMed for GBR 1302, the former's bispecific antibody targeting HER2 and CD3 for the treatment of HER2-positive cancers. Potentially worth more than $120 million in addition to royalties, the deal covers the development, manufacture and commercialisation of GBR 1302 in the Greater China territory, with the Indian company scouting for partners in other parts of the globe. The region has a “predominance of certain HER- 2 positive cancers (which) presents a significant clinical need,” said Glenn Saldanha, Chairman and Managing Director, Glenmark, in a press statement. Of course, such licensing deals have their own challenges. Though Glenmark will receive an upfront payment, further payments will be dependent on achieving pre-specified development, regulatory and commercialisation milestones, as well as tiered royalties on net sales for any approved products from Harbour BioMed. The Chinese company will lead the clinical development and commercialisation of GBR 1302, with the option to manufacture GBR 1302 for the Greater China market. Or take Lupin’s strategy for its biosimilar etanercept (YLB113). Developed in partnership with Japanese Yoshindo and YL Biologics, a joint venture between Lupin’s subsidiary Lupin Atlantis Holdings SA (LAHSA), the company recently partnered with another Japanese firm, Nichi-Iko for the distribution, promotion and sale of YLB113 in Japan. These are but two examples of many such transnational deals struck by big Indian pharma companies. Success has been mixed but the experience has left us wiser. Thus if we want to retain the reputation of being 'the largest supplier of generic medicines globally' (IBEF website), we will have to play by the new rules of the game. And the answer as of now seems to be collaboration. To paraphrase a quote attributed to Henry Kissinger (“America has no permanent friends or enemies, only interests,”) India Pharma Inc cannot consider countries or companies as permanent friends or enemies. It has to look for partners with permanent interests.

VIVEKA ROYCHOWDHURY Editor viveka.r@expressindia.com

MARKET I N T E R V I E W

The key focus for Boehringer Ingelheim India is diabetes, stroke, oncology and respiratory Dr Michel Pairet, Member of the Board of Managing Directors, Innovation Unit, Boehringer Ingelheim, discloses about the company’s strategic plans for both, global and the Indian markets, in an exclusive interaction with Sanjiv Das At the annual press conference in Ingelheim, several investments in China were announced. What is BI’s strategy when it comes to investing in India? In 2017, Boehringer Ingelheim (BI) in India invested 125,000 euros in property, plant and equipment. BI India has a focused strategy of bringing its innovation based research molecules to India to address evolving needs of the patients. Co-marketing partnerships have also played a major role in strengthening our presence and reaching a larger target audience. The key focus for Boehringer Ingelheim India is diabetes, stroke, oncology and respiratory. Our launches over the last few years are Pradaxa (dabigatran for stroke prevention in atrial fibrillation) and Trajenta (linagliptin in diabetes) in 2012, Trajenta Duo (FDC of linagliptin and metformin) in 2014, followed by the launch of Xovoltib (afatinib) for NSCLC and co-marketing agreement with Lupin for the launch of 2nd brand of linagliptin and linagliptinmetformin under the brand names Ondero and Ondero Met respectively in 2015. In 2016, we launched Jardiance (empagliflozin) in diabetes and had a strategic

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August 16-31, 2018

metformin) and Glyxambi (empagliflozin-linagliptin) as well as the expansion of our collaboration with Lupin for co-marketing of two oral antidiabetic drugs Gibtulio Met (empagliflozin – metformin) and Ajaduo (empagliflozinLinagliptin). BI has a robust pipeline for the future and we are enthusiastic about the introduction of the same over the next 10 years. Currently, we are evaluating the product pipeline for India, with a focus on our Human Pharmaceuticals and Animal Health verticals. BI India is currently evaluating introduction of its global products. A number of products will be in the specialty areas such as oncology.

Currently, we are evaluating the product pipeline for India, with a focus on our Human Pharmaceuticals and Animal Health verticals partnership with Lupin for the 2nd brand of empagliflozin, under the brand name Gibtulio. In 2017, Boehringer Ingelheim India entered the respiratory space

with the launch of Cyendiv (nintedanib) for IPF (Idiopathic Pulmonary Fibrosis). This year saw the launch of FDCs Jardiance Met (empagliflozin-

What are the global pharma trends that BI is looking to tap? At BI, we are driven by the desire to serve mankind by improving human and animal health. Aiming to make significant contributions to healthcare, we focus on diseases, which have so far not been satisfactorily treated. We innovate to make breakthrough therapies and life-enhancing improvements available to patients. The company continues to be successful because it excels in innovation and delivers the

highest quality. Therefore, BI constantly monitors global trends and pioneers in several future-oriented fields. This striving for innovation is deeply rooted in the company’s DNA.

Two examples ◗ Open collaboration approaches in research: In research, the company relies on open cooperation on selected substances. The principle is ‘learning by sharing’. On the BBI web portal www.opnMe.com the company has for some months made selected and well-characterised molecules available to scientists worldwide in order to give impetus to scientific innovations. ◗ Digital projects for patients and physicians: BI is well aware of the potential of digital innovations that start to transform the healthcare industry. Therefore, the company develops digital solutions to support patients and physicians, i.e. the smart stethoscope: It transmits the patient’s lung sounds to a mobile phone with cloud support. An algorithm analyses the lung sounds and is able to identify the corresponding pathological changes in breathing sounds. The doctor immediately gets feedback and can take

further diagnostic and therapeutic actions. BI recently established the BI X digital laboratory. Tell us more about it and the impact it seeks to create. With BI X as an independent subsidiary, BI focuses on breakthrough innovative digital solutions in healthcare from idea to pilot. The start-up works closely together with all three business units of the company – Human Pharmaceuticals, Animal Health and Biopharmaceuticals. It provides a platform for collaborating with specialists in the field of data science, agile software development and user experience design. BI X develops prototypes for new products and solutions and tests them together with the company’s business units in pilot phases. The business units then use the successfully developed new products and solutions themselves and brings them to the market. This approach is to ensure that knowledge and experience accrued at BI X are being quickly integrated into the digital lab’s parent house. An example: Together with our Animal Health Unit, our BI X colleagues are currently refining an app, PetPro Connect, for pet parents. It enables a digital connection to the veterinarian. Users can access different online services that will help to strengthen the relationship with their veterinarians. Another plus of the app: simplification of the rebate submission process for pet owners on their smartphone. In the near future, pet parents could access all their information on medications, vaccinations and appointments with the veterinarian. The first users are currently testing the app in the US.

cardiometabolic, respiratory, CNS, oncology and inflammatory and autoimmune diseases. Beyond this, we are constantly exploring emerging new disease areas, such as infectious diseases and hearing loss, new therapeutic modalities, like

August 16-31, 2018

By 2025, BI is lining-up candidates for:

◗ 15 new medicines, to be potentially approved (probability-adjusted), and many clinical phase transitions, stemming from our clinical and preclinical pipeline of currently around 80 projects. ◗ 65 per cent of these projects have first-in-class and/or

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MARKET DEAL TRACKER

Health industry posts 60 deals worth $4.3 billion Domestic acquisitions contribute much to deal value in July 2018 IN JULY 2018, the healthcare industry reported 60 deals worth $4.3 billion, as compared to five months average of 57 deals worth $43.2 billion. Domestic acquisitions contributed 54 per cent of the total deal value in the pharmaceutical and healthcare industry in July 2018. Some of the notable transactions include PTC Therapeutics’ proposed acquisition of Agilis Biotherapeutics for $945 million to expand and diversify its pipeline with four gene therapy programs; Biogen’s acquisition of ALG-801 and ALG-802 from AliveGen for $562.5 million to expand its product portfolio related to neuromuscular diseases; and Otsuka Pharma’s proposed acquisition of Visterra for $430 million to expand its research horizon. The healthcare industry reported 41 venture capital (VC) deals worth $1.3 billion in July 2018, as compared to five months average of 76 deals worth $1.96 billion. Gossamer Bio raising $230 million in series B financing round; Ascentage Pharma raising $150 million in series C financing round; and Alector raising $133 million in series E financing round are some of the major deals reported in July 2018.

Deal Date

Acquirer (s)

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August 16-31, 2018

Deal value (US$ m)

19-July-18

PTC Therapeutics Inc (US)

Agilis Biotherapeutics LLC (US)

945.0

24-July-18

Biogen Inc (US)

ALG-801 and ALG-802 (US)

562.5

11-July-18

Otsuka Pharmaceutical Co Ltd

(Japan) Visterra Inc (US)

430.0

20-July-18

Cambrex Corp (US)

Halo Pharma Inc (US)

425.0

11-July-18

Gerresheimer AG (Germany)

Sensile Medical AG (Switzerland)

410.7

Deal Date

Acquirer (s)

Target

Deal value (US$ m)

23-July-18

Abu Dhabi Investment Authority; Omega Fund Management, LLC; The Invus Group, LLC; Polaris Partners LLC; ARCH Venture Partners LP; The Baupost Group LLC; Hillhouse Capital Group

Gossamer Bio Inc (US)

230.0

17-July-18

CCB International Capital Ltd; Oriza Seed Venture Capital; ArrowMark Partners; Ascentage Pharma YuanMing Prudence Fund; Teng Yue Partners LP; HDY International Investment; Group Corp Ltd (China) CTS Capital Advisors LLC

150.0

25-July-18

Amgen Ventures; Orbimed Advisors LLC; Undisclosed Investor(s); New Leaf Venture Partners LLC; Mission Bay Capital LLC; Polaris Partners LLC; Deerfield Management Company LP; Federated Kaufmann Fund; Foresite Capital Management LLC; Lilly Asia ventures; Perceptive Advisors LLC; Euclidean Capital LLC; Dementia Discovery Fund; Casdin Capital LLC; MRLVentures Fund LLC; Section 32; AbbVie Ventures; GV Management Co LLC

133.0

12-July-18

Orbimed Advisors LLC; Borealis Ventures LLC; Alexandria Venture Investments; Compass Therapeutics BioMed Realty Ventures; Ulysses Holding Corp.; Thiel Capital, LLC; Biomatics LLC (US) Capital Partners, L.P; Cowen Healthcare Investments; F-Prime Capital Partners

132.0

26-July-18

Merck KGaA; Amgen Ventures; Tekla Capital Management LLC; Alta Partners; Lilly Ventures Management Company, LLC.; Skyline Ventures; Celgene Corp; SV Health Investors LLP; Eventide, Inc.; Samsara BioCapital LP; Vida Ventures LLC; Surveyor Capital Ltd; Nexthera Capital LP

85.4

M&A (Including Private Equity) Trend Analysis

Source: GlobalData

Target

Alector LLC (US)

Sutro Biopharma Inc (US)

Venture Financing Trend Analysis

Source: GlobalData

MARKET POST EVENT

Angle Training Forum hosts first ever ‘Kumbh Mela’of pharma trainers The Training Conclave organised by ‘Angle Training Forum’ had representation from almost two thirds of the pharma industry, by turnover

MORE THAN 100 senior professionals representing over 50 top pharmaceutical companies, from six major metro cities, Kolkata, Hyderabad, Delhi, Bengaluru, Chennai, Mumbai attended a Training Conclave recently organised by Angle Training Forum in Mumbai. The event was also a webcast live with overseas participant logging in. An online social media forum founded by Milind Mangle founder and internationally certified coach of Angle Consultancy & Services, the Angle Training Forum’s WhatsApp group has reportedly evolved into one of the leading resources for trainers in the sector, with members from more than 100 top pharma companies. A core team of 10 members from the Forum organised the Angle Training Conclave. More than 100 senior professionals from over 50 top pharma companies attended the Conclave, calling it the “first ever training conclave in the history of the Indian pharma industry.” Pharma industry doyen D G Shah was the Chief Guest of the event who inaugurated the event and was felicitated by Mangle. “Almost two thirds of

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August 16-31, 2018

MARKET the pharma industry, in terms of turnover, is represented in the Conclave” said Shah in his opening comments. Rituraj Sar, Global Head – Learning & Development, Lupin spoke on sustenance of L&OD initiatives for better business impact. Any learning initiative in the corporate world has to be designed keeping in mind the impact on the business. It should not be an one-time event but an ongoing process. He tackled this aspect by discussing how learning programmes can be designed to have a sustained impact on the business. Taking this theme ahead, Hemalakshmi Raju, Global L&D Head, Cipla, presented the next session on Instructional design, where she pointed out that in order to create a learning programme that would have a long lasting impact on the business, content is very crucial. For this, a trainer needs instructional design and design thinking skills to create impactful content. Augmented Reality is a new technology which is catching every one’s fancy. How can it help pharma trainings was explained by informative demos by Dr Maruthi Vishwanathan, CEO, Rx Prism. He says, “Augmented reality is being increasingly used to create interesting and highly engaging content. To provide flexibility to the learners, the solution has been designed in two modes with AR App and without AR App. Augmented reality adds exciting experience to the traditional e-learning courses and grabs attention quickly.” The focus of this Conclave was technology, strategy and best practices and the event witnessed two interesting panel discussion on the same. More than 50 per cent of the topics focused on technology including a panel discussion on how technology can be used to reduce the cost and increase the learning. Other aspects covered included how can we provide the learning whenever it is required? How can we use mobile technology to increase the reach of training?

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DG Shah inaugurating the conclave

More aspects on the impact of technology in training were part of a panel discussion moderated by B Ramanathan, Sr Manager Training, Sun Pharma with eminent panelists Ashish Ghai, L&D Head Sanofi India, Jagmohan Rishi, Vice President – L &D, Digital & Analytics, Wockhardt, Vishwanathan of Rx Prism, and Dr Pankaj Gursahani, L&D Head, Astra Zeneca. Many companies have Online Learning Management System (LMS) to improve the productivity of employees through learning, believing that learning should be made available whenever required and wherever required. Jagmohan Rishi, Vice President – L &D, Digital & Analytics, Wockhardt explained how

A Training Conclave of this magnitude wouldn’t have been possible without a core team of accomplished trainers from world-class organisations which supported this learning initiative by Angle Consultancy and Services. From right to left: Vinayak Gokhale, Associate Director- Sales T&D, Abbott India, Pankaj Sharma, Sr. Manager L&D, Zydus Cadila, Srinivas K, Principal Training Specialist, Medtronic. Vinod Warrier, Sr. Manager Training Bharat Serums, William Fernandes , DGM – Corporate Training, Blue Cross Laboratories, Yashwant Mishra, Sr. Manager Training, Torrent Pharma, B Ramanathan, Sr L&D Professional, Sun Pharma and Sushil Barkur, L&D Head, Alkem (not seen in the picture)

Sundar Ramchandran, L&D Head South Asia, GSK was the surprise guest at the Conclave

Mangle felicitates Kirti Pratap from Torrent Pharma

MARKET organisations can make such systems work. He said the success of such initiatives depend upon the digital quotient of the event. Millennials have grown up and will soon become the part of the corporate world. The way they learn is completely different from the previous generation. So how can train-

Pankaj Gursahani

Dr Maruthi Vishwanathan

Sujata Kapoor

Hemalakshmi Raju

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August 16-31, 2018

ing content be modified so that this new generation finds it interesting? Sujata Kapoor, Sr. Consultant, Jombay explained the same in her session “The Future of Learning” with a lot of research and analytics. Every organisation undertakes many innovative initiatives, it is very important to share such initiatives with oth-

ers. Angle Training Conclave served as an excellent platform for the same. In order to get maximum ideas about innovative initiatives a panel discussion on “Best Practices in Training” was organised which was moderated by Vinayak Gokhale, Associate Director- Sales T&D, Abbott India The eminent panel mem-

bers were Hemalakshmi Raju, Global L&D Head, Cipla, Sushil Barkur, L&D Head Alkem Labs and Manisha Vithaldas, L&D, Head Abbot Healthcare. The last session of the event was presented by Pankaj Gursahani, Director- Sales Training, AstraZeneca Pharma India on L & D

MARKET

Jagmohan Rishi

Rituraj Sar

Panel discussion – Best Practices

Statergy. His unique delivery style, interspersed with witty comments and insightful tips, held on to the audience’s attention, even though his was

Panel discussion on technology in training

Milind Mangle felicitating D G Shah

the last session. One of the reasons for the success of Angle Training Conclave was the topics, which were well researched

and the speakers were experts in their subjects. The Conclave was so enriching in terms of content and learning that there was a spontaneous

feedback to have more such Conclaves. Participants even went to the extent that Angle Consultancy & Services should start certification pro-

grammes for the L&D professionals. The Conclave concluded successfully with a vote of thanks by Mangle. EP News Bureau

PRE EVENT

analytica Anacon India,India Lab Expo to be held in Hyderabad The event from September 6-8, 2018 will give profound insights into science and research analytica Anacon India and India Lab Expo are India’s largest and most important platform for the analysis, laboratory-technology and biotechnology market. They have the potential for more than 259 exhibitors and more than 7,714 visitors in three halls. The event will be held in Hyderabad from September 6-8, 2018. The event will focus on innovative and applied product and

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August 16-31, 2018

system solutions for laboratories in the industrial, research and science sectors. As the industry’s definitive forum, fair and conference gather all relevant information about the latest developments. Both events will cover the entire value chain for industrial and research laboratories. The focussed exhibition sectors will give visitors a comprehensive overview of the market, in-

The conference will give insights into science and research. International experts will present latest techniques novations and best-practice examples: analysis, biotechnology,

laboratory technology, quality control, measuring and testing.

The conference is tailored to the Indian market, so it will give profound insights into science and research. It is where international experts present the latest techniques in all application sectors. International market leaders as well as local Indian manufacturers will participate in the trade shows. EP News Bureau

MARKET EVENT BRIEFS PHARMATECH EXPO 2018 & LABTECH EXPO 2018

Website: www.Kenya PharmaExpo.com

Date: August 22-24, 2018 Venue: Ahmedabad Summary: The event is dedicated to pharma innovation, technology and knowledge, which will showcase the latest cutting-edge technologies needed to cost-effectively develop and manufacture quality products. Contact expo@pharmatechnologyindex.com

GULF CONGRESS ON PHARMACY AND PHARMACEUTICAL SCIENCES Date: September 17-18, 2018 Venue: Abu Dhabi, UAE Summary: The theme of the conference is Global Innovations & Recent Advancements in Pharmaceutical Science. Pharma Conference 2018, an international event, will focus

GLOBAL PACK 2018

on the core knowledge and major advances in the ever-expanding field of pharmacy and pharma sciences. Contact Catherine Jones Program Manager Pharma Conference 2018 47 Churchfield Road, London, W3 6AY, United Kingdom

KENYA PHARMA EXPO 2018 Date: October 17 -19, 2018 Venue: KICC, Nairobi, Kenya Summary: The international pharma exhibition on technologies and trade will focus on East & South African Pharmaceutical Industries. The expo will be organised by GPE Expo where pharma machin-

ery and allied-industries OEMs across the world will exhibit their Technologies/ Services. Contact details: Paresh Jhurmarwala CEO KENYA PHARMA EXPO 2018 E-mail: contact@ kenyapharmaexpo.com

Date: November 23-25, 2018 Venue: Labh Ganga Exhibition Centre, Indore, MP Summary: GLOBAL PACK 2018 is an International Trade Exhibition & Tech Summit for the packaging material, machinery and ancillary industry. Organised by Integrral Business Exhibitions & Media in association with SIES School of Packaging, it is being designed to serve as a platform for the packaging and printing industry, both in terms of business and technical content. Contact Email: info@ibem-india.com

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EXPRESS PHARMA

August 16-31, 2018

cover )

EXPRESS PHARMA

August 16-31, 2018

(

n the first part of our Independence Day special coverage, the August 115 issue examined how the three ‘Is’ - Indigenisation, Innovation and Information – can be leveraged to help India achieve true independence in the pharmaceutical sector. A large part of this independence comes from financial stability. Hence, exports have bulked up the balance sheets of most of India’s pharma companies, right from market leaders to SMEs. India has bagged 20 - 22 per cent share of global pharma export volume, is one of the lowest cost manufacturing destinations and is expected to rank among top three pharma markets in terms of incremental growth by 2020. Take for example, the jugalbandi between India and China, which has been built over the past few decades on complementary strengths. While India focussed on becoming a global source of cost-effective quality formulations, China excelled in making low cost active pharmaceutical ingredients (APIs) and key starting materials (KSMs). Companies on both sides expanded their geographic foot print

THE MAIN FOCUS

across the world, thanks in part to this relationship. But exports come with their own threats, with each country presenting a different challenge. Thus future growth in exports will not be a cakewalk. For instance, India’s equation with China has changed, due in part to geo-political circumstances. Many pharma companies in India, and other countries as well, found themselves overtly dependent on China for APIs. The first warning bell went off in 2008 before the Beijing Olympics. Faced with increasing pollution, not the least deteriorating air quality, China feared that its global image would suffer a huge dent when it hosted teams from across the world for the 2008 Olympics. China decided to clean up its act and as a consequence, there was a crack down on polluting industries and factories. Many of these factories were API manufacturing units and as a consequence, supplies of key APIs dwindled. Formulators in India and other countries were left high and dry and had to scramble to find alternate sources of APIs.

The Beijing Olympics taught China a very important lesson: that while it is easy to 'develop first and clean up later', it is much more difficult to clean up the environment than previously estimates. Hence China continued to come down heavily on polluting companies and has expanded the scope to formulations. Recent examples include the substandard DTP vaccines supplied by Chinese vaccine maker, Changchun Changsheng Biotechnology, sold to the Disease Prevention and Control Centre of Shandong Province. This July, the US FDA and EU recalled formulations containing valsartan API supplied by Linhai, China-based Zhejiang Huahai Pharmaceuticals which had detected the impurity — nitrosodimethylamine (or NDMA) — in their API.

So, a decade later, are we in a better situation? Dr Ajaz Hussain, President, National Institute for Pharmaceutical Technology and Education (NIPTE), estimates that for several years, about 90 per cent of API formulated in India was imported from

The key question here is why it is more economical to import certain formulations from China for the market in India? ... The changing regulatory stance in the US, EU, UK and Japan has become probably the largest barrier to pharma exports from India Dr Ajaz Hussain President, National Institute for Pharmaceutical Technology and Education (NIPTE), Founder, Insight, Advice & Solutions, LLC and former Deputy Director of Pharmaceutical Science, US FDA

While trade barriers are generally in the form of high direct taxes, it’s the non trade barriers (NTBs) which are generally more detrimental and cannot be directly accounted for as these are veiled Sahil Munjal President & CEO – Exports, Ind-Swift Laboratories

The new law (EU's new trademark legislation) could be an attempt to create a trade barrier to check India’s exports of low-cost generics to the markets in Latin America and Africa as large pharma companies, many of them based in the EU, feel threatened by India’s low-cost but high-quality medicines Lokesh Sharma Head, Public Health – Africa, Middle East, South Asia, IQVIA

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EXPRESS PHARMA

August 16-31, 2018

cover ) China. “In recent years, the per cent API imported has declined and this trend is expected to continue. An interesting observation is the increasing import of formulation from China into India for the local market. Export of formulations from India to China has increased and likely to increase further in the next several years.” A former Deputy Director of Pharmaceutical Science, US FDA, Hussain raises further questions, “To understand these macro trends one has to get to the micro trends; i.e., specific API and formulations. The key questions here are why it is more economical to import certain formulations from China for the market in India? How might these micro trends inform us of the evolving local pharma and environmental regulatory stance and government pricing policies in the two countries? And, what might be the consequences of these micro trends to shape the macro level dynamics; particularly in the context of intellectual property, API and formulations complexity and the changing regulatory stance in the US, EU, UK and Japan?”

The only threat we see now is news of reversing of policies by the Trump administration in the US (which is by volume and value, India's biggest export market for generic drugs) which could heavily tax imports of drugs manufactured outside US Vickram Srivastava General Manager, Global Demand and Supply (GDSO), Zydus Cadila

Some times it is felt that all these frequent (regulatory) changes are pro big operations. For MSMEs, they become a big challenge to adopt or survive the change Vinod Kalani Co Chairman FOPE & promoter, Cris Pharma India

Given the challenges emerging from China we have increasingly begun to build alternative sources in India and/or make the intermediate captive wherever the economics works out Saurabh Gurnurkar Executive Director, Uquifa

A silver lining? But could these fluctuating API supplies be a blessing in disguise? Global CDMOs seemed to have worked on risk mitigation strategies in the last decade and India is clearly part of these plans. For example, take the case of Uquifa, an 80-year-old API franchise headquartered in Barcelona, Spain with manufacturing footprint across Spain, Mexico, Hungary and India. The company historically bought nearly 60 per cent of their KSMs from China, according to Saurabh Gurnurkar, Executive Director, Uquifa. “Given the challenges emerging from China, we have increasingly begun to build alternative sources in India and/or make the intermediate captive wherever the economics works out, says Gurnurkar.” Vivimed Labs, a pharma and specialty chemicals company headquartered in Hyderabad,

20 EXPRESS PHARMA August 16-31, 2018

India, acquired Uquifa way back in 2011 for $55 million, so it is evident that the alternate sourcing plans are well advanced. In his view, the large component of the cost of goods sold (COGS) in their business, is the KSM cost followed by solvent costs, environmental costs. So any fluctuations in this component has a massive impact on product pricing. “We can see that there are four-five new projects of such nature that we have commenced in recent past to risk mitigate ourselves better,” informs Gurnurkar. But such strategies take time to plan and roll out. “Qualifying new sources takes time (regulatory, quality requirements) especially since 100 per cent of our business is focussed on the regulated pharma markets. However we are committed to work

closely with our supplier base (existing and new) to ensure timely delivery of our product to our customer base and eventually the patient population.”

Widening the large-SME divide The question is, are India's contract manufacturers as prepared as their global peers with secure alternate supplier chains beyond China? And beyond this issue, India's pharma companies, like all their rivals in other countries, face an even greater long-term threat: falling in line with regulations of various export destinations. Lines that apparently keep shifting in the sand. Indeed, ''the changing regulatory stance in the US, EU, UK and Japan'' as Hussain puts it, has become probably the largest barrier to the pharma exports

from India. Even though India's pharma exports to the US, a key market, registered a double digit growth this April, (a growth of 17.47 per cent as compared to a 10 per cent decline in the same month last year), there is speculation that the previous level of pharma exports will not be achieved. The reasons range from more protectionist regimes as well as increased competition in a commoditised space. But here too, the impact seems to affect some companies more than the other. For example, according to Vickram Srivastava, General Manager, Global Demand and Supply (GDSO), Zydus Cadila, “We have not noticed any trade barriers except regulatory control for export of generic pharma drugs from India.” He see this as a clear indication of “our robust low-cost manufacturing edge

and cost-efficient talent pool topped by strong R&D pipeline both for chemical-based drugs and next generation biologics and biosimilars.” Contrary to common perception, he says, “Even China does not have any particular trade barrier for exports from India.” He admits that the long and nontransparent filing/approval cycle by Chinese FDA and heavy drug price control was a deterrent to companies in the past but points out that the Chinese market is now opening up and even the regulatory filing and approval timeline/process has been eased, encouraging some Indian companies to start looking at China as a potential export market for generic drugs. Looking at other geographies, Srivastava opines, “In EU, US and many other developed countries like Russia, South Africa and Brazil, etc, the regulatory agencies have improved the filling and approval transparency clearly highlighting goal dates and approval milestones further easing export planning to these markets.” Ironically, the largest pharma market in the world could turn out to be the darkest cloud on the horizon. “The only threat we see now is news of reversing of policies by the Trump administration in the US (which is by volume and value, India's biggest export market for generic drugs) which could heavily tax imports of drugs manufactured outside US.” Gurnurkar comments that they are definitely seeing a reset in expectations from regulators and customers pertaining to the regulated markets. “Be it Quality, Safety, Health & Environment (SHE), data sufficiency — the expectations are rising and evolving so manufacturers focused on the regulated markets have to cope with that,” is his take on the situation. Larger companies seem to have borne the losses from export revenues and taken regulatory headwinds in their stride. This is understandable, given the much larger resources at their command. But the impact on smaller companies would

( tend to last longer and could even become a struggle to survive. (See box: Small is not beautiful?)

Rule or trade barrier? Countries can resort to two basic kind of export barriers - trade and non-trade barriers (NTB) to ring fence their local industries from overseas competition. Both kind of barriers are not new to India and the pharma sector is not immune to it, says Sahil Munjal, President & CEO – Exports, Ind Swift Laboratories. “While trade barriers are generally in the form of high direct taxes, it’s NTBs which are generally more detrimental and cannot be directly accounted for as these are veiled. According to WHO, NTBs include import licensing, rules for valuation of goods at customs, pre-shipment inspections, rules of origin ('made in'), and trade prepared investment measures etc to just name a few.” Vinod Kalani, Co Chairman FOPE & Promoter, Cris Pharma India, who represents various industry associations and is a promoter of companies like Cris Pharma India, Oasis Infotech, and Oasis Test House cites the 'America First' policy as well the US bypassing WTO agreements as some examples of NBTs. According to him, the definition of quality and implementation of quality parameters keeps changing from time to time, within individual countries, even while varying from country to country. He points out that adapting to these changing regulations slows down the process and adds to the costs as well. Giving examples of NBTs, Lokesh Sharma, Head, Public Health – Africa, Middle East, South Asia, IQVIA says, “Several countries like Russia, Vietnam, Iraq, Zimbabwe, Pakistan, Nepal and Nigeria are notifying negative lists for pharma imports with an objective to protect domestic industry. Some countries have come out with domestic policies compelling local manufacture. EU has started a system of written confirmations to be issued by Central Drugs Standard Control

THE MAIN FOCUS

Small is not beautiful?

inod Kalani, who represents various pharma industry associations like the Federation of Pharmaceutical Entrepreneurs India (FOPE), Confederation of Indian Pharmaceutical Industry (CIPI), Indian Drug Manufacturers' Association (IDMA), and Rajasthan Pharmaceutical Manufacturers Association (RPMA) points out,“In India our policies are revised keeping in view the global requirements (which keep on changing).This results in very frequent changes in our country’s regulatory requirements for the Indian pharma companies.This is a very tricky subject as some times it is felt that all these frequent changes are pro big operations. For MSMEs, they become a big challenge to adopt or survive the change.”Industry members of FOPE, CIPI, IDMA and RPMA span the gamut of the pharma sector in India in terms of market cap, from SMEs to MSMEs as well as transnational corporates. Increased registration fees, prolonged time lines and detailed documentation are common issues which seem to hit SMEs harder than larger companies.The basic documentation work required for registration of the plant and products in various countries, which was much faster and cheaper earlier, was one of the factors for the fast growth in pharma exports from India over the last two decades.This is no longer the case. As Kalani further explains,“Several countries like the US, Russia, China and Brazil have increased registration fees and have prolonged time lines (three- five years) for registration making it prohibitive for mid-size pharma companies to start exports. Now it takes one to three years to register the unit and the products even in African countries. Many ROW markets like Vietnam, Combodia, Sri Lanka etc too have introduced barriers like one company can register a molecule with one brand only while in the past there was no such restriction.”

Common barriers to pharma exports ◗ ◗ ◗ ◗ ◗ ◗ ◗ ◗ ◗ ◗ ◗ ◗ ◗

Multiplicity of drug approval agencies High import duties, import licensing Regulatory delays Increase in registration fees Frequent revisions in procedures and requirements Notification of negative lists for pharma imports Complusory local manufacture Insistence on site inspections Rules for valuation of goods at customs Pre-shipment inspections Rules of origin Use of trademark laws to block in transit consignments Language barriers

Organisation (CDSCO) for every exported API even after the product has an active Drug Master File (DMF) from reputed regulators like US FDA.” Thus higher regulatory standards, at least in the beginning, will depress exports. As Sharma says, “With PIC/S becoming an important global compliance and standard criteria, it will act as one of the very crucial trade barriers for India as India would need to develop and promote harmonised GMP standards and guidance documents as per PIC/S standards. Insistence on site inspections in spite of holding WHO Good Manufacturing Practice (GMP) /Pharmaceuticals Inspection Co-operation Scheme (PICs) approvals is increasing.” Among tariff barriers, Sharma's list includes high import duties, regulatory delays, registration procedures and multiple regulatory agencies

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across countries. He draws attention to European Union’s (EU) new trademark legislation which stipulates stricter enforcement measures on goods in transit through its territories which not only blocks trading of goods within the bloc with logos found similar to the ones registered in the EU, but also permits the seizure of such consignments at EU ports and airports even if they are meant for a third country. This legislation has raised considerable concern for Indian drug manufacturers shipping items to Latin America or Africa using European ports and airports in transit. Sharma therefore reasons that the new law could be an attempt to create a trade barrier to check India’s exports of lowcost generics to the markets in Latin America and Africa as large pharma companies, many of them based in the EU, feel threatened by India’s low-cost

but high-quality medicines. Referring to the same issues Kalani says, “There are variations in the definitions of counterfeit and spurious drugs in various regulated markets resulting in seizure and award of punitive damages against Indian exporters. Especially in the EU, the definition covers even generic versions of innovator drugs without authorisation even if they meet quality standards as well as trademarks and copyrights leading to monopolistic practices. Even exports of such drugs to a country where patents are not granted to them and fully legal are liable for seizure if such products touch European ports during transit.”

In the same boat To be fair, India is not the only country to face such trade barriers. As Munjal of Ind Swift Laboratories points out, “Turkey has put restrictions on import of finished product from overseas countries due to their localisation project, however this is imposed on all countries, not only India.” While the member countries of the APAC region do not currently impose any sort of trade / non trade barriers for Indian pharmaceuticals and India has a good access to this market, certain countries in other trade blocs do pose problems due to their internal issues. For instance, he points out that in the MENA region, there are no

trade barriers except in countries like Syria , Yemen and Iraq due to the current fluid political situation. Similarly, for Iran, the biggest impediment is its isolation from the international banking system arising due to US sanctions. Secondly the government in Iran has imposed high tariffs on imported medicines to support the domestic pharma industry. Continuing this trend, Munjal says that the LATAM market, except for Venezuela, also poses no barriers in pharma from India. Venezuela was one of the most profitable markets of LATAM but is currently out of reach due to the collapse in economic activity. Europe too does not impose any trade/non trade barriers for Indian companies for pharma trade. In the case of Japan, Kalani points out that exports are restricted due to language barriers. Other mandates like the need for pharma export companies to keep an inventory of products for five years and partner with Japanese enterprises for local marketing add to the barriers. The language barrier also comes up in Africa, EU, Commonwealth of Independent States (CIS), LAC, and the Asean countries as they provide information in their local languages. In the absence of websites in English, information on drug registration, registrations granted, markets, etc. is not freely available to Indian exporters.

The devil in the details He also points to other discrepancies. For instance, while the US, Canada, Europe, South Africa, Australia and various countries accept bio equivalence (BE) studies conducted in India as per international guidelines, Japan, Mexico and now Thailand, want the BE studies to be conducted on their local populations in their countries. He explains that a BE study merely compares the drug levels as compared to the original drug in-vivo, there is no clinical efficacy evaluation. With each additional BE study costing

EXPRESS PHARMA

August 16-31, 2018

cover ) more than ` 40-50 lakhs for each additional country, the impact on Indian pharma exports will be extensive if this technical barrier is adopted in more countries. On the documentation side, he points out that the registration of drugs is extremely detailed, and it is often very expensive to provide such dossiers such as DMFS or ANDAS, etc. The complete process details, site plans and all intricate details are demanded and have to be provided. He also hints at another aspect, which could have more severe long-term implications. As Kalani puts it, “The cost of documentation and review not only costs a lot of money but also provides free access to knowledge to employees in such agencies which benefits their system.” Thus in chasing export revenues today, are we trading away our tomorrows by giving away our trade secrets? And will we be able to move to the next level fast enough to prevent being obsolete? Moving to the US, Kalani avers that despite the challenges of price erosion, the US continues to be an attractive market for Indian firms. But here too, the challenges are only going to increase as it is in the process of negotiating or has concluded Free Trade Agreements (FTAs) with several countries which are pharma producers, for example, Thailand, Morocco, Chile etc. These agreements stipulate IPR related provisions such as data exclusivity, which prohibit pharma exports from other countries such as India. These stipulations by the US in its FTAs with different countries may be going beyond TRIPS and obviously such FTAs have implications for export of generic medicines from countries like India. In CIS countries, the queries raised during the registration and approval process varies from reviewer to reviewer. The standards in these countries also vary and it takes as long as two years for drug registration in these countries. Drug registration fees are also high in these countries, points out Kalani.

22 EXPRESS PHARMA August 16-31, 2018

(Source: Pharmexcil, IBEF websites)

Lending a helping hand The barriers seem insurmountable but they are common to all India’s peers vying for a slice of the global pharma exports pie. What could make the crucial difference is political will to recognise that the pharma sector is not just a source of foreign exchange revenues, but also key to India's image as a knowledge economy and contributor to the social cause of reducing disease burdens. The Government of India (GoI) has been stepping forward to resolve these issues through diplomatic and trade channels. Citing a recent example, Srivastava of Zydus Cadila recounts, “Recently in April this year, the Department of Revenue under the Ministry of Finance had notified bringing Tramadol under the Narcotic Drugs and Psychotropic Substances (NDPS) Act 1985. This meant all imports, exports and domestic

movement of formulations and active having Tramadol would need a No Objection Certificate (NoC) from Dept. Commissioner's office. Pharmexcil represented the industry’s case to the GoI asking for time to allow industry to get the necessary framework ready to meet the government requirement with success. The notification was postponed till August allowing import and export to continue and allowing companies to set up their process to manage NoC in advance to avoid delay in planning.” Sharma of IQVIA too mentions that post the Indian Prime Minister’s recent visit to China, China has taken the decision to remove import duties on 28 medicines, including cancer drugs, thereby reducing the trade imbalance between China and India. Munjal of Ind-Swift Laboratories too mentions that the ease

of doing business with APAC and MENA countries is a result of inter-governmental negotiations and goodwill. He emphasises the interplay of industry, associations and the government when he says, “I think associations like Pharmexcil play a pivotal role as it is our duty to apprise the government of the actual issues being faced by us. The government will take up the issues in the stride we project/represent, though ultimately it’s for the government to take up the issues with respective governments and ensure timely redressal/reversal. But Munjal too feels there is a lot of scope of improvement and furthering the coordination between industry associations (Pharmexcil) and the government. He specifically suggests that the government should be more open and liberal to industry suggestions, must ensure prompt actions and more

importantly organise frequent industry outreach programmes. While there is a lot of support from government agencies available on home ground, companies often need help in the overseas markets itself. Sharma of IQVIA points out a crucial missing link when he states that currently, we do not have government affiliated associations present in any of the foreign countries to help the Indian players liaise with the foreign counterparts in setting up businesses. “We feel that we need to have government and industry associates located in countries that pose a huge opportunity for Indian companies,” reasons Sharma. “Government associations like Export Promotion Councils and Federation of Indian Export Organisation should have country-specific local teams to initiate promotional activities that would help us strengthen business ties with relevant local entities. We should also create an ombudsman and have a proactive approach towards resolving export related problems and disputes within stipulated timeframe.” Srivastava also points out to other long-term policy and image building initiatives. “Allowing 100 per cent FDI, creation of SEZs for the pharma sector, export benefits, etc backed by stable and transparent government polices have further encouraged global industry leaders to come to India (many a times through M&A route) and invest to meet both India and global demand of life saving drugs. The role of both the government and Indian pharma companies, has been especially commendable in projecting India as the premier country in supply of cost-effective superior quality sophisticated ARVs (drugs for HIV/AIDS treatment) across the globe and in Africa.”

Forging ahead But governments too have their limits. If pharma companies want to increase their exports, they will have to be more proactive. They will have to anticipate and plan in advance

( for further trade barriers as well as NBTs in order to gain market access to sustain and expand their geographic footprint. “The key to entering other geographies like China, South America, APAC etc,” according to Srivastava of Zydus Cadila, “would be decoding the regulatory path way.” He also emphasises that many Indian companies have learnt the hard way that it is crucial to have distribution networks/local tie-ups in the export destination country. Munjal opines that “an uncompromising focus on patient safety and quality at reasonable cost should be the basic guiding principal for all of us” to reach these goals. On the strategy front, Sharma suggests that Indian pharma companies should

look at strategic alliances and partnerships with the local manufacturers and/ or distributors for market penetration in other geographies. “Additionally, the business processes including bidding and procurement vary across geographies. Hence, before promoting our pharma product imports to foreign countries, we need to have a deep understanding of the processes and market requirements, especially related to quality of medicines, of each geography. Only after that, the Indian companies can build a differentiated product portfolio that not only would be aligned to the prerequisites of the targeted geography but will be also mapped with the local country demand.” His third suggestion is that large cap Indian pharma companies who spend

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10 per cent of their revenue on R&D, should collaborate with academia and industry to develop new chemical entities and differentiated product portfolio as per the need of the markets they are keen on entering. Hussain also reminds us of the responsibilities of the importers, saying, “Importing manufacturers are responsible for controlling and assuring quality of the raw materials they accept. A combination of analytical tests, supplier quality agreements and other considerations under a quality management system are the responsibility of the importer. Deviations from these fundamental requirements point to, at minimum, lack of competence and, on the other side, a deliberate economically motivated disregard, for quality and safety.”

THE MAIN FOCUS

He cites the heparin tragedy in 2007 and as a way forward, Hussain advices that compliance with existing laws, regulations, and established international guidelines would ideally be an immediate, short-term solution. But he feels that the foundation on which manufacturing controls of many of existing products are based are weak and error prone. The way forward is strict compliance which can reduce efficiencies, increase rate of out of specification (OOS), but this might also reduce profits. He points out that breaches in assurance of data integrity (BAD-I) is a symptom of this problem. “To a large extent US FDA and EU regulatory scrutiny of BAD-I had been on QC lab data; manufacturing batch records and in-process controls

remain vulnerable.” Concluding on a note of caution he says, “I would recommend senior managers and management to be engaged like never before and work hand-in hand to prevent a failure. Supplier quality agreement should be carefully reviewed and vulnerabilities mitigated. They should take steps to ensure business plans, targets and quotas reflect actual efficiencies and OOS rates. They should invest in professional development as well.” Thus, while the opportunities exist, further gains in the global pharma export market will need superior staying power and strategy. But one thing is clear. India Pharma Inc will remain a sizable presence across the globe. viveka.r@expressindia.com

EXPRESS PHARMA

August 16-31, 2018

MANAGEMENT LEGAL EAGLE

Direct to consumer advertising of medicines and medical devices — a call for action! Dr Milind Antani, Anay Shukla and Darren Punnen from Nishith Desai Associates, give an insight on the scope of laws that regulate direct to patient advertising in India

irect-to-Consumer (DTC) advertising is key to any business. However, DTC advertising has always been a challenge for pharmaceutical and medical device companies in India. Any marketing professional from either of these industries, will admit that there is an instinctive hesitation to advertise medicines and medical devices before the end consumers. This begs for the question - what is the basis of this hesitation? Do laws in India stop DTC advertising of medicines and medical devices? In the paragraphs below, we have explored the scope of laws that regulate direct to patient advertising in India. In India, the business of medicines is regulated by the Drug and Cosmetics Act, 1940 (DCA) and the Drugs and Cosmetics Rules, 1945 (DCR). Until 2015, the DCA and DCR did not regulate DTC advertising except for the content that appeared on the label of the product. The DCR now prohibits the manufacturers of medicines identified in Schedule H, H1 and X of the DCR from indulging in any form of advertisement. The language used to prohibit DTC advertising makes it amply clear that ‘public interest’ is not a cushion any longer to advertise medicines. Unfortunately, the language of the prohibition under the DCR sheds no light on the following crucial aspects of DTC advertising: 1. What is the scope of the expression ‘advertisement’? Does spreading knowledge and awareness of facts such as the results of successful clinical trials before patients amounts to an advertisement? Do patient

24 EXPRESS PHARMA August 16-31, 2018

Milind Antani

Anay Shukla

Darren Punnen

testimonials constitute an advertisement? Can the presence of facts and testimonials on the global website of a pharmaceutical company amount to an advertisement of the drug in India? 2. Whether the restriction on advertisement applies to distributors and marketers? In India, several medicines are only imported and several oth-

ers are manufactured on a contract basis by third-party manufacturers. The DCR defines the activities that would amount to ‘manufacture’ and leaves out import and distribution from the definition. This clearly implies that importers and marketers of medicines should not be referred to as manufacturers under DCR. So, is it fair to assume that DCR

gives a free hand to importers and marketers to advertise their medicines directly to the end consumer? Does this fulfil the objective? Interestingly, from January 1, 2018, the business of certain notified medical devices is regulated by a set of new rules called the Medical Devices Rules, 2017 (MDR). The MDR has absolutely no restriction

for the advertisement of medical devices. Does that mean that manufacturers of medical devices can advertise their medical devices directly to consumers under the provisions of DCR? Apart from the restrictions on advertising certain drugs, there are restrictions on advertising cure for certain stipulated diseases and conditions using medicines and medical devices. The Drugs and Magic Remedies (Objectionable Advertisements) Act, 1954 (DMRA) and Drugs and Magic Remedies (Objectionable Advertisements) Rules, 1955 (DMRR) identifies certain diseases and conditions whose diagnosis, cure, treatment, prevention and mitigation cannot be advertised by a medicine or a medical device. Unlike DCA, the DMRA and DMRR apply to all individuals and not just manufacturers of the medicines. However, the sad truth is that DMRA and DMRR have become anachronistic and irrelevant. For example, it is well known that Cataract can be cured and Asthma can be mitigated. Does DMRA permit the advertisement of the intra-ocular lens for treatment of Cataract and corticosteroidsinhalers for mitigation of Asthma? It just doesn’t, period. Thus, it may not be an overkill to state that DMRA AND DMRR is fairly out of sync with the advancements in the field of science and medicine. The problem doesn’t end there. Some of the diseases and conditions identified in DMRA and DMRR are described broadly and are capable of misinterpretation by the regulator. Take for

example a condition called ‘rheumatism’. Many doctors are of the view that rheumatism and rheumatoid arthritis are totally different. However, the regulator believes that rheumatoid arthritis is a subset of rheumatism and has prosecuted companies who have advertised a treatment for rheumatoid arthritis. Such liberty in interpretation taken by the regulator is a serious cause of concern. Given the questions on the applicability of restrictions on direct to patient advertisement under DCA and irrelevancy of DMRA, one wonders whether the drug and medical device industry has matured enough to self-regulate against unwarranted advertising. This will, perhaps, allow the government to concentrate its resources on enforcement and updation of

rules that govern critical aspects of business such as quality of medicines and medical devices. In fact, the Organization of Pharmaceutical Producers of India (OPPI) had published a 'Code of Ethics for the members for the Advertisement of OTC drugs in India’ long time ago. The language of the code feels in-tune with time and one wonders why the government has hesitated to adopt it into a full-fledged law. It contained very forward-looking guidelines such as prohibition on using statements in advertisement that may create fear or apprehension in the minds of the public (eg. a person may suffer from ailment by not using a product), prohibition on implying that a medicine is recommended by health professionals, prohibition on offering

rewards or other inducement leading to excessive use of the drug by a consumer, prohibition on giving impression that a medical consultation or surgical operation is necessary, mandatory use of warning such as “use only as directed” etc. This piece would be incomplete without referring to broadcasting laws. Basically, in addition to the laws that restrict DTC advertisements by businesses, there are laws and guidelines that restrict broadcasters of radio and television from accepting advertisement of drugs and medical devices. For instance, there is a code called 'Code for the Self-Regulation of Advertising Content in India' (ASCI Code) published by the Advertising Standards Council of India. It does not prescribe restrictions on advertisement of medicines and

medical devices but stipulates that the content of advertisements should not be misleading or offensive to the public. ASCI Code is to be mandatorily complied with by the television networks only owing to the Cable Television Network Rules, 1994. However, its compliance is not mandatory for pharmaceutical and medical device industry. It would be improper to conclude that the hesitation within the pharmaceutical and medical device businesses to undertake DTC advertisement of medicines and medical devices is misplaced. The fact is that the laws in India have not matured with time to allow DTC advertisement, unlike the science and people around it. The pharmaceutical and medical devices companies today suffer from over-regulation of DTC

advertisement, unlike sister industries such as healthcare, food as well as many nonhealthcare sectors. However, it is very much possible even today to educate consumers about the advances in the field of medicine and medical devices within the four corners of law. It is also possible to enter into arrangements with stakeholders who are not governed by the aforementioned laws to gauge their interest in undertaking consumer education and awareness. The time has arrived for the government to act and give the necessary cushion to the industry to do what is not only required for the industry to grow but also for the patients to remain educated about their health. After all, we all aspire for Ayushman Bharat (i.e. healthy India)!

Mr. Rajib Baidya Zydus Healthcare Limited, Ahmedabad e-mail : rajibbaidya@zyduscadila.com

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EXPRESS PHARMA

August 16-31, 2018

MANAGEMENT

Customer Voice – It means business! Mohan G Joshi, International Business Coach and Former President, SCHOTT Glass India elaborates on unlocking the hitherto untapped potential of a business with customer voice IF YOU are a theatre or dramatics person, you will know that business is much like drama – with so many characters, all the possible drama and histrionics thrown in; the only thing missing is the script. In this unrehearsed drama, there are no prizes for guessing who the central character is. Who else can it be but the customer of course. Business cannot exist without the customer. The customer is so integral to business! So, while we all focus on winning new customers, we tend to inadvertently ignore another most important factor in and for business – the customer’s voice!

What is ‘Customer Voice’? Customer Voice is a collection of all the good things that the customer says about you, your business, your company, your product, your brand – it is the customer’s experience with all of these. She has expressed this in a formal meeting, or on email or on text or even social media or WhatsApp (in all probability, many times on this channel), on phone or even in a candid F2F (face-2-face) chat. Often, it is not pre-planned and comes unexpectedly like a cool, blessed shower on an extraordinarily hot, humid afternoon. Other times, it is planned and recorded as a special byte or a video; what is classically referred to as a ‘testimonial’. Sometimes, it is specially requested, other times it comes without asking. In whatever form, this is a voice that is nothing less than pure gold. It is the key to unlock the hitherto untapped potential of your business. It is the curtain raiser to a new phase in your business, the start of an upward trajectory.

It is important how you ‘play’ this golden Customer Voice. Will you leverage it? Irrespective of how much we value our Customer’s Voice, we forget to leverage it. How many of you use this voice in your presentation, whether it is your company presentation in a

26 EXPRESS PHARMA August 16-31, 2018

PowerPoint or a video that you are sharing on email, or presenting on a Mac or in your Keynote Speech? The impact of embedding your Customer’s Voice in your business presentations cannot be adequately emphasised. For a new, first-time prospect, the impact of this voice is tremendous. To the new prospect, the Customer’s Voice is ‘real’, very real. It is credible and honest. It is living proof that your product/or company is worth talking about; worth telling the world about! While there is a semblance of ‘advertising’ in any business presentation by you or your business representative, the Customer’s Voice speaks the truth. If you haven’t already used the Customer’s Voice in your upcoming presentation, it’s never too late!

Customer Voice needs to be specific The voice that will resonate the most is the voice that talks about ‘specific’ value that the customer has received from your company. It could be talking about one or more of the following or anything equally important: 1) Quality of product that stands out and how the customer experienced it 2) How it impacted the customer’s performance or of his people 3) Ease of use 4) Speed of response from your company 5) Service team support, friendliness, speed and solutions 6) How it added value other than price 7) Durability of the product 8) What about your company/offering/service the customer prefers over another one he had used earlier 9) Any other specific point of importance

Your voice vs Your Customers’! Why is Customer Voice important? For once in business, it helps to let someone else win over you

– in this case, we are speaking about letting your customer’s voice win over yours. Why? Because, in the short and the long run both, it is going to help YOU more than any other sales tool. A prospect – warm, hot or that one sitting on the fence is going to be watching you and when they see someone else who has bought from you, talking highly about you, they are going to believe that other voice and sit up and take notice. A few of these prospects are then going to jump into the field and act, which could culminate in sales for you. That is why and how Customer Voice is important. In addition, customer voice takes care of all possible concerns, blocks and obstacles during the sales process. It helps the salesperson (you) in offering proof for the claims made by your company, it helps address the very real concerns of the prospect regarding your product/features/ service/ and that too, through the mouth of the actual user – your customer.

Word of mouth (WoM) Word of mouth travels faster than you can blink; and although positive WoM lags behind negative WoM, it still shoots past any marketing effort. Customer Voice is another word for word of mouth

How to make sure Customer Voice is positive and negate the negative People do talk and social media

it appears has given an unwritten license to people to talk and kill the sellers’ reputation in one big blow. If you have highly unsatisfied customers, you should refrain from using Customer Voice as it will do you more harm than good. Instead, you should focus on eliminating the causes of your customer’s dissatisfaction. Only when the customer has had a good and consistently good experience with you, is the Customer Voice going to be worth your while. So, focus on the positive and ignore the negative.

Customer Voice depends on customer experience Customers, even if they have had an excellent experience with your company, shy away from speaking out – maybe because of lack of time or a simple bout of forgetfulness. Ask anyone and you will hear the same story – “It is difficult to catch hold of your customer and ask him to say a few good things about you.” The truth is that people shy away, hesitate or simply do not pay heed to or do not think it is important to speak about their good experience. However, they will be the first ones to speak up after one small bad experience. For you to have a Customer Voice, it is very important for you to ensure a good customer experience.

Repeat customers come in if the experience is good Customer Voice gets in repeat customers especially for products where brand loyalty is at a low. The Customer Voice they hear or read about, helps your former customers recall your brand and their own good experience with it and helps to draw them again to your product.

How can you, as a business, build good Customer Voice? Knowing your customer, understanding his likes and pet

peeves regarding your product/brand/ company, knowing his concerns like the back of your hand and having an excellent sales and support team with a grip on the best sales processes, will help you deliver the best of experiences to your customer. When you mind the gap between what you promise the customer and what you deliver, it will help you build a consistent, long lasting good Customer Voice.

The right of review In today’s fast-moving life with social media dominating lives, the need to review is like an uncontrollable itch. Everybody who is a somebody or a nobody thinks and practices his rightto-review. These reviews are gold mines for a good Customer Voice. You can mine these reviews, create a bank of good reviews and use this Customer Voice to enhance your sales process.

Influencer marketing – the Customer Voice champion Influencer marketing is another selling tool which helps to pull in the right prospects to your product/offering. Influencers are people who are somebodies in their fields – which is also the field or sphere in which your company operates. These influencers have large followers who respect these influencers and ‘follow’ their words and what they say. It is like a fan following of an idol/icon. If your company uses these influencers as a tool, typically they will write about your product after having used it, thus creating a ripple effect of Customer Voice. This is called championing a product or company. Influencer marketing is a sunrise field and needs to be further explored for its advantages in selling. Whatever you call them – customers, followers, fans, champions, these are people you don’t take lightly in business. Because their voice means business!

MANAGEMENT REPORT

Players in global cancer supportive care products market focus on getting approvals from governing bodies Leading manufacturers are enhancing their business operations and encouraging R&D activities AS STATED by the World Health Organization (WHO), over 8.8 million people in the world succumbed to cancer in 2015. The World Cancer Research Fund International (WCRF) predicts that this number is likely to increase up to 24 million over the span of next 20 years. Lung cancer, breast cancer, and colorectal cancer are among the most common types of cancer, which also the leading causes of death among men and women across the world. The chronicity of this disease creates strong demand for cancer supportive care products, especially in developing and underdeveloped countries. Increasing geriatric population in the world and rising pervasiveness of cancer is boosting

the growth of the global cancer supportive care products market. Even though high cost of research and stringent regulations create challenges for market players, increasing purchasing power of consumers is stimulating the growth of the market. Leading manufacturers in the market are enhancing their business operations and encouraging R&D activities to launch newer and more effective products. Johnson & Johnson, Amgen, Hoffmann LARoche, and Teva Pharmaceuticals Industries, are among the leading players in the global market for cancer supportive care products. Amgen, a leading biopharmaceutical company based in the US, recently launched

MVASI (biosimilar bevacizumab) in collaboration with Allergan, a pharmaceutical company headquartered in Dublin. It is an anti-cancer biosimilar, which can be used in treatments for different types of cancer such as metastatic breast cancer, lung cancer, renal cell cancer, and epithelial ovarian cancer. After receiving approval from the US Food and Drug Administration (FDA), MVASI recently was approved by the European Commission (EU) for the treatment of certain types of cancers. MVASI is the first product Allergan launched in collaboration with Amgen, for which the companies received marketing authorisation by the EU in Europe.

Johnson & Johnson is one of largest multinational pharma companies in the world and a leading player in the global cancer supportive care products market. ERLEADA (apalutamide) by Johnson & Johnson is an androgen receptor inhibitor, which can be used in the treatment of non-metastatic resistant prostate cancer. The company announced that ERLEADA has received an approval from the US Food and Drug Administration (FDA). It also claims that ERLEADA is the first therapy for treating non-metastatic castration-resistant prostate cancer that received an FDA approval. ZYTIGA (abiraterone acetate), another product by Johnson & Johnson, can be

used in the treatment for metastatic prostate cancer (CSPC). The company announced that ZYTIGA (abiraterone acetate) recently received an FDA approval, which marks a crucial step in the companyâ&#x20AC;&#x2122;s growth. Apart from launching nextgeneration cancer care products, Johnson & Johnson established a partnership with the Ministry of Health, Kenya to support the implementation of the National Cancer Control Strategy 2017-2022. The company will support awareness and dissemination workshops arranged by the Ministry of Health, Kenya, which will ultimately result in reversing the cancer burden in the country. EP News Bureau

MANAGEMENT

Ind AS 115 - Key impact for life sciences entities Jalpa Sonchhatra, Director, Financial Accounting Advisory Services, EY India speaks on the strategies needed to ensure compliance with IndAS 115 THE MINISTRY of Corporate Affairs (MCA) has notified Ind AS 115 – Revenue from Contracts with Customers with effect from 1 April 2018. The new standard will supersede virtually all revenue recognition requirements under Ind AS that apply to life sciences entities today. The key issues for life sciences entities include determining how the new standard applies to: Collaboration arrangements, arrangements with variable consideration and licenses of intellectual property. Further, application of Ind AS 115 will require life sciences entities to use significant judgement and make more estimates than they do under Ind AS 18. Companies also need to recalibrate their internal control, policies and systems for financial reporting to ensure compliance with new requirements.

Collaboration agreements Life sciences entities frequently enter into complex collaboration agreements with other parties. In certain arrangements, a counterparty may not be “a customer” of the entity, as defined in Ind AS 115. Instead, the counterparty may be a collaborator or partner that shares risks and benefits of developing a product to be marketed, for example, when two pharmaceutical (pharma) companies enter into a collaborative arrangement to develop a product candidate. In absence of additional application guidance, life sciences entities may find it challenging to determine whether their collaborative arrangements are within the scope of Ind AS 115.

Participation on a joint steering committee Collaborative R&D arrangements often include provisions requiring constitution of, and participation in, a joint steering committee (JSC) to make deci-

28 EXPRESS PHARMA August 16-31, 2018

sions about the collaborative activities. For example, a biotechnology entity that has a revenue contract with a pharma entity could be required to provide its expertise through participation on a JSC in addition to licensing a product candidate and performing R&D services. If participation in the JSC is determined to be a promised service in the arrangement, resultant revenue recognition implications will follow accordingly.

Customer options to acquire additional goods or services Life sciences contracts may include a right for the customer to purchase additional goods or services at a discount. For example, if a life science entity sells the intellectual property for a specific drug to another entity. At the same time, it also grants the counterparty an option to sub-contract the manufacture of the drug back to the entity at a fixed price, which is lower than the market price. If this option represents a material right for the customer, the seller will need to allocate a portion of the transaction price to the option and recognise revenue when control of the goods or services underlying the option is transferred to the customer, or when the option expires. In this particular scenario, the entity selling the license will need to evaluate whether some of the revenue receivable at the time of granting the license should be deferred and recognised at a later date. Some items that are considered marketing incentives or incidental goods or services under legacy Ind AS will have to be evaluated under Ind AS 115 to determine whether they represent promised goods or services in the contract.

Milestone and other variable payments Many life sciences entities en-

ter into long-term contracts which may include significant variable payment, such as rebates, incentives, performance bonuses, contingencies or concessions. For example, the transaction price may vary depending on the price at which the product is sold by a reseller or distributor or on achieving certain milestones. Also, variable consideration can result from explicit contract terms or can be implied by a life sciences entity’s past business practices or intentions under a contract. Ind AS 115 requires an entity to estimate variable consideration using the method (i.e., most likely amount or expected value) that best predicts the amount to which the entity will be entitled. Life science entities need to consider all information (e.g., historical, current and forecast) that is reasonably available to them while estimating such variable consideration.

Rights of return Life sciences entities often provide customers with a right to return a transferred product for a specified period of time after sale. A right of return creates variability in the transaction price that a life sciences

entity needs to estimate. A life sciences entity will recognize revenue based on the amount to which it expects to be entitled through to the end of the return period. Therefore, it will not be able to recognise the portion of the revenue till the end of the return period resulting into refund liability till that point. The standard also requires a return asset to be recognised at the time of the initial sale, if an entity expects to receive the returned product in saleable or repairable condition. Separately presenting the right of return asset and refund liability on the balance sheet will be a change in practice for some medical technology entities. For other entities in the life sciences industry, returns frequently have no value because of product expiration or requirements to destroy returned inventory.

Licenses of IP Life sciences entities commonly enter into arrangements with customers that include licenses of IP, such as licenses for product candidates or patented drug formulas. Ind AS 115 distinguishes between licenses that represent the transfer of a right to use an entity’s intellectual property and licenses that represent the provision of access, over a period of time, to an entity’s intellectual property and specifies criteria to determine which type of license is being sold. Revenue for the former will typically be recognised at a point in time, revenue for the latter will typically be recognised over the period of access. Ind AS 115 also provides application guidance on the recognition of revenue for sales-based or usage-based royalties received in exchange for licenses of IP and requires that royalties are recognised at the later of when: (1) The subsequent sale or usage oc-

curs; or (2) The performance obligation to which some or all of the sales-based or usagebased royalty has been allocated is satisfied (in whole or in part). A life sciences entity will have to analyse the facts and circumstances of each contract (or type of contract) in order to determine when and how to apply the application guidance to licenses of IP and may need to use more judgement than it did under legacy Ind AS. The units of account and timing of revenue recognition may also change.

Next Steps Ind AS 115 requires either a full retrospective adoption in which the standard is applied to all the periods presented or a modified retrospective adoption. Certain practical expedients are available under both methods. Irrespective of transition choice applied, all open contracts which are outstanding as of 31 March 2018 need to be revisited for its appropriate accounting and disclosures in relation to timing and the amount of revenue to be recorded through the financial statements. All transition related changes will be recorded through opening retained earnings. In addition to the key changes discussed above, Ind AS 115 introduces detailed guidance in many areas regarding the reporting of revenue and entities will need to ensure that they have considered all of these when assessing the extent to which their accounting policy for revenue may need to be amended. Life sciences companies should perform an assessment of how they will be affected as soon as possible so they can determine how to prepare to implement the new standard for the current fiscal year. While the effect on entities will vary, some may face significant changes in revenue recognition.

RESEARCH

Aptamers in cancer therapeutics Dr Harleen Kaur,Senior Scientist, AstraZeneca USA, through her research paper, talks about collaborative approaches which can make huge difference in treating cancer

ancer is a disease caused by genetic mutation, which leads to uncontrolled proliferation of abnormal cells and their infiltration in normal tissues and organs of human body. Cancer is a global health problem and one of the leading causes of death worldwide including India. According to World Health Organization (WHO) reports, in 2015, cancer was responsible for 8.8 million deaths in 2015 with approximately 70 per cent cancer deaths occurring in low and middle-income countries. In India alone, cancer accounted for about 949,000 new cases and 634,000 deaths in 20081. Air pollution and smoking and chewing tobacco are the chief causes of cancer in India. One of the common challenges facing Indian oncology system and many other less developing countries is the lack of enough funding for basic cancer research and unaffordable cost of cancer drugs. Shortage of funds holds back innovation and new breakthrough research that provides compelling evidence to move the molecule forward in the therapeutic and diagnostic pipeline. In order to overcome this challenge, Indian scientists and academicians are working in collaboration with scientists and prominent institutes across the globe, particularly the United States of America, Singapore and Germany to generate enough funding for cutting edge cancer research and bring affordable medicines and cost effective treatments to patients. This collaborative approach can make a huge difference and is leading to huge advances in the cancer scenario in the years to come. In the pursuit of finding an utmost effective cancer treatment and with an interest in scientific research and drug

development, I worked on probing high affinity DNA aptamer sequences against heparin binding domain (HBD) of VEGF165 protein and investigating the antiproliferative activity of the obtained high affinity aptamer sequence on cancer cells. VEGF is a mitogenic protein that causes angiogenesis and cancer progression in human body and is a popular therapeutic target for cancer treatment. I feel that this research can help scientists seeking a cost-effective way to synthesise aptamers. I believe it has the potential to deliver innovative and life-changing treatment for cancer patients and thereby making an impact on the society globally. Aptamer are single stranded nucleic acid molecules that bind with high affinity and high specificity to their

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VEGF, a mitogenic protein causing angiogenesis and cancer progression in human body is a therapeutic target for cancer treatment cognate targets. I adopted a novel stem-loop structural modification strategy to locate high binding sequences in 66-mer long DNA antiVEGF aptamer sequence. It resulted

in discovering many truncated high binding affinity sequences with one of the obtained sequence displaying >200-fold increase in the binding affinity for HBD of VEGF protein. The binding affinity and specificity was confirmed both on the purified protein and colorectal cancer cells. The sequence was further chemically modified to enhance its biostability and its antiproliferative activity was investigated on different cancer cells. The modified sequence demonstrated antiproliferative activity of >50 per cent against Hep G2 cancer cells and >20 per cent breast cancer cells in hypoxia conditions and also displayed downregulation of Jagged-1 protein in delta/jagged-notch signaling pathway. The research has been published in peer-reviewed journals and cited by scientists and researchers

worldwide2,3. The unique stem-loop modification strategy employed in this work could be useful in identifying binding domain (s) in a aptamer sequence resulting in elimination of unnecessary nucleotides in the sequence and cost-effective synthesis of aptamer sequence (s) for future research work. In addition, the identified sequence in this work has lot of potential in oligonucleotide based cancer therapeutics and diagnostic applications. Most recently, my review paper as first author on “Aptamers in the therapeutics and diagnostics pipelines” got published in a well-reputed and peerreviewed “Theranostics” journal4. This review paper discusses in detail about the theranostic potential (both therapeutic and diagnostic potential) of aptamers in the current and future therapeutics and diagnostics pipelines and challenges associated with them. Few of the aptamers mentioned in my paper have potential to hit the market in the coming few years. The links for some of the scientific work could be find below in this article.

References 1. http://www.searo.who.int/india/topics/cancer/Cancer_fact_sh eet.pdf 2. Kaur H, Yung L-YL (2012) Probing High Affinity Sequences of DNA Aptamer against VEGF165. PLoS ONE 7(2): e31196. 3. Kaur H, Li JJ, Bay B-H, Yung L-YL (2013) Investigating the Antiproliferative Activity of High Affinity DNA Aptamer on Cancer Cells. PLoS ONE 8(1): e50964. 4. Kaur H, Bruno JG, Kumar A, Sharma TK (2018) Aptamers in the Therapeutics and Diagnostics Pipelines. Theranostics 8(15):4016-4032.

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RESEARCH UPDATES

Genome editing using CRISPR-Cas9 system shows tremendous promise Research published in Nature Medicine describes collaborative effort to reduce off-target CRISPR-Cas9 genome editing, removing barriers for human therapeutic applications GENOME EDITING using the CRISPR-Cas9 system has tremendous promise for therapeutic correction of genetic errors in human cells. Prior to adoption as a medical therapeutic, safety concerns relating to off-target effects must be minimised to mitigate risks that may arise from the unintended action of this system at sites similar, but not identical, to the desired gene target site. In a study published in Nature Medicine, researchers at Integrated DNA Technologies (IDT) and the laboratory of Prof Matthew Porteus at Stanford University describe a novel Cas9 mutant that shows improved specificity and maintains high activity when used in the medically relevant ribonucleoprotein (RNP) format. Potential for medical use of the new mutant enzyme was

demonstrated in human haematopoietic stem and progenitor cells (HSPCs), where it was able to correct the mutation in the beta-haemoglobin gene responsible for sickle cell disease (SCD). Several groups previously described Cas9 mutants with improved specificity; however, all show significantly reduced activity when used in the clinically relevant RNP format. These previous mutants were developed using intelligent design based on known protein crystal structures. Instead, IDT scientists used an unbiased method to screen approximately 250,000 random Cas9 mutants to identify those rare mutants that improved specificity without compromising activity. After several rounds of selection, a single mutant emerged, now known as Alt-R

HiFi Cas9 nuclease, that provides the desired high on-target, low off-target characteristics. In the published study, a collaborative team from IDT and Stanford demonstrates the robust on-target editing and minimal off-target cleavage achieved by HiFi Cas9 in several therapeutically relevant loci in hard-to-edit HSPCs. They also show HiFi Cas9-mediated correction of the sickle cell disease-causing p.E6V mutation in patient-derived HSPCs. Mark Behlke, Chief Scientific Officer, IDT and a co-author of the study, said, “Previous attempts at improving Cas9 specificity characterised the mutants using plasmidbased methods that result in sustained over expression of the Cas9 protein, which increases off-target activity and

is not ideal for medical applications. This sustained over expression, however, rescued function of the mutants that otherwise showed low activity when used in the more transient RNP format. We specifically performed a broad screen to identify a mutant that performs well when used at the lower protein levels achieved with RNP delivery, maximising safety and further reducing unwanted side effects. Prof Porteus demonstrated utility using the new system to correct the SCD mutation in normal human blood-forming stem cells while minimising known off-target activity. We anticipate significant interest in use of the new Cas9 mutant in translational medical applications.” EP News Bureau

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RESEARCH

Eisai/Biogen to advance Alzheimer’s drug,provide fresh hope According to Eisai, the company had already contacted various regulators and plans to pursue accelerated approvals EISAI CO and Biogen will move forward with late-stage clinical trials of their Alzheimer’s disease drug, BAN2401, and are working with regulators to design the next studies and gain expedited review as a breakthrough therapy. The companies announced this month that despite failing at an earlier stage, the drug slowed Alzheimer’s progression at its highest dose, providing renewed hope in a field littered with failures. Japanese drugmaker Eisai said the treatment also generated positive trial results at lower doses. Full results were presented at the Alzheimer’s Association International Conference in Chicago. “Our plan would be to start more trials,” Dr Lynn Kramer, Chief Medical Officer, Eisai’s neurology unit, told Reuters. “Whether it be Phase III in the same patient population, or other populations. We are thinking about a number of things.” Kramer said the company had already contacted various regulators and plans to pursue accelerated approvals. “We are certainly considering ‘prime’ status in Europe, ‘breakthrough’ in the US and ‘sakigake’ in Japan,” he said of various paths to potentially swifter approvals. The companies said after 18 months of treatment, patients who received the highest dose of BAN2401 saw a statistically significant improvement in cognitive and biological measures of Alzheimer’s versus placebo. That was a welcome surprise as the drug did not appear to be working at the 12-month mark. The news marked a rare success for Alzheimer’s research following failure after failure of candidates from companies including Pfizer, Eli Lilly and Merck & Co. It also raised hope for aducanumab, another Biogen/Eisai drug in final stage testing. Both treatments are antibodies aimed at removing toxic clumps of amyloid from the brain. Any successful Alzheimer’s treatment is virtually guaranteed to become a multibillion-dollar seller. Alzheimer’s, the most common form of dementia, affects nearly 50 million people worldwide and is expected to rise to more than 131 million by

2050, according to Alzheimer’s Disease International. “All the chips are on the table with these two trials,” said Dr Ronald Petersen, an Alzheimer’s expert from Mayo Clinic in Rochester, Minnesota. One difference, experts say, is that the Eisai/Biogen drugs are among the first to use PET scans to ensure study participants all have amyloid in their brains. Many dementia patients in previous trials later proved not to have the amyloid plaques the experimental drugs targeted, greatly increasing the likelihood of failure. The US Food and Drug Administration has said it is open to trials that measure effects on biomarkers, such as beta amyloid, rather than symptoms like memory loss, to allow companies to test treatments much earlier in the disease. The trial of 856 patients with early Alzheimer’s tested BAN2401 at five doses against placebo. Participants were evaluated using an Eisai-devised tool that drew from three established Alzheimer’s assessment scales. Kramer said the custom endpoint was important as prior cognitive scales were developed for people with later-stage disease. The trial also used an ‘adaptive’ design that allowed Eisai to place new enrollees into groups receiving what appeared to be the most effective doses. Kramer would not reveal how many patients received the highest dose. “We believe that there are plenty of patients at the higher doses. When people see the results, they will think so too,” he said. While the news release only mentioned the highest dose, Kramer said positive results were seen for other doses. “There is a clear dose response,” he said. The companies will likely face some skepticism. The 12-month results used a predictive “Bayesian” statistical method, while the 18-month results used traditional statistical methods to assess the drug. Reuters

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PHARMA TECHNOLOGY REVIEW I N T E R V I E W

For emerging technologies in pharma, choosing the right solution is always a challenge As pharma companies in India strive to tap opportunities in large emerging markets, lean manufacturing techniques will play a major role in enhancing profitability and compliance. Sajiv Nath, MD, Yokogawa India tells Viveka Roychowdhury that automation is the first step towards achieving improvement in compliance, which is why they are seeing increased traction from the pharma sector since last couple of years As a provider of industrial automation and test and measurement solutions, which sectors/industries form the bulk of Yokogawa’s global revenues? Envision a pharmaceutical plant where people are watchful and attentive as the business responds to change quickly and efficiently. As digital transformation ensues to disrupt, transform and reshape industries, we can now picture an operation that delivers consistent production, real-time information and accurately controlled and safe processes that comply to the regulatory and demanding requirements of the pharma industry. The pharma industry has recognised the value of automation as we have come to recognise that industrial automation is a business tool, not just a control tool, which can help process businesses meet their industrial challenge. It is imperative for pharma companies to achieve compliance and safety while maintaining cost efficiency as any deviation in the set standards can lead in jeopardising the lives of the end users. Ideally an intelligent and scalable Plant Information Management System is in the heart of the system which provides an analysis and reporting application that collects, stores and displays

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August 16-31, 2018

current and historical data from batch production, equipment and recipe viewpoints. This enables production and recipe management, process engineering, quality management and operations staff to easily access batch information for decision support, production planning and scheduling, analysis, process improvement and quality purposes. These are ideal productivity improvement tools that enables user to focus on KPIs (Key Performance Indicators) such as a cycle time and frequency using the web based browsing, analysis and reporting user interface and to develop action plans for process improvements. Intelligence and scalability varies from developer to developer and user needs to exercise right diligence to select the one suitable for present and as well future needs. Yokogawa’s global revenues come from various segments, viz, pharma, oil & gas, chemicals, power, iron and steel, pulp and paper, foods and beverages. Yokogawa spans across 60 countries, sales exceeding $3 billion, has more than 4500 patents and registrations, 18 manufacturing facilities, dedicates 6 per cent annual revenue towards research and development and is the

world's first distributed control system and digital sensors. We have state-ofthe-art staging facility for distribution control system in Bengaluru which is spread across 15000 sq ft area and a local manufacturing facility under the ‘Make In India’ slogan. The factory is the mirror image of our facility at Yokogawa’s Kofu factory in Japan.

Yokogawa is committing itself to the achievements of goals that are based on a vision of where our society should be by the year 2050

Which are the sectors served in India? How much percentage comes from the pharma sector? Yokogawa has developed sustainability goals that will guide its efforts to make the world a better place for future generations. To ensure flexible response to environmental and technology changes and guide its long-term efforts to address social issues. Yokogawa is committing itself to the achievements of goals that are based on a vision of where our society should be by the year 2050. We will work to achieve net-zero emissions, take a transition to a circular economy and pharma companies operate in a global marketplace and the industry is encouraged to comply with international initiatives such as the PIC/S Good Manufacturing Practice (GMP) Guide and the ICH Guidelines. GMP facilities need to follow established

best practices and automated production equipment and computer systems are expected to adopt current computerised system validation (CSV) practices such as Good Automated Manufacturing Practice (GAMP). As a company our goal is to contribute to society through broadranging activities in the areas of measurement, control and information. Individually, we aim to combine good ctitizen with the courage of innovation. Automation of processes and embedding rules helps companies in ensuring that the data produced is compliant. It can be thus concluded that automation is the first step towards achieving improvement in compliance from the regulatory point of view. Contribution from pharma industry is seeing a high growth rate since last couple of years. With innovative IIoT solutions, inherent reliability and quality –hallmark of Yokogawa and synonymous with pharma undustries , we are poised for higher growth in this segment. As profit margins continue to decline, pharma companies are forced to look for ways to cut cost. How can Yokogawa help them cut costs without compromising on quality,

• Secure data storage with minimal administration

given that regulatory strictures are only rising by the day? The automation of data knowledge insights is an area of focus in the immediate future. In order to get to this stage of maturity, we find that majority of the organisations are significantly unprepared to be data driven. Often, customers replace existing big data technologies and the culture has not yet transformed to leverage data as a critical digital asset. Some of the other critical issues in transforming an organisation to become data driven include organisational alignment on analytics, overcoming existing master data issues, recruit new talent (data scientists, machine learning experts) and best-in-class data governance practices. In essence, organisations should leverage data as a pathway to drive operational efficiency, growth and sustained operational value improvements. Both compliance and regulation are required while manufacturing the products and packaging them. In today’s new age IIoT age process automation system is applied in the primary manufacturing of the active pharma ingredients and process and discrete automation techniques are applied during packaging and formulation — which include compounding, washing, labelling machine, and packing. Pharma companies can look for◗ Secure flexible reporting incorporating data from batches, master recipes, equipment, trend values, alarms and events. ◗ Built-in reporting workflow to

configure templates, approve templates, assign to report scheduler, run templates to generate reports, approve reports and view reports. ◗ 21 CFR Part 11 capable option is available, if required. Big Data, the Industrial Internet of Things (IIotT), AI, machine-tomachine (M2M) learning etc are buzz words in this data-driven era. How is Yokogawa helping pharma companies leverage this data to enhance productivity? For emerging technologies in pharma segment, choosing the right solution is always a challenge. So best way to depend on the leaders known for technological innovation, customer centricity and reliability. Here are few guidelines: 1. ‘Out of the box’ integration with batch control systems, providing immediate usability and benefits without complex engineering and database configuration. 2. Standard data analysis capability, providing: ◗ Automatic calculation and charting of cycle times and unit utilisation for each batch. ◗ Automatically calculated performance ratings for each batch. ◗ Comparison of batches to peer groups. ◗ A powerful tool for sorting and comparing batch history data. 3. A customisable web-based user interface providing: ◗ Batch, master recipe and equipment data accessible from one place ◗ Ad-hoc web access to data without custom display generation.

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August 16-31, 2018

PHARMA TECHNOLOGY REVIEW

Pre-shipment inspection,testing and certification of pharmaceutical goods Quntrol provides complete transparency and ensure integrity through their advanced proprietary digital software platform. Riddhi Javeri, Director, Quntrol Laboratories, gives an insight ACCORDING to the World Health Organization (WHO), one in ten medicines in developing countries is fake or substandard. Malaria drugs and antibiotics are among the most commonly reported. However, substandard drugs for cancer, heart disease and HIV, as well as contraceptives and painkillers are also on a rise. Poor quality drugs could endanger health, prolong illness and can also add to the danger of antibiotic resistance. For its part, the London School of Hygiene and Tropical Medicine has estimated that 116,000 additional deaths from malaria could be caused each year by poor quality antimalarials in Sub-Saharan Africa. The WHO estimated that up to 72,000 deaths from childhood pneumonia could be attributed to the use of substandard or fake antibiotics. A report published by WHO on November 28, 2017 highlighted that of the 1500 reports of fake and low-quality medicines, 42 per cent were from Sub-Saharan Africa, 21 per cent from Europe and 21 per cent from the region of the Americas. The Ministry of Health, Government of Mozambique has taken a leap towards curbing substandard goods from being imported into Mozambique. To this effect, they have implemented a programme of pre-shipment inspection and testing of all pharmaceuticals goods imported into Mozambique. They have started this programme with imports from India since India is their largest supplier of medicines. Approximately, 60-70 per cent of its pharma imports are from India. In value terms, Mozambique imports approximately $88 million worth of medicines from India according to EXIM Database. The Ministry of Health, Government of

34 EXPRESS PHARMA August 16-31, 2018

Mozambique has exclusively appointed Quntrol Laboratories in India to implement the process of pre-shipment inspection and testing for pharma consignments exported from India to Mozambique. Quntrol Laboratories Private is an independent thirdparty company offering services of inspection, testing, verification and certification of pharma products. In June 2017, the Ministry of Health signed the MoU with Quntrol to solely appoint us to carry out this process for all pharmaceutical consignments shipped from India to Mozambique. Quntrolâ&#x20AC;&#x2122;s core expertise is in pharmaceuticals wherein they carry out document verification, inspection and sampling of pharma consignments, conduct analytical testing of the samples and provide a Clean Report of Inspection and Analysis (CRIA) for the goods exported from In-

dia. Quntrol follows best-inclass practices to provide the services. Most importantly, they provide complete transparency and ensure integrity of the process through their advanced proprietary digital software platform. Quntrolâ&#x20AC;&#x2122;s CRIA is a mandatory document required by Mozambique customs to authorize import of the consignment into Mozambique. The process has had a big impact across every stakeholder, namely the manufacturers, importers, the government and lastly the patients who consume the medication. The exporter is benefited by getting added assurance of the quality of their goods through a third party validation and can save resources by avoiding potential recalls. The importers are assured of the quality of the medicines they are importing and satisfied by knowing beforehand that they are importing what they have ordered. The

government is assured of importation of quality medicines and with this policy it can safeguard the health of its citizens. Finally, the consumers have more trust in the medicines they are consuming and is assured of desired outcomes due to independent proof of quality and safety of medicines. One of the key challenges with respect to pharma quality assurance is known to be integrity of data. Quntrol has developed a software called Quntrol Advantage which is a digital platform that ensures complete transparency and integrity of the process of preshipment inspection and testing. Exporters create an account on the portal after they complete registration. Thereafter, they can raise inspection requests and all export related and product quality related documents are uploaded by them on the portal. Quntrol verifies the documents on the portal and schedules the inspection. All relevant documents pertaining to the inspection and testing of the samples drawn during inspection and tested in the laboratory are made available to the Ministry of Health in a special section of the portal, allowing them to be viewed in real time. Apart from the digital software run process, Quntrol has also ensured various checks and balances to ensure complete integrity of the process. This includes anonymity of the laboratories where analysis takes place, sampling plan generated automatically on the software through an algorithm, sampling plan kept confidential until the time of inspection and security features in the CRIA to avoid duplication. The analytical laboratories are state-of-the-art, highly accredited and fully equipped to

conduct complete analysis of tablets, capsules, oral liquids, topicals, inhalers and all other dosage forms. 21-CFR compliance is followed to ensure data integrity. With this process being implemented for Mozambique since April 1, 2018, there has been considerable positive impact that has been created. Mozambique has traceability to where the goods were manufactured and whether those sites have adequate licenses and GMP certificates to carry out manufacturing. They can now view data regarding the importers in their country, which products are most commonly being imported, and when the majority of imports take place. Several products have been rejected on the grounds of low content in assay and above limit impurities in related substances. Hence, importation of substandard goods has been avoided. Third party validation of quality has increased seller, buyer and consumer confidence. Manufacturers in India have begun to pay much closer attention to their documentation and quality of products as well. This can only help the manufacturers in the long run, as with better quality control measures being implemented internally, their opportunities for expansion into more tightly regulated markets greatly increases. For a long time now, India has been known as the pharmacy capital of the world. What is also spoken about by importing countries is the lack of quality control implemented by Indian manufacturers. It is the aim of Quntrol Laboratories that India will be referred to as a nation exporting pharmaceutical goods of the highest quality, and make Indian pharma products the envy of nations worldwide.

PHARMA TECHNOLOGY REVIEW I N T E R V I E W

‘ALEX provides guaranteed express delivery of pharma goods cost-effectively’ Virendra Chaudhary, Director, Algor Logistics in a tête-à-tête with Express Pharma, speaks on the crucial role played by temperature-controlled logistics services in India’s challenging domestic pharmaceutical market

Give us an overview of the services offered by your company. Algor Logistics is a specialist in the temperature- controlled logistics services space. We transport a range of pharmaceutical goods including active pharma ingredients (APIs), intermediates, formulations, cosmeceuticals, vaccines, and drugs under clinical trial. In addition, our refrigerated trucks ship highly sensitive cargo such as bioplasma, stem cells, and live animals for lab testing, to name a few. How big is your company in terms of number of employees and market presence? We have about 50 people on our direct payroll at all-India level as of now. However, we are in the process of hiring new people. So, our headcount is expected to grow by another 10 per cent within a fortnight from now. We are just a three-yearold company. In 2015 we have already established a panIndia business footprint. Algor has a fleet of over 100 reefer trucks running on Indian roads, delivering high-value materials at client destinations. Of these, nearly 60 vehicles are dedicated to pharma vertical. What are the challenges faced by pharma companies in India? It may not be inappropriate or an exaggerated claim to describe India’s pharma sector as vibrant. Besides being the second largest

contributor to the world’s biotech and pharma workforce, the industry is also one of the fastest growing sectors in the world. Within two years from now, this globally competitive sector is expected to touch $55 billion in terms of value. Besides the quality norms under CGMP regulations, pharma companies have to comply with stringent Good Distribution Practices (GDP) laid down by World Health Organisation (WHO). GDP norms mandate that pharma goods be transported in such a manner that their safety, identity, strength, quality and purity characteristics of are well maintained during transportation. Being highly sensitive, pharma materials (such as APIs, intermediates, formulations, cosmeceuticals, and vaccines) require special handling and care during transport. The pharma substances being shipped must remain stable during transport. Sensitive materials such as drugs, blood, and blood components must be stored safely at the right temperature. APIs, vaccines, formulations and biologicals should not be tilted and be handled with utmost care. These materials also need to be protected from microbes and pests throughout the duration of their transport. How does Algor help pharma companies overcome these challenges? Algor helps pharma companies in India meet their

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transport routes connecting key metropolitan centres such as Mumbai, Ahmedabad, Pune, Delhi, Bengaluru, Hyderabad, Kolkata and Chennai. Given India’s expansive pharma sector, we are looking at adding a few tier-II destinations and giving next day delivery to the cities within 700 km to 1,000 km range.

GDP compliance objectives comprehensively. Our fleet of trucks (and vans) are specially designed to ship the pharma cargo. The active and heavyduty precision cooling inside our reefer vehicles provides a safe, speedy and direct connectivity between the origin and destination. What are the new developments in Algor? Are there any expansion plans? As mentioned earlier, we are in the process of inducting fresh talent. The bigger staff strength is essential if we have to undertake business expansion. This expansion is happening on multiple fronts. We are hiring people not just in Mumbai but at various locations in the country to give us a wider market access. Secondly, we are exploring a few new routes to be added to our network. Already, Algor covers all pharma zones in India as well as the major good

Are there any major projects on the cards? One key project this year is the introduction of ALEX, India’s only temperaturecontrolled, scheduled and express shipment services. This is a unique service and will be in high demand very soon. Let me briefly explain what is unique about ALEX. There are two types of shipment options available for pharma companies today. Your consignments can either be full truckload (FTL) or less than truckload (LTL); either scheduled express or consolidated. So when a company wants to ship only a few kilograms of material, it has to either spend as per FTL rates for express delivery or wait for indefinite time for it to get delivered. ALEX combines all the three ingredients of a great service: Fast (Delivery), Good (Quality) and Cost Efficient. With ALEX, pharma companies can send small consignments with scheduled express delivery timelines without having to spend at FTL rates. With specially designed reefer trucks, ALEX offers

two temperature ranges—20C to 80C and 150C to 250C—to pharma clients. So companies can concurrently ship their goods with differentiated cooling requirements, thus, saving time and costs. This may be a great news for SMEs as well as enterprises. Your comment. Certainly! In addition to the big pharma, ALEX can be a great temperature-controlled transportation option for micro, small and medium enterprises (MSMEs). ALEX respects everyone’s budget concerns and offers a solution that offers a truely competitive advantage. Our message to all MSMEs as well as large pharma companies is: Your wait for the right transport option is over. ALEX provides guaranteed express delivery of pharma goods costeffectively. Moreover, being GDP compliant and SOP-driven, ALEX scores 100 per cent on all the quality parameters. Ensuring zero-damage to sensitive cargo is our motto. Our field-staff is well-trained to handle pharma materials during transport. Customers can demand real-time temperature monitoring of goods up to the package level. Our backend support team keeps a constant vigil on your consignments with satellitebased monitoring technology. Starting with Mumbai, Hyderabad and Visakhapatnam, ALEX is going to storm all the busy pharma routes in the country very soon. EP News Bureau

EXPRESS PHARMA

August 16-31, 2018

PHARMA TECHNOLOGY REVIEW VENDOR NEWS

Covert-Hologram Seal from Schreiner MediPharm offers tamper protection conforming to EU directive The innovative Covert-Hologram Seal is transparent, inconspicuous and thus appears like a simple packaging seal THE EUROPE-WIDE Falsified Medicines Directive 2011/62/EU coming into force in February 2019 requires all pharmaceutical manufacturers to mark their prescription medicine packaging with a serial number and an additional tamper protection device. Schreiner MediPharm’s multifunctional Covert-Hologram Seal with an irreversible, holo-

graphic effect offers reliable first-opening indication and tamper evidence, plus counterfeiting protection, and complies with the requirements of the EU Directive. The innovative Covert-Hologram Seal is transparent, inconspicuous and thus appears like a simple packaging seal. However, the first time the seal is opened, an invisible effect be-

comes visible. A hologram emerges that shows various inscriptions and design elements

in different colours depending on the viewing angle. The holographic effect is irreversible and the seal’s fully transparent original condition cannot be restored. Thus, manufacturers, suppliers, and patients can tell at first glance if the packaging has been previously opened or if the medicine is an originally packaged product. Covert anti-counterfeiting

features embedded in the specialty closure seal add extra security. Thus, the Covert-Hologram Seal effectively combines the reliable first-opening indication required by the EU Directive with additional counterfeiting protection in a single seal, enhancing security throughout the entire supply chain. EP News Bureau

OPTIMAPharma,OPTIMALife Science combine their expertise at P-MEC in Madrid An array of products will be displayed at the exhibition VISITORS TO the exhibition stand of Optima Pharma and Optima Life Science at P-MEC will have the opportunity to find out how the time between an order being placed and production starting can be kept to a minimum. The MultiUse concept, which consists of highly flexible, fully automated filling machines that can process different types of containers, will also be taking centre stage. Another key feature of the companies' exhibition presence will be the modern engineering technologies that enable Optima Pharma to complete complex turnkey projects on budget and on schedule. One area of emphasis at the exhibition will be Comprehensive Scientific Process Engineering (CSPE), which has revolutionised the planning and implementation of pharmaceutical filling machines. A combination of scientific methods and technological processes ensures that the time from the order being placed to the start of

36 EXPRESS PHARMA August 16-31, 2018

production is as short as possible. The MultiUse concept developed by Optima Pharma is the ideal solution for small batch sizes and different container types in the pharmaceutical industry. This type of machine can be used for production on a laboratory scale up to mediumsized batches and for the first time is fully automated and also highly flexible. The MultiUse Filler can quickly be adjusted to

different format sizes and types of containers, including vials, pre-filled syringes, and cartridges. The turnkey experts will inform visitors to the exhibition about complex projects involving filling and sealing, isolator technology, and freeze-drying. Optima Pharma takes overall responsibility for developing and implementing projects of this kind, from online planning and design through to integrated factory acceptance tests (FATs), building site management, site acceptance tests (SATs), and a comprehensive range of services, using the latest engineering technologies such as flow visualisations. The experts from Optima Pharma in Mornshausen and

Metall+Plastic in Radolfzell add the finishing touches to the portfolio of products and services on show at P-MEC. Metall+Plastic is a world leader in the design, production, installation, qualification, and validation of customised isolators. The company attracted attention at ACHEMA 2018 with its exciting new technologies, including DECOpulse, a new contamination system, and the user friendly, modular STISO sterility test isolator. Optima Pharma in Mornshausen develops state-of-theart freeze-drying machines. The company's most recent innovation is the CS freeze-dryer. It is designed for products that are new on the market and are initially being produced in small and medium-sized batches. The CS freeze-dryer is ideal for installation in existing buildings and can easily be configured to ensure an efficient overall layout for the production system. Its space-saving design also makes it highly cost-effective.

Optima Life Science has a strong reputation as a converting specialist across a number of industries. As well as combined manufacturing and packaging machines for wound dressings, transdermal patches, and oral film strips, the company makes systems that automatically coat microtiter plates for use in ELISA test kits. At ACHEMA 2018 the company announced a new alliance with Coatema Machinery. The alliance, which is known as Comedco, will make it easier for pharmaceutical companies to move into manufacturing and packaging transdermal patches and oral dispersable films with pharmaceutical active ingredients. Optima Pharma and Optima Life Science are part of the Optima packaging group GmbH, which has its headquarters in Schwäbisch Hall in southern Germany. Optima has 2250 employees and 14 sites worldwide. EP News Bureau

PHARMA TECHNOLOGY REVIEW

Waters UNIFI mass spectrometry data acquisition technology compatible with Mass-MetaSite and WebMetabase UNIFI’s application programming interface pairs with leading MS Metabolite identification processing software/platform WATERS CORPORATION announced new capabilities that provide greater data visibility and faster throughput analysis of metabolites during drug discovery. By integrating UNIFI acquired data from the Vion IMS QTof or Xevo G2 XS mass spectrometers with Molecular Discovery’s Mass-MetaSite and WebMetabase processing software, drug metabolism and pharmacokinetics (DMPK) scientists now have new analysis capabilities across a variety of molecules. Waters UNIFI Scientific Information System is the first software platform to merge LC

and high performance MS data (both quadrupole and time-offlight) into a single solution that encompasses data acquisition, processing, visualisation, reporting, and configurable compliance tools within a networked laboratory environment. This is the first time that the UNIFI Application Programming Interface (API) has been made accessible to an outside party and signals a larger Waters initiative to open its UNIFI products to thirdparty developers, ensuring flexibility and optimal fit-forpurpose functionality. “Waters helps our cus-

tomers accelerate drug discovery and development to bring life-changing therapeutics to market. Coupling the superiority of our high resolution, ion mobility spectral data acquisition capabilities with the industry’s leading drug discovery metabolite identification software allows us to deliver new capabilities for DMPK scientists,” said Jeff Mazzeo, Vice President of Marketing, Waters. Mass-MetaSite features automatic peak detection, structure elucidation, and batch processing – attributes important for high throughput identi-

fication of known and unknown compounds, including those with complex structures such as cyclic peptides. WebMetabase accommodates a number of ADME dedicated workflows, such as soft spot analysis, glutathione reactive metabolite trapping, cytochrome reaction phenotyping, and species comparison. This integrates processed metabolite ID information into the broader context of DMPK and the discovery designmake-test cycle. "The collaboration with Waters’ scientists and developers has opened up a great op-

portunity for our clients to have direct access to data acquired in UNIFI, which has not only enabled HDMSE processing, but also improved processing quality for other Waters data sets,” said Ismael Zamora, CEO and Scientific Director, Lead Molecular Design. “The third-party approach implemented by Waters has been a great way for Molecular Discovery to enhance our software capabilities and help our clients attain even higher efficiencies in their DMPK workflows.” EP News Bureau

PRODUCTS

Gandhi Automations’clean room high speed doors a necessity BETTER QUALITY or better yield is the primary reason for investing in a cleanroom space. It goes straight to the bottom line. Numerous manufacturing facilities now require a controlled environment in which one can limit the amount of dust and dirt in the area of the manufacturing. Medical instrument manufacturing and packaging, electronics and computer manufacturing, food preparation and some military applications are but a few of the instances that have strict requirements for maintaining a clean environment. One needs to know the requirement for specific product or process. Clean rooms have become integral part of pharma manufacturing facilities. One of the most important aspects of cleanrooms is the doors which needs to be chosen for cleanroom facility. Time for which door is open will play a

critical factor in avoiding dust, outside temperature, humidity etc. Opening and closure of door has to quick enough to isolate the outside environment and internal facility. Gandhi Automations provide clean room high speed doors specifically designed for above purpose. The clean room high speed doors are best suited for facilities when there is a requirement of controlled environment. The open-

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ing and closing of door is quick enough to separate outside environment and internal facility. High speed clean room doors designed by Gandhi automation are engineered carefully with feature below:◗ Concept of low air permeability in pressurised rooms with positive and negative air pressure ◗ Designed to fit inside the columns

◗ Self-supporting construction ◗ Minimises air leakage ◗ Can be equipped with transparent PVC horizontal sections or vision windows ◗ Special side guides to tightly integrate the curtain ◗ High leak tightness due to the close filling curtain in the guide rails ◗ High door efficiency with and low permeability values, EN 12426 EN 12427: < 12 m3/m2 h Δ 50 PA .

◗ Control device enclosure in Stainless Steel SS 316 Contact details Gandhi Automations Chawda Commercial Centre Link Road, Malad (W) Mumbai – 400064, India Off: +91 22 66720200 / 66720300(200 Lines) Fax: +91 22 66720201 Email: sales@geapl.co.in Website : www.geapl.co.in

EXPRESS PHARMA

August 16-31, 2018

PHARMA TECHNOLOGY REVIEW

CAPAplan: The right approach Freyr recently released a white paper which demonstrates that CAPA should not only correct and prevent the quality issues, but also proactively apply the approaches practiced to prospective areas where the issues might ensue INVESTIGATING QUALITY related issues and tracking them to closure is one of the most critical activities in quality management system (QMS). The increased importance of risk-based approaches is leading regulators to look for a well-defined process in investigating and identifying the root cause and method of implementation of the Corrective and Preventive Action (CAPA) plan. The crucial questions, most frequently asked by auditors during a CAPA review, include: ◗ Have the correct root causes been identified? ◗ Have the CAPAs been tracked and closed on time? ◗ Have the proposed CAPAs been reviewed for quality? ◗ Have all the proposed actions been implemented? ◗ Have the CAPAs been effective in preventing recurrence of the same problem? Most pharma companies view CAPA as an activity intended to address identified quality issues but fail to take a holistic approach to address them. This is evident from the warning letters published by Regulatory Agencies. Such a partial approach to CAPA results not just in rework, but also loss of time and revenue. Successful CAPA management requires addressing quality issues efficiently and effectively. CAPA should not only correct and prevent the quality issues, but also proactively apply the approaches practiced to prospective areas where the issues might ensue. By evaluating industry trends and pain points, going forward in this article will look into insights that help achieve regulatory compliance.

used for fixing any quality issue is the Corrective and Preventive Action (CAPA) plan. Following is a trend analysis of all non-conformities published by the Food and Drug Administration (FDA) in their 483s, which clearly outlines the impact of CAPA process on Regulatory agencies. The analysis clearly shows that almost 25-29 per cent of

The most common method

38 EXPRESS PHARMA August 16-31, 2018

audits, an analysis was conducted on the areas where issues related to CAPA are identified by the auditors. All CAPA related observations were broadly classified into the following categories: ◗ Inadequate procedures for CAPA ◗ Inadequate CAPA documentation ◗ Incorrect / inadequate /

non-compliant CAPA On detailed analysis of non-conformances, it was inferred that all the three categories: inadequate procedures, inadequate documentation and inadequate controls were interlinked. Inadequate measures were taken when there were inadequate processes. Inadequate documentation was ob-

Frequency of observations Type of CAPA observations Fiscal Year 2017 Fiscal Year 2016

Fiscal Year 2015

Fiscal Year 2014

Fiscal Year 2013

Inadequate Procedures

400

344

378

362

380

Inadequate Documentation

115

101

133

Inadequate Controls / Actions

Total CAPA Related Observations

518

444

480

470

516

Total Observations in FY

1839

1709

1809

1763

1980

Percentage of Observations on CAPA

28.17

25.98

26.53

26.66

26.06

2050

540

1600

420

1650 440

1700 1750

460

1800 480

1850 1900

500

1950 520 2000 1550

Overview

non-conformities are CAPA related, which translates into more than ¼ of all the FDA’s observations. Thus, establishing a robust CAPA system warrants that the number of non-conformances is reduced by a quarter. To understand if the existent CAPA system / process for companies is fool-proof and can withstand stringent

FY 2013

FY 2014

FY 2015

———— total observations in drugs, biologics and medical devices

FY 2016

FY 2017

———— CAPA observations

400

PHARMA TECHNOLOGY REVIEW served when there were no adequate measures to record them, and hence no artefact to submit.

concrete process which leaves no scope for errors, organisations fail to consider the challenges that the ground level staff encounter. This makes the process difficult to adhere to, which in turn leads to other non-conformities and errors despite proper training. Assessing risks to the process with appropriate stakeholders will identify various hurdles in implementation and thus prevent such issues.

CAPA observations in FYs

Inadequate procedures Understanding and implementation of current Good Manufacturing Practice (cGMP) includes updating the procedures in line with current Regulatory requirements. Legacy procedures do not include mitigations for known risks in the process and risks due to CFT interactions. Additionally, lack of proper training and procedure implementation is a widespread problem in the industry.

■ Inadequate Procedures ■ Inadequate documentation ■ Inadequate controls

Conclusion

THE FOLLOWING INFOGRAPHIC ILLUSTRATES THE KEY STEPS FOR EFFECTIVENESS CHECKS

Effectiveness checks The cases discussed above reiterate the untapped stepwise-verifying effectiveness of CAPA. If the measures taken on the CAPA are not effective, the process requires re-opening of CAPA, re-investigation, identification of root cause, and if required, a new CAPA plan. Freyr’s 40+ years of combined compliance resource experience has been providing effective and efficient solutions to its customers on a wide range of CAPAs. Implementing simple changes in a procedure and re-training of personnel is a key as a CAPA

Identifying metrics that determine effectiveness of CAPA

Establishing acceptance criteria based on sound scientific justification

action requires a straightforward approach to measure effectiveness. Some CAPAs propose more extensive changes, such as changes in testing process, change in vendors, changes in infrastructure layout, implementing a new system, to name a few. Effective-

CASE STUDY - I Incorrect / Inadequate / Non-compliant CAPA A warning letter issued to a drug manufacturer in the year 2017, stated, “during inspection of your analytical lab, the firm invalidated 101 out of 139 (about 72 percent) initial, out-of-specification (OOS) assay results for six-month stability assay, without conducting proper investigation. The initial failing result was invalidated without sufficient investigation, following which re-testing was performed and then reported as being within the limits. The firm failed to determine the assignable cause and did not take appropriate CAPA to ensure that the significant “analytical bias,” to which the initial analysis failure was attributed to, did not impact other analyses performed in the laboratory. The firm’s investigation assumed that there was analytical bias in the laboratory but failed to determine how this error in analysis could be eliminated or

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Defining sampling methodology or areas for monitoring

ness checks for such CAPAs require niche experience since this involves analysis and monitoring of adequate sample data. Quantitative approaches are recommended over qualitative ones to measure effectiveness checks since the former not only provide

Gathering and recording data from various sampling / monitoring points

Data analysis and reporting

proof of effectiveness, but also offer opportunities for improvement. Effectiveness checks not only help us to determine if the CAPA is constructive, but also helps us to determine if it is feasible to implement. In the process of establishing a

mitigated in the future. The firm’s response was termed inadequate by the FDA since they failed to implement CAPAs to mitigate the issue that was attributed to their process. However, the firm initiated an investigation into the OOS identified and a CAPA was assigned for the same. Despite the firm’s efforts, this was considered inadequate by the authorities. Authorities expect the CAPA plan for a given issue to be effective in preventing its recurrence. This, unfortunately, did not happen in the above-mentioned case, resulting in its relapse. To address this non-conformity, it is crucial to identify exactly where the process was ineffective. The non-conformity may be due to any one of the following reasons: 1. The root cause identified after investigation was inappropriate: The OOS identified could have been the result of some other issue such as complications in manufacturing, faulty storage conditions for the sample etc., which led to its 138-times recurrence. 2. The CAPA plan was not suitable: The root

To resolve institutional complications, every organisation should conduct an effective investigation, identify root cause(s), and implement timely and practicable corrective and preventive action(s) (CAPAs). An effective CAPA process should aim to promote critical thinking within the organisation at all the levels. The process must provide a common model and risk-based framework within the organisation, which allows investigators to master the process quickly and easily. This would anchor common logic behind investigations and bring unity to problem solving. The goal is to implement a reusable, standardised, and complete process that can avoid similar CAPAs.

cause identified, i.e., analytical bias, may have been due to a variety of reasons such as material, machine, calibrations, persons, methods and so on. The cause identified is far from the bull’s eye and identifying a CAPA for an unknown factor with vague causes is difficult to achieve. Additionally, it was not evident if the CAPA plan covered all the areas of analytical bias and efficiently rectified them. 3. The proposed CAPA plan was not validated for its effectiveness: Effectiveness checks need to be periodically conducted during the CAPA process. Not performing these effectiveness checks to determine if the identified plan has resolved the issue, results in repetition. In the above case in point, the issue has occurred over a span of six-months. Some issues may even occur over a longer duration. Monitoring every issue that occurs in a facility and trending them on periodic basis is beneficial to the process. Additionally, validating the CAPA for its effectiveness closes the loop between issue identification and remediation, while also providing proof for the same. Thus, leading to a closed loop CAPA process.

EXPRESS PHARMA

August 16-31, 2018

PHARMA TECHNOLOGY REVIEW

CASE STUDY - II

CASE STUDY - III

In a warning letter issued to a Medical Device company, the FDA stated, “Failure to establish and maintain procedures for implementing corrective and preventive action, as required by 21 CFR 820.100(a). For instance,

In a warning letter issued, FDA states, “IM-CAPA-007 was opened in for bladder ruptures and remained open for (b)(4) days. The root causes identify (b)(4); (b)(4); and (b)(4) of the (b)(4). The corrective actions include implementing an (b)(4) and adding preventive maintenance on the (b)(4). Your effectiveness verification after three months was performed with a review of complaints which determined that the corrective actions were effective. The effective summary opened for the Intermate and Infusor bladder ruptures states that the validation document number V07-055 demonstrated that the (b)(4) of the bladders improved by (b)(4) %. Protocol document number V07-055 validated the new compounding rubber process using (b)(4) equipment with water-cooling system. A review of the documentation (protocol and records) revealed: ◗ The protocol specifies that the (b)(4) test is for information only and it does not specify an (b)(4) acceptance criterion for bladders ◗ There is no record showing 50 samples were pulled from three production lots, ◗ There are inconsistencies within the production lot numbers as specified in the protocol and final report” In the illustration, the organisation did have an efficient procedure for addressing issues through CAPA. However, the organisation failed to implement and enforce the same at an operational and process level. Gaps and discrepancies in processes and documentation gave rise to irregularities in data, thus presenting difficulties in validating effectiveness. In the above case, the firm failed to establish a sampling methodology, hence leading to inconsistencies in sampling and documenting them. Also, it failed to define the acceptance criteria based on which the process could be deemed effective. In addition to this, there was an increased risk of receiving observations on data integrity and Attributable, Legible, Contemporaneous, Original and Accurate + (ALCOA+) practices in the organisation. The outcomes of adequate documentation are bountiful. It not only helped us in achieving the famed ‘0 Observations’, but also provides the management with opportunities for improvement

Your firm’s CAPA control procedure, does not include requirements for: ◗ Analysing all sources of quality data to identify existing and potential causes of non-conforming product, or other quality problems ◗ Verifying or validating the CAPA to ensure that such action is effective and does not adversely affect the finished device ◗ Implementing and recording changes in methods and procedures needed to correct and prevent identified quality problems ›

Your firm’s procedures indicate that three different CAPA forms can be used: ◗ The CAPA and Improvement Record ◗ Customer Complaint Record ◗ CAPA and Non-conformance Record During the investigator’s review of the CAPA files, four CAPAs were found to be documented on forms called “Quality Problem Records”, that was not mentioned in your firm’s procedure. None of the four CAPA files included documentation of all corrective actions, implementation dates, or effectiveness check information as per your CAPA procedures. Your firm stated that a retrospective analysis of all historical and open CAPAs would be performed. However, your firm did not include documentation or evidence of the correction and the corrective action.” When such non-conformities are identified, the integrity and oversight of the Quality Assurance (QA) department are questioned. In the iterated instance, the procedure does not define various triggers for a CAPA, such as internal and external audit observations, out of specifications, deviations from procedure and so on. All these are quality issues which ideally should have been included in the procedure. Adopting a risk-based approach will help in identifying more failure scenarios for CAPA initiation. When an issue or discrepancy is identified, it is difficult to identify all possible causes without usage of rational methods. Detailed investigation involving use of methods such as 5-why analysis or Ishikawa diagrams in conjunction with critical thinking methodologies such as K-T problem solving techniques help in the identification of the accurate root cause. Once the root cause has been identified, it is imperative for the organization to correct the issue immediately to avoid having repeated issues. The correction may be technical or procedural or both, which did not occur in the above case. Designing a standard operating procedure (SOP) that encompasses every possible error, that is easy to comprehend and practical, as well, is the first step to address the above observation. This, in turn is critical for efficient operation and seamless closure of retrospective investigation of CAPA

Inadequate documentation Regulatory authorities emphasise on the availability of documented proof or objective evidence for any activity performed. Failure to provide the same consequently leads to non-conformities. For an inspection, manufacturers are required to present CAPA documentation that can demonstrate to the auditors that the manufacturer’s QMS is efficient and effective in identifying issues quickly and can implement effective CAPAs. Any discrepancy in the documentation provided attracts unwarranted questions and mistrust from the agency.

40 EXPRESS PHARMA August 16-31, 2018

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Pycnogenol,women’s best kept secret Dr Frank Schoenlau, Director of Scientific Communication, Horphag Research, talks about natural botanical remedy Pycnogenol, which can be taken everyday as a dietary supplement by women WHILE WOMEN SACRIFICE themselves for their family well-being, little is talked about their own needs, healthand well-being necessities. Women in their fertile years have their specific needs and reproductive organs may cause tremendous challenges at times. Some ladies experience considerable impairment related to their monthly period. Many women silently suffer from particularly heavy pain during their period, which may be barely tolerable even with generously applied pain medication. Medical literature points to 40 per cent of women at reproductive age being affected by dysmenorrhoea, the medical term for severe spasmodic abdominal period-pain [Lind et al., Hum Reprod 2012]. This severe suffering is commonly not openly talked about, especially as there are natural, non-hormonal, side-effect-free remedies which are proven to provide relief from period pain, as demonstrated in large, controlled clinical studies. The knowledge of efficacious, natural and side-effect-free help from plants deserves to be much more communicated among women.

Pycnogenol makes ladies’ lives easier A mainstay for ladies’ health and well-being represents the natural botanical remedy Pycnogenol, which is extracted from bark of a particular pine tree, growing exclusively in a pristine forest in south-western France. The French government controls the forests for absence of pollution and sustainability, which is the reason for high quality herbals commonly originating particularly from this nation. Pycnogenol is re-

peatedly demonstrated in several controlled clinical trials to significantly ease ladies’ sufferings. Unlike pain medication, which is taken on demand, Pycnogenol shall be taken every day, as dietary supplement. In turn, pain sensation, especially the cramping pain, decreases progressively from one day to the next, which may take a week to fully set in, but the patience is much rewarded with an easier life. More importantly, continuous daily supplementation with Pycnogenol will help keep inflammation at bay preemptively before tissue harm and pain may manifest [Rohdewald P. 2002]. Numerous controlled clinical studies, carried out at universities across the world, validated the suggested health contributions of Pycnogenol. In one of the earliest clinical studies it was discovered that daily supplementation with this natural plant extract helped about 80 per cent of the participating ladies to overcome the particularly bothersome period cramping pain [Kohama & Suzuki, 1999]. Encouraged by the good outcome for ladies well-being, clinicians further investigated Pycnogenol also with 47 women, diagnosed with dysmenorrhoea, the medical term defining particularly severe monthly periods [Kohama et al., 2004]. Compared to period burden prevailing prior to supplementation with Pycnogenol, the daily supplementation with Pycnogenol made the subsequent two periods with Pycnogenol easier, with less days with pain and decreased pain severity too. Japanese gynaecologists further investigated the efficacy of Pycnogenol for serving as natural, side-effect free, period

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pain-relief [Suzuki et al., 2008]. A total of 116 healthy women participated, who had unlimited access to pain medication, required that dosage and time of day were recorded in a diary, which was provided to the ladies at trial start. During the course of the multi-centre study, which monitored five consecutive menstrual periods, the group taking Pycnogenol (double blind, placebo controlled) progressively lowered on-demand pain medication necessity, from one month to the next, with ladies eventually requiring only half the dosage of non-steroidal anti-inflammatory medications, than they did require before taking Pycnogenol. This is good news for ladies having problems with non-steroidal drugs like ibuprofen, related to bleeding, stomach problems and cardiovascular issues. Pycnogenol was further

tested also for women diagnosed with endometriosis, a disorder affecting the lining of the uterus, which gets inflamed causing severe pain. Effective remedies exist for managing the often heavy pain burden; however, these are of hormonal nature, which disables affected women to get pregnant. Because Pycnogenol provides pronounced anti-inflammatory activity, it was taken by ladies with period pain in addition to oral contraceptives, which lowered pain from baseline score 9/10 to just 2/10, a huge improvement after three months treatment. The group taking contraceptives only, without additional Pycnogenol, had a pain reduction to only 6/10. [Maia et al, 2014]. Japanese gynaecologists also successfully applied Pycnogenol to ladies affected by endometriosis. In endometriosis the tissues which lining the uterus interior grow outside the womb, causing inflammation with severe pain. In the clinical investigation the benefits of Pycnogenol for endometriosis were investigated in 58 women, in comparison to another group of ladies receiving standard hormonal treatment for endometriosis. The hormonal treatment proved to progressively lower women’s pain from ‘severe’ to ‘mild’ within 24 weeks. The group of women supplementing with Pycnogenol, presented with equivalent pain situation at baseline, and daily supplementation decreased pain to ‘mild’. A celebrated outcome of the Pycnogenol group was the circumstance that five of the ladies actually got pregnant during the trial [Kohama et al., 2007].

Pycnogenol quenches inflamation Natural quenching of inflammatory processes in the body can be achieved by potent antioxidants, such as ideally the most potent and best researched one: Pycnogenol. Women suffering severe period pain, in medical terminology referred to as dysmenorrhoea, are often treated by physicians applying contraceptive hormones. Women taking part in a clinical trial presented with considerable pain sensation at arrival in the clinic, scoring eight out of maximum 10 on the pain scale, despite the fact that they were hormonally treated with the aim for reducing period pain. When women were supplementing with Pycnogenol in addition to hormonal treatment, the pain subsided markedly, scoring merely two out of maximum 10 on the pain scale, representing a sensational pain reduction for the previously suffering ladies. This outcome exemplifies how beneficial particular natural remedies like Pycnogenol may be [Kohama et al., 2007].

Stay healthy at heart with Pycnogenol Cardiovascular health issues are of stealth nature, because we lack senses such as for rising blood pressure, or blood platelets coagulating, or fats greasing blood vessel walls. Because cardiovascular parameters are unknown to us until we visit a physician, they may progressively deteriorate unnoticed. Far too often heart health may worsen to a point at which a critical incident occurs, which alerts us to urgently visit the physician whom we haven’t seen in years. There exist indications, such

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PHARMA TECHNOLOGY REVIEW as headaches in some people, related to hypertension, though this and other such ‘indicators’ are by no means reliable, as many hypertensives have no head aches and those who do suffer from headaches, may have a splendidly healthy blood pressure. If this makes you thinking; when you might have had the last health check-up; please make an appointment. Pycnogenol has been dubbed ‘the blood vitamin’, because this particular pine bark extract has been clinically evaluated for cardiovascular and related health benefits since the 1960’s with scores of corresponding clinical publications. Pycnogenol acts as catalyst, enabling blood vessels to generate more nitric oxide, the latter representing the most important cardiovascular mediator for relaxing constricted arteries. Every artery in the body benefits from smoother blood flow, more efficiently delivering oxygen and nutrients to even the remotest and tiniest tissues. Even in healthy students Pycnogenol was proven to enhance arterial relaxation, double-blind placebo controlled [Nishioka et al., 2007]. A Swiss double blind, placebo-controlled, cross-over study demonstrated that Pycnogenol improves arterial dilatation in cardiac patients [Enseleit et al., 2012]. Blood platelets respond to more abundant nitric oxide presence with decreased tendency to form blood clots [Pütter et al.,1998], Pycnogenol thus provides protection from thromboses as well rising blood pressure [Hosseini et al., 2001; Zibadi et al., 2008]. Pycnogenol has once been dubbed the ‘blood vitamin’, owed to its benedictory contribution to cardiovascular health in totality. Pycnogenol greatly facilitates the availability of the most important messenger in heart health: nitric oxide. This molecule is required to release artery constriction, which in turn abolishes high blood pressure. Especially the widened tiny capillaries are thus able to better perfuse needful tissues with oxygen and nutrients. Unhealthy foods, and cigarette smoke and lack of physical activity are the culprits affecting cardiovascular health.

42 EXPRESS PHARMA August 16-31, 2018

Celebrate the golden age By the time we have grown wise, the body engages in a transition period, with fundamental hormonal changes, with far reaching consequences and many nuisance alterations, influencing women's golden years. Well prepared and taking the right precautions, this period of life may well prove to be perceived as particularly intense. The climacteric transition period will present with some challenges, but there is nothing which cannot be dealt with. It may reach the reader with some disbelief, that Pycnogenol again represents the solution for also easing climacteric symptoms, but Pycnogenol does indeed help tremendously, and Pycnogenol is again demonstrated to not affect women’s hormone levels a bit! Among the greatest changes in women going through the perimenopausal transition period is the circumstance that declining oestrogen levels affect artery’s ability to relax, which unnoticed increases blood pressure and disrupts the ability for radiating-off excess body heat, with heat instead trapped in the body and women experiencing the troublesome hot flushes. The impairment to widen peripheral arteries limits the capacity for radiating-off excess body heat, representing the primary cause for afore mentioned commonly experienced hot flushes and sweating in menopause. As result, ladies in menopause, or those in transition, often perceive a too hot ambiance and wish to open the windows or turn on air-conditioners. The diminished arterial dilatation has another, yet more serious consequence to menopausal women, which is related to steadily rising blood pressure. This again is the consequence of women’s normal steadily declining estradiol hormonal levels in transition to menopause. Foremost the decreasing oestrogen prevalence translates into arterial constriction, which in turn is responsible for the tendency of rising blood pressure, as the same blood volume travels in less space. Fortunately, Pycnogenol promotes improved

arterial dilatation, thus helping to normalise blood flow and re-installing proficient heat dissipation. Pycnogenol indeed does wonders to ladies in menopause! Ladies in disbelief haven't tried Pycnogenol yet. All three studies were carried out with significant numbers of volunteering ladies. The first study was carried out with 200 Chinese ladies, in double-blind, placebo controlled fashion [Yang et al., 2007], and another study with 70 European women [Errich et al., 2011], and yet another with 170 Japanese ladies in double-blind placebo-controlled protocol [Kohama et al., 2013].

Pycnogenol in pregnancy In the first three months of pregnancy it is generally advised to refrain from taking medications, unless the physician advises to do so. Especially at later stages of pregnancy, however, pain may set in, resulting from rapidly accelerating weight gain. A Japanese clinical study revealed that women in their last three months of pregnancy, during which rapid weight gain sets in, could effectively soothe various pains with Pycnogenol: lower back pain, hip joint pain, pelvic pain, and pain due to varices or calf cramps. A control group did not experience soothing of pain and symptoms [Kohama & Inoue, 2006]. Researchers in Europe recently discovered that supplementation with Pycnogenol may help recover varicose veins which came into existence during pregnancy [Belcaro et al., 2017].

Be as pretty as you feel Time takes its toll on the appearance and attractiveness of the skin. A quick view at the skin of the hands tells more about the age of a person than the face. The latter is well taken care of with cosmetics, but a person’s hand reveals age mercilessly. Wouldn’t it be nice if the skin of the entire body would regain some more of its self-regenerative capacity? While we cannot turn back the time, the skin proves to be an amazingly regenerative organ also at advanced age, which may be witnessed following mi-

nor injuries. At higher age the healing of a little wound may take a little longer than in a teenager, but tissue regenerative competence persists. Skin renewal requires vitamin C, such as from citrus fruits, as this vitamin is crucial for creation of new collagen. Vitamin C quickly gets oxidised in the body, therefore antioxidants are helpful for saving vitamin C from oxidation, which Pycnogenol does tremendously well. Moreover, Pycnogenol promotes better skin perfusion, with better hydration, -nutrition and detoxification. Amazingly, Pycnogenol turns out to contribute much more to our skin than merely regenerating vitamin C. In a group of 20 menopausal ladies, aged 55 to 68 years, who supplemented daily with Pycnogenol for twelve weeks, a stimulated generation of both collagen (+40 per cent) and hyaluronic acid (+ 44 per cent) was discovered in their skin. In turn, ladies’ skin elasticity measurements were found to increase significantly by 25 per cent and their skin humidity increased by 21 per cent. Dermatologists attributed the increased skin humidity with Pycnogenol to the elevated dermal hyaluronic acid generation, the latter greatly absorbing and retaining quantities of water, which contributes a taut skin appearance. The same research group discovered that supplementation with Pynogenol over a period of twelve weeks, abolished overly intense skin pigmentation formation, which was discovered to result from Pycnogenol inhibiting expression of tyrosinase, the enzyme involved in generating pigments in skin. Pycnogenol contributes a verifiable difference to skin physiology from inside, manifesting in visibly increased skin vibrancy.

References Belcaro G, Dugall M, Luzzi R, Corsi M, Ledda A, Ricci A, Pellegrini L, Cesarone MR, Hosoi M, Errichi BM, Cornelli U, Cotellese R, Agus G, Feragalli B. Management of varicose veins and chronic venous insufficiency in a comparative registry with nine venoactive products in comparison with stockings. Int J Angiol 26: 170-178, 2017.

Kohama T, Inoue M. Pycnogenol® alleviates pain associated with pregnancy. Phytother Res. 20: 232-234, 2006. Kohama T, Suzuki N, Ohno S, Inoue M., Analgesic efficacy of French maritime pine bark extract in dysmenorrhea: an open clinical trial. J Reprod Med. 10 : 828-832, 2004. Kohama T, Herai K, Inoue M. Effect of French maritime pine bark extract on endometriosis as compared with leuprorelin acetate. J Reprod Med. 52: 703-708, 2007. Kohama T, Suzuki N, Ohno S, Inoue M. Analgesic efficacy of French maritime pine bark extract in dysmenorrhea: an open clinical trial. J Reprod Med 49: 828-832, 2004. Kohama T, Negami M. Effect of low-dose French maritime pine bark extract on climacteric syndrome in 170 perimenopausal women: a randomized, doubleblind, placebo-controlled trial. J Reprod Med 58: 39-46, 2013. Maia H, Hadadd C, Casoi J. The effect of Pycnogenol® on patients with dysmenorrhea using low-dose oral contraceptives. Int Womens Health 6: 101-122, 2014. Lindh I, Ellström AA, Milsom I. The effect of combined oral contraceptives and age on dysmenorrhoea: an epidemiological study. Hum Reprod. 7:676-682, 2012. Rastogi S, Arora V, Bhalla V. Pycnogenol: The Hercules of antioxidants. Indian Journal of Drugs 3: 5-10, 2015 Rohdewald P. A review of the French maritime pine bark extract (Pycnogenol), a herbal medication with a diverse clinical pharmacology 2002. Maturana MA, Irigoyen MC, Spritzer PM. Menopause, estrogens, and endothelial dysfunction: current concepts. Clinics 62: 77-86, 2007. Suzuki N, Uebaba K, Kohama T, Moniwa N, Kanayama N, Koike K. French maritime pine bark extract significantly lowers the requirement for analgesic medication in dysmenorrhea: a multicenter, randomized, double-blind, placebo-controlled study. J Reprod Med 5: 338-346, 2008. Yang HM, Liao MF, Zhu SY, Liao MN, Rohdewald P. A randomised, double-blind, placebocontrolled trial on the effect of Pycnogenol® on the climacteric syndrome in peri-menopausal women. Acta Obstet Gynecol Scand 86: 978-985, 2007.

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Planning ahead: How to move smoothly and quickly into Asian markets? Biopharmaceutical companies looking to manufacture in the Middle East or India may find they can’t simply transfer the plant they’ve been using successfully in Europe, for logistic as well as regulatory reasons. An expert in integrated process technology and engineering, Glatt Engineering & Consultancy Division of Glatt Group, outlines the potential pitfalls and solutions

TRANSFERRING production of any pharmaceutical that contains biotechnologically produced active ingredients such as insulin, vaccines or antibodies using micro-organisms to a new country – especially one on a different continent – creates a number of challenges. Not only do technical documentation and technology have to be considered, but regulatory guidelines, which vary from country to country, and compliance issues must be addressed. The technology and engineering experts at German company Glatt Engineering know how to tackle these issues and have helped several companies to set up manufacturing facilities successfully and smoothly across the Middle East and India.

Fundamental questions For many pharma projects, early availability is important and fast time-to-market are imperative for the manufacturer. Effective project management and scheduling are therefore crucial. Working to a clearly defined structure based on sound experience, when it receives an initial enquiry from a pharma manufacturer, Glatt asks two fundamental questions: does a suitable biotechnological production process already exist within the company? Or will it need to be purchased from a technology provider or licensor? As soon as these points are clarified, the Glatt engineering team will begin to evaluate and

Training staff early on helped Julphar Gulf Pharmaceuticals to achieve speedy commissioning and operation start at its new biotech plant in the UAE. (© Julphar)

compare the relevant technologies, in line with the pharma company’s specific criteria. It is important that a defined and stable micro-organism or a high yield cell line exists, and that the scale and status of the biotechnological process has been assessed to attain regulatory approval for

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the pharma production in the Middle East, in India or other process technology receiving regions. If the procedure only exists in a laboratory, scale-up may be available at a pilot plant or – better still – a proven and commercial-scale process may have already been established at a potential process

technology donor location. This status report determines the schedule of the entire project. Additional evaluation criteria include, among other things, secured patent status, any royalties to be paid, material requirements, expected turnover rate and yield. It is also important to know whether

guarantees can be given regarding process parameters such as yield and product purity.

The right choice of technology The next milestone is technology comparison, which will result in the selection of preferred technology candidates.

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PHARMA TECHNOLOGY REVIEW Subsequent negotiations will hopefully lead to a Tech Transfer Agreement (TTA); and, with the signed TTA or a licence agreement in place, the technology supplier will provide the planning input. Alongside a process description, characteristic flow diagrams, quality and measurement parameters and Standard Operating Performances (SOPs) from reference systems should also be available. Local authority requirements for the approval of the technology required to manufacture the products must also be considered. For instance, the reference authority for all Arabian Gulf Co-operation Council (GCC) countries is the Saudi Food and Drug Authority (SFDA), which is oriented towards biopharmaceutical products at the European EMA. For customers on the Arabian Peninsula, a European regulatory consultant can accompany the entire approval dossier according to European standards. The regulatory compliance of an active biological substance (ABS) and final dosage form plays an important role. Technology transfer is usually carried out by an established pharma company, which, in turn, has specific standards as well its own constraints. It is therefore advisable for the manufacturer to define their specific requirements or design basis documents clearly. General requirements such as “all our operational standards must be taken into account as well as the company standards of the licensor” simply lead to duplication and don’t necessarily fit the project and this can sometimes render a clear design solution impossible. By comparing Tech Transfer Packages and applied practices, user requirements and SOPs can often be used as a future design base for projects in countries with similar requirements.

Cross-country partnerships deliver cost benefits Biopharmaceutical projects in Asia and the Middle East are under pressure from Indian manufacturers with low-cost production capabilities. Thus, when procuring equipment components, it is vital to con-

44 EXPRESS PHARMA August 16-31, 2018

Holistic engineering from Glatt’s point of view: a three-dimensional CAD model of a fermentation plant in the Middle East. (Source: Glatt Ingenieurtechnik)

neering offices in Germany. Part of the technology transfer involved increasing the scale of production, so Glatt’s biotech team conducted a series of tests with appropriate equipment manufacturers. The results of the multi-week trials were included in the project plan, as were the additional transport, time and costs involved. To reduce production costs, it is important to involve regional specialist planners and suppliers. Another crucial project management strategy is to procure equipment components in “Best Cost Countries”. Glatt Engineering’s procurement strategy remains independent of its own portfolio of equipment, and takes into account the best manufacturers, suppliers, references and fulfilment requirements for the task in question. In addition to set ups in Germany, Switzerland and the US, the Glatt Group has offices in Eastern Europe and in India (Glatt (India) Engineering Pvt Ltd). Stainless steel equipment and containers are manufactured to comply with Western European standards. While components are being produced for the plant, it is vital to keep track of suppliers. Clearly structured project management and central data systems should serve as a cockpit for this. At the very least, acceptance tests for complex units should include the future operator.

Staff training ensures easy commissioning

(Source: Glatt Ingenieurtechnik)

Not only do technical documentation and technology have to be considered, but regulatory guidelines, which vary from country to country, and compliance issues must be addressed duct a global search and to source the most cost-effective solution. Finding a partner who can assist with both engineering and process development is also crucial. GMP reviews regarding

process planning, zoning and layout should be implemented at an early stage – during the concept phase. They should involve the technology providers, the engineering service team and the future operator. Regular design

review meetings are also essential. A previous project, for example, involved several meetings between a biotech company from the Arab GCC region and technology licensors from the United States at the Glatt engi-

It is Glatt’s policy to ensure that key staff from the client company is given a proper training at the Licensors plant in Europe to prepare for technology transfer. In all cases, Glatt’s biotechnologists recommend early sourcing of key staff, joint training with the technology provider and the engineering team, and the participation of key personnel during Factory Acceptance Tests (FATs) and Site Acceptance Tests (SATs), commissioning and Installation Qualification (IQ) and Operational Qualification (OQ). This way, and by expanding the team in a step-by-step manner, full operational efficiency can be achieved more quickly than might be imagined. Contact: www.glatt.com

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EXPRESS PHARMA

August 16-31, 2018

EXPRESS PHARMA

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BUSINESS AVENUES

August 16-31, 2018

EXPRESS PHARMA

BUSINESS AVENUES

EXPRESS PHARMA

August 16-31, 2018

BUSINESS AVENUES

August 16-31, 2018

EXPRESS PHARMA

BUSINESS AVENUES

EXPRESS PHARMA

August 16-31, 2018

PHARMA LIFE APPOINTMENT

Dr R Ananthanarayanan appointed as Cipla’s Global Chief Operating Officer He will oversee R&D, manufacturing, supply chain, the API business and the key geographies of North America, Europe and Emerging Markets

ipla has announced the appointment of Dr R Ananthanarayanan as its Global Chief Operating Officer (GCOO). Dr Ananthanarayanan will oversee R&D, manufacturing, supply chain, the API business and the key geographies of North America, Europe and Emerging Markets to help leverage and grow Cipla’s generics portfolio and competencies in these markets. He will report to Umang Vohra, Managing Director & Global Chief Executive Officer, Cipla.

66 EXPRESS PHARMA August 16-31, 2018

Dr R Ananthanarayanan served Teva API and Biologics as the President and CEO from December 2014 to July 2018. He also served as the President of Pharmaceutical Services and Active Ingredients (PSAI) and Member of Management Council at Dr Reddy's Laboratories. He has over 20 years of experience in the pharmaceutical industry with specialisation in research and development, manufacturing operations, regulatory affairs, quality assurance, business development,

global strategic sourcing, mergers and acquisitions. He served as the President of Business Development of CMG and President of International Operations at Piramal Healthcare (also known as Nicholas Piramal In-

dia) and also served as its Director of Pharma Solutions until July 23, 2009. He worked at Piramal Healthcare for over seven years and was involved since the inception of Pharma Solutions business. He served as Managing Director of Asia and Head of Global Sourcing for Galpharm International, a UK-based manufacturer/distributor of specialty pharmaceuticals and baby products. He led strategic outsourcing of product development, launch product manufacturing, and management of late lifecycle

products. He involved in various other positions of increasing responsibility in both Indian and multinational pharmaceutical companies like Zydus Cadila, Wockhardt and Rhone-Poulenc Rorer. He has been a Member of the Supervisory Board of OctoPlus NV since January 2013. Dr Ananthnarayanan has a PhD in Pharmaceutical Technology from University of Mumbai, India and a Bachelor’s degree in Pharmaceutical Sciences from University of Mumbai, India. EP News Bureau

REGD.WITH RNI NO. MAHENG/2005/21398, POSTAL REGD. NO. MCS/164/2016 – 18, PUBLISHED ON 5TH / 20TH EVERY FORTNIGHT, POSTED ON 5TH, 6TH, 7TH & 20TH, 21ST, 22ND OF EVERY FORTNIGHT POSTED AT MUMBAI PATRIKA CHANNEL SORTING OFFICE, MUMBAI – 400001