Pharma Focus Asia Magazine - Issue 27

Issue 27 2017

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Safe Pharmaceutical Shipments Turkish Cargo Continuous Manufacturing Are we there yet?

Failing Data Integrity Audit is not an Option

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P h a rm a F o c u s A s i a

ISSUE - 27 2017

Foreword Reviving Pharma Productivity Pharma industry has witnessed a staggering decline

operating environment increasingly difficult. While

in R&D productivity and is now a major cause of

innovative deal-making and pre-competitive collabo-

concern for the industry players. This decline contrib-

rations continue to evolve and spark innovation, the

uted to a downfall in the return on investments

pharma industry needs to find a way to address

over the last two decades. Interestingly, there has

structural and productivity challenges in order to

been a trend reversal with increase in clinical trial

grow and produce new medicines.”

success rate and drug development during 2010-14.

An interesting development in the recent past is

Increasing unmet patient needs coupled with fall

a rise in external R&D models across the industry

in pharma productivity owing to the rising costs,

with companies adjusting a portion of their invest-

and increased rate of drug failures have forced

ments directed to internal versus externally sourced

pharma companies to identify and implement new

programmes. A few examples highlighting change

processes for increasing productivity. Declining

in the ecosystem of innovation in pharma indus-

revenues, rising payer pressures and a changing

try are: Allergan’s Open Science model, Takeda’s

regulatory landscape have also contributed to this

Center for External Innovation, and Celgene’s R&D

decline. Though a quantitative measure, pharma

Partnership approach. Initiatives such as these

productivity has been measured by the number

can, in all likelihood, increase R&D productivity,

of drugs approved (the output) per dollar of R&D

by accessing innovation outside the company’s

spending along with the difficulty and complexity of

R&D platforms and tapping into the huge potential

the FDA’s drug approval process. Return on R&D

of securing strong future pipeline by means of risk-

among the world's largest pharma companies is

taking approach. In this age of start-ups technologi-

in the down fall.

cal changes, new approaches and organisational

While this has been a cause of concern for the industry, there is a ray of hope amidst the chaos.

challenges can redefine the business strategies for pharmaceutical and biotechnology companies.

A few companies have been successful in rising

In the article ‘Reviving Pharma R&D Productivity

against the tide generating stronger returns while

with New Modalities’, Eric Valeur of Astra Zeneca

delivering value. So what have they done different

talks about how the pharma industry can leverage

from companies with returns matching the costs of

new modalities of drug development to increase

capital? Organisational effectiveness, operational

productivity. Eric suggests drugging well-validated

efficiency and collaboration between industry and

targets can increase chances of success in clinical

academia, rather than operating in silos, appear to

trials and thus revive R&D productivity.

be the key for these companies to stay ahead of the competition. Neil Lesser, US principal and life sciences R&D strategy lead at Deloitte, states, “As patients, the health of pharma R&D is important to us all. The global pharma industry continues to face regulatory and reimbursement hurdles that make the

Prasanthi Sadhu Editor

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COVER STORY

Contents 12

52 Pharmaceuticals are in Good Hands with Turkish Cargo Ĺžeref KazancÄą, Senior Vice President Turkish Cargo, Istanbul

46

Strategy 06 China Biopharma

Is a Wave of GMP Exports in Our Future?

Vicky Qing XIA, Project Director Leo Cai Yang, Project Manager Eric S Langer, President and Managing Partner BioPlan Associates, Inc., USA

12 Failing Data Integrity Audit is not an Option Gary Cameron, Director, Informatics Sales and Marketing, Waters Corporation, Australia

Research & Development 20 Reviving Pharma R&D Productivity with New Modalities

Eric Valeur, Associate Director, New Modalities, Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, UK

28 Research and Development of Medical Countermeasures in Asia for Pandemic and Bioterror Threats

Zachary Peter Smith, Tufts Center for the Study of Drug Development, Tufts University, US

Christopher-Paul Milne, Center for the Study of Drug Development (CSDD), Tufts University Medical School, US

Manufacturing 38 Added Costs for Added Protections

The impact of implementing safety features in pharmaceutical packaging and labelling

2

Jorge Izquierdo, Vice President, Market Development, PMMI, The Association for Packaging and Processing Technologies, US

P h a rm a F o c u s A s i a

ISSUE - 27 2017

46 Continuous Manufacturing

Are we there yet?

Dilip M Parikh, President, DPharma Group Inc., US 56 The Impact of Implementing Safety Features in Pharmaceutical Packaging and Labelling

Sathyanarayanan Krishnamurthy, VP Regulatory Operations, Freyr, India

60 Responding to the Needs of an Evolving Industry

Dan Stefanoiu, Chief Business Officer, Datwyler, Switzerland

Expert Talk 62 The Asian Healthcare Market

Rapid growth and accompanying increasing regulations lead to the need for serialisation Bernd Stauss, Senior Vice President Production/Engineering, Vetter, Germany

66 Pharmacogenomics

Saleem Mohammed, Founder & CEO, Xcode Life Sciences, India

Abdur Rub, Co-founder, Xcode Life Sciences, India

SPECIAL FEATURE 65 Books

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Advisory Board

Editor Prasanthi Sadhu Alan S Louie Research Director, Health Industry Insights an IDC Company, USA

Christopher-Paul Milne Director of Research, Tufts Center for the Study of Drug Development, Tufts University, USA

Douglas Meyer Senior Director, Aptuit Informatics Inc., USA

Frank Jaeger Regional Sales Manager, Metabolics, AbbVie, USA

Georg C Terstappen Director and Head of Biology, Neuroscience Discovery AbbVie Deutschland GmbH und Co. KG, Germany

Kenneth I Kaitin Director and Professor of Medicine, Tufts Center for the Study of Drug Development, Tufts University, USA

Editorial Team Debi Jones Grace Jones Art Director M Abdul Hannan Product Manager Jeff Kenney Senior Product Associate David Nelson Sussane Vincent Product Associate Peter Thomas Tina Williams Circulation Team Naveen M Nash Jones Sam Smith Subscriptions In-charge Vijay Kumar Gaddam Head-Operations S V Nageswara Rao

Laurence Flint Head Clinical Research Cough, Cold & Respiratory Disease Novartis Consumer Health, Inc., USA

Neil J Campbell President & CEO, Helomics Corporation HealthCare Royalty Partners University of Liverpool, UK

Pharma Focus Asia is published by

In Association with

A member of

Phil Kaminsky Chair, Department of Industrial Engineering and Operations Research University of California, Berkeley, USA

Rustom Mody Senior Vice President and R&D Head Lupin Ltd., (Biotech Division), India

Sanjoy Ray Director, Strategic Alliances & Health Innovation Merck, US

Confederation of Indian Industry

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The products and services advertised are not endorsed by or connected with the publisher or its associates. The editorial opinions expressed in this publication are those of individual authors and not necessarily those of the publisher or of its associates.

Copies of Pharma Focus Asia can be purchased at the indicated cover prices. For bulk order reprints minimum order required is 500 copies, POA.

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ISSUE - 27 2017

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Strategy

China Biopharma

Is a Wave of GMP Exports in Our Future?

China today, according to our recent studies, is actively growing its domestic industry, not only to support its huge domestic demand for high quality therapeutics, but also to develop an export market capability. The industry is making progress with substantial investments in equipment, quality management, and staffing. China’s bio-processing capabilities have grown quickly and substantively in the past decade as shown by the study and analysis published in the Top 60 Biopharmaceutical Facilities in China, 2017.

Vicky Qing XIA, Project Director Leo Cai Yang, Project Manager Eric S Langer, President and Managing Partner BioPlan Associates, Inc., USA

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I

t’s been a long road, beginning with China’s ‘opendoor’ policies in the 1980s, and membership in the WTO in 2002; but China’s recent and rapid expansion into high-tech biopharma manufacturing suggests a future that will involve exports of biologics to Western markets.

Even before it became the world’s source of toys, and electronics, China had been an important exporter of Active Pharmaceutical Ingredients (APIs) for chemical drugs. But the domestic biopharmaceutical industry has been

Strategy

lagging behind in exports, especially to regulated markets. Nearly a decade ago when Bioplan first published its Top 60 Directory of China Biopharmaceutical companies, the results showed a picture of a low(er) quality manufacturing environment for bio-generic products, intended almost exclusively for its domestic market. This scenario is changing, and a recently published second edition of the Top 60 Biopharmaceutical Facilities in China (2017 ed) shows signs that China likely has potential to play a more significant role in GMP exports of biopharmaceutical products over the next couple decades.

Current export of biopharmaceutical products from China

Currently China exports five categories of biopharmaceutical products including bio-chemicals, recombinant insulin, blood products and therapeutic antibodies, vaccines, as well as EPO. According to Medicine Economic

Reporter, in 2015 China imported US$6.1 billion worth of biologics from overseas, which translates to 23.8 per cent growth over 2014. On the other hand, China exported US$2.7 billion of biologics in 2015, a 4.07 per cent growth over 2014. In the first half of 2015, China imported 32 different biologics, among which 71.6 per cent were blood products and immune products (US$950 million in mAb).

The China Chamber of Commerce for Export and Import of Medicine and Health Products states China exported biologics to 174 countries in 2015, with 34 per cent of exports going to Asian countries (Guo Xiaodan).

From this analysis, China exports API of biologics to EU or US (such as heparin), while finished biologics products are exported to developing countries. Currently, no finished biologics or biosimilar products from China have been approved in the EU or US. Though some biopharmaceutical

products posted double-digit export growth in recent years, overall exports are only a fraction of what China imports in biopharmaceutical products.

The deficit may be explained by the fact that China imports value-added products such as monoclonal antibody therapeutics from Western countries while made-in-China biopharmaceutical exports are geared toward lower-end markets.

China upgrading its bioprocessing facilities

China is actively growing its domestic industry, not only to support its huge domestic demand for high quality therapeutics, but also to develop an export market capability. At present, according to our directory, many facilities are upgrading/expanding their bioprocessing facilities and specifying new technology that may help the industry to develop its capability in GMP production and potential exports

Partial Breakdown Analysis of China’s Export of Biologics in 2014 Category

Amount (USD)

Export Destination

Manufacturer

Extract and API from extract (human origin)

$11.49 million

India, Korea, Holland

Kangyuan Pharma, Tianpu Biochemical, etc

Heparin (API)

$586 million

Europe, US, South America, Middle East

Qianhong Pharma, Hepalink, etc

Recombinant insulin

$32.24 million

Mexico, Bangladesh, Ukraine, Poland

Tonghua Dongbao, Gann & Lee, Wanbang Pharma, Kexing Pharma, Zhuhai Union Pharma

Blood products and immune protein

$312 million

US, India, France, Germany, Turkey, etc

Most of them are foreign companies’ operation in China, and the exports are mostly for IVD use

mAb (belong to the above category)

Columbia, Mexico, India

Zhongxin Guojian (3Sbio subsidiary)

Vaccine

$43.03

India, Egypt, Thailand, Bangladesh, Uzbekistan

Shenzhen Maigao, Chengdu Biologics Institute and Liaoning Chengda Biologics Institute

EPO

$12.78

Southeastern Asia, South America, Middle East, Africa

3SBio, Shandong Kexing

Table 1

(Source: Export and Import Manager, 2015, 10) www.pharmafocusasia.com

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Strategy

China Imports of Bio-processing Supply 30 25

26.4

26.6

2014

2015

27.0

22.9

20.8 20 15 10 5 0

2012

2013

2016 E

Imports (in million USD) Source: China Statistics Bureau

Figure 1

Despite the fact that current export of biopharmaceuticals start from a quite low baseline in China, the industry is making progress with substantial investments in equipment, quality management, and staffing. It is actively attracting industry talent from developed countries. China’s bio-processing capabilities have grown quickly and substantively in the past decade as shown by the study and analysis published in the Top 60 Biopharmaceutical Facilities in China, 20171.

Many of the facilities under expansion have plans to incorporate some of the most advanced technologies, including modern Single-use Technologies (SUT), and modular strategies. For example, on June 28th, 2016 Pfizer China broke ground for its first biologics production facility in China, which is fully based upon GE’s modular factory platform. According to a Pfizer press release, the new centre will feature GE’s single-use technology in a KUBioTM modular facility.

JHL Biotech, the biologics CMO founded by veterans from Genentech, also attributes the fast-track opening of its Wuhan base to the KUBio modular factory. “The new contract manufacturing base is able to kick off official 8

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Chinese biologics managers indicated their company currently plans to target global distribution of GMP produced biologics within 10 years.

operation in only 18 months, while the process to reach GMP production may take more than 2 years for a similar company without Kubio’s support”, stated Dr. Cui from JHL Biotech. The trend in adopting more advanced bioprocessing technologies is consistent with statistics of China’s imports of bio-processing supply (from multinational vendors), which grows quickly during the past several years.

Regulatory reforms in China

Regulatory authorities in China are also making efforts to help the

industry develop GMP capabilities.

China’s CFDA promulgated new GMP regulations which became effective in 2011.In April of that same year, several other GMP-inspection related changes were proposed by the Chinese Ministry of Health, which included establishing a process by which CFDA can more easily refuse, suspend, or revoke a manufacturer’s GMP certification by adopting a risk-based approach during inspections; expanding the circumstances under which CFDA can take enforcement actions and establish timelines for GMP certification; and proposing GMP inspections every two years during the five year time period that the GMP Certificates are valid. In the beginning of 2017, CFDA also announced plans to replace current GMP certification of every 5 years by a dynamic unannounced inspection system. These policy moves are intended to bring China’s GMP code in-line with that of European Union (EU) and US codes and regulations.

Analysts believe that such reforms by regulatory authorities will improve manufacturing practice as well as bring a better overall quality image of madein-China biopharmaceuticals, which in turn will help with potential exports of GMP products.

New pipeline of products in China

China is also focusing on developing its innovative pipeline and ramping up its clinical trials activities in regulated markets. Clearly, the industry’s ambition is to establish GMP exports. In a recent BioPlan survey of 50 Chinese members of its Biotechnology Industry Council™ (BIC) panel of bio-processing experts, we evaluated how and when China biopharma companies plan to fill the gap and become a global hub for bioprocessing2.

Domestic manufacturers show ambition of becoming a global bio-pharma manufacturer over the next decades. While they do recognise clear gaps between their capabilities and the capabilities necessary to become a global player, nearly 90 per cent of responding Chinese biolog-

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Strategy

ics managers indicated their company currently plans to target global distribution of GMP produced biologics within 10 years. Study respondents also identified top ‘strength’ attributes most important to China, if it is to expand its presence in global biopharmaceuticals. A total of 58 per cent cited the Chinese biologics industry as requiring more innovative biopharmaceutical pipelines (Figure 2).

While we see the concern relates directly to China’s limited R&D investments, especially insufficient investment in early stage research on products and platforms, there are signs of improvements in pipeline development in recent years. In 2016 alone, CFDA publicised close to 200 new biological entering clinical trials in China and altogether, and Bioplan’s own study shows that over 170 mAb therapeutics are under clinical development in China, with CD20, HER2, EGFR, VEGF, TNF-alpha as the hottest targets (Figure 3).

The most ambitious Chinese companies are already conducting clinical trials in regulated markets.

For example, Genor Biopharma has started phase I clinical study of its antiHer2 mAb in Australia, and Teruisi, an antibody therapeutics company founded by returnee scientists, is also going to apply for IND for one of its projects in US this year. We expect to see a more robust biological pipeline from Chinese companies in the near future.

Contract manufacturing in China

Biologics CMO businesses are also growing quickly due to strong domestic and global market needs. Though China currently does not export finished biological therapeutics to regulated markets, domestic contract manufacturing companies are already attracting business from global clients. WuXi Biologics, winner of Asia-Pacific Bio-processing Excellence Awards 2017 from IMAPAC, worked with TESARO, the Waltham, MA based bio-pharmaceutical company on Anti-TIM-3 Antibody, whose IND application to FDA was submitted in 2016. The company also completed 10

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Top ‘Strength’ Attributes Required for China’s Biologics Companies to Expand Globally (Selected Responses)

More innovative biopharmaceutical pipeline

58%

Overall 'quality' image

50%

Capacity: Commercial scale

50%

Scientific / technical expertise

48% 42%

Compliance track record / expertise Figure 2

mAb Therapeutics under Clinical Development

by Chinese Companies for 5 Targets

CD20

2

HER2

9 4

11 3 1 9

EGFR 1

3

14

VEGR

2

7 0

3 1

10

12

TNF alpha

2 1

11 10

3 1

8 8 20

1

4

1 3 30

Figure 3

construction of Asia’s largest perfusion biologics manufacturing facility using disposable bioreactors in 2016. The new facility “will uphold the highest quality standards to expedite global development of biologics for both international and domestic clients”, as announced by Dr. Li Ge, CEO and Chairman of the company. JHL Biotech, another important biologics CMO in China, has announced strategic biologic alliance with Sanofi. The company also partners up with Singapore-based ASLAN for manufacturing services of the latter’s

ASLAN004, a fully human monoclonal antibody that blocks the signaling of the IL-4 and IL-13 receptors.

Conclusions

The Chinese biopharmaceutical industry is actively investing in both the biologics pipeline for innovative domestic products, and the bio-manufacturing infrastructure needed to commercialise these innovations. While our studies find that the industry is focusing first on its domestic markets and exports to lesser-regulated markets, the improvement in its quality

Strategy

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Eric S Langer, President and managing partner at BioPlan Associates, Inc., a biotechnology and life sciences marketing research and publishing firm established in Rockville, MD in 1989. He is editor of numerous studies, including “Biopharmaceutical Technology in China,” “Advances in Large-scale Biopharmaceutical Manufacturing”, and many other industry reports. elanger@ bioplanassociates.com 301-921-5979. www.bioplanassociates.com

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Leo Cai Yang, Project Manager, BioPlan Associates, has business development experience in biotech and pharma segments and 10 years in market research. He graduated from East China Normal University with a bachelor’s degree in Biotechnology in 2006, and has worked with equipment manufacturers in pharmaceutical and medical device industries, in Switzerland, Austria and Germany. He has also project managed studies involving new biopharmaceutical technology applications in China including analysis and strategy development.

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Vicky Qing XIA Project Director, BioPlan Associates has her MS in biology from University of Texas-Houston, MBA from University of Pittsburgh. She has experience in consulting, business development, as well as alliance management in China’s bio-pharmaceutical industry. Her expertise includes developing research and analysis on multiple global market segments, and has managed a team of industry experts, and projects.

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References: 1. Top 60 Biopharmaceutical Facilities in China, BioPlan Associates, Inc., Rockville, MD USA, March2017.

2. China’s Advances in Global Biopharma and Bioprocessing: A 10-year projection in need for innovation and quality improvements; January 2017, White Paper Survey of 50 Chinese Biopharmaceutical Executives, BioPlan Associates, Inc. Rockville MD, www.bioplanassociates.com

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Strategy

Failing Data Integrity Audit is not an Option

12

The time-to-market of blooming Asian pharmaceutical companies, especially from India and China, are being slowed by the increasing concerns of global and local regulators over data integrity. How can they meet regulators’ audit expectation on data integrity and provide assurance of acceptable product quality, purity, safety, identity and effectiveness through data governance systems with compliance in mind (e.g. unauthorised access control, missing or disabled audit trails, or even data falsification)?

sia’s pharmaceutical manufacturers have seen huge growth in recent years. India, for example, is now the world’s third largest supplier of generic drugs by volume while its domestic market is expected to grow at 15 per cent to 20 per cent CAGR to reach US$50 to US$74 billion in the next decade according to PwC1. India

Gary Cameron, Director, Informatics Sales and Marketing, Waters Corporation, Australia

1 http://www.pwc.in/industries/pharmaceuticals-and-lifesciences.html

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Strategy

currently supplies 40 per cent2 of overthe-counter and generic prescription drugs consumed in the US. China is another emerging pharma manufacturing powerhouse. China accounts for over 50 per cent of the global Active Pharmaceutical Ingredients (API) market and the US Department of Commerce forecasts China’s own market to grow from US$640 billion in 2015 to US$1.1 trillion by 2020.

However, as profit margins decline over time, any delay in time to market begins to erode the strategic positioning and profitability of pharmaceutical manufacturers. The natural response is to double efforts to speed up the time to deliver new products and that can lead to a raft of new problems. Rushing new products to market can place drug quality, purity, and safety in question – and put pharma manufacturers at odds with government regulatory bodies.

Despite the rising influence of pharmaceutical manufacturers in India and China, their time-to-market is being slowed by regulatory concerns over data integrity. Regulators see data integrity as an assurance of acceptable product quality, purity, safety, identity and effectiveness. Any data integrity failures can lead to safety alerts, warning letters, or even a multi-market withdrawal -– the worst possible nightmare for the concerned company, and perhaps even worse, for patients using the drug.

To put it in perspective, the US Food and Drug Administration (FDA) issued 1023 drug GMP warning letters last year, compared to 42 such warnings in FY2015. Last year, data integrity deficiencies accounted for approximately 80 per cent of all warnings issued to firms outside the U.S (OUS) -– a significant increase compared to the previous year.

What is most concerning to the Asian pharmaceutical industry is that when we look into regional breakdown, India 2 https://www.nytimes.com/2014/02/15/world/asia/medicines-made-in-india-set-off-safety-worries.html?_r=0 3 https://www.pharmaceuticalonline.com/doc/an-analysisof-fda-fy-drug-gmp-warning-letters-0001

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To fulfil data integrity expectations, companies are required to overhaul their operations by focusing on several key regulatory concerns like Culture and Governance, the Data Lifecycle and the System Lifecycle.

and China received approximately 71 per cent of the warning letters issued to OUS. One warning letter comment stands out to best describe the gravity of data integrity violations on a global level: “…demonstrates a general lack of reliability and accuracy of data generated by the laboratory –- a serious Current Good Manufacturing Practice (CGMP) deficiency that raises concerns about the integrity of all data generated by your firm.”

1.How Asia’s pharma manufacturers can benchmark their companies against data integrity deficiencies

Unauthorised access control, missing or disabled audit trails, or even data falsification are among many of the data integrity deficiencies regulators pinpointed in audit trails. To make it easier for pharmaceuticals to follow, we have classified them in four key areas: 1. Lack of basic access control and security measures which easily allow unauthorised changes 2. Shared use of logins - authentication of individual and attribute ability of action 3. Lack of disabled audit trails 4. Lack of contemporaneous recording of activities

The most common questions regulated companies receive are: Is it the hard copy report which is printed from the instrument at the end of an analysis?

Are the source electronic files on the instrument only a back-up copy of the printed data? Or is there more to it? Is information available in the electronic source files that may never be printed, yet may implicate data integrity or reliability? Do your laboratory supervisors and QA unit know how to access this information? Or are they only looking at printouts? These all lead to an increase in the level of risks requiring additional controls to be put in place. Worse, it not only complicates and slows down the audit processes of regulating agencies, it also makes your audit trails more susceptible to data integrity scrutiny.

2.Understand the audit trails’ role in data governance

Before we dive into some tricky data integrity issues, it is important to understand what regulating agencies mean by audit trails. Audit trails refer to a secure, computer-generated, time-stamped electronic record that allows for reconstruction of the course of events relating to the creation, modification, or deletion of an electronic record. An audit trail is the chronology of the “who, what, when, and why” of a record.

For instance, the audit trail for an HPLC in a laboratory run could include the username, date and time of the run, integration parameters used, and details of reprocessing, if any, including change justification for the reprocessing. Electronic audit trails include those that track creation, modification, or deletion of data such as processing parameters and results, and those that track actions at the record or system level such as attempts to access the system or rename or delete a file.

From our perspective, audit trails that capture changes to critical data should be reviewed with each record and before final approval of the record. Audit trails that should be subject to regular review should include, but are not limited to, the following: the change history of finished

Strategy

product test results, changes to sample run sequences, changes to sample identification, and changes to critical process parameters. It is recommended that routine scheduled audit trail review be based on the complexity of the system and its intended use.

The spirit of CGMP-compliant record-keeping practices prevent data from being lost or obscured. In some extreme cases, regulated companies may even attempt to move away from the computerised system. The reason why they go back to manual or paper-based systems is because they are concerned about their ability to apply appropriate technical controls. Although paper-based systems may be permissible, these pharmaceutical companies incur more potential human risk.

As the UK’s Medicines and Health Products Regulatory Agency’s (MHRA) latest guideline4 on data integrity puts it, a paper-based audit trail could be implemented if it ‘achieves equivalence to integrated audit trail[s].’ If equivalence cannot be demonstrated, firms must ‘upgrade to an audit trailed system by the end of 2017.’ The WHO guidance takes a bit more stringent approach and states: 4 https://www.pharmaceuticalonline.com/doc/comparingrecent-data-management-integrity-guidances-from-mhrawho-pic-s-0001

“The use of hybrid systems is discouraged, but where legacy systems are awaiting replacement, mitigating controls should be in place.”

We would recommend adopting an electronic record-keeping system that can assist regulated companies to fulfil these CGMP requirements more easily instead of looking for alternative approaches to meet data integrity requirements.

3.Foster the right company culture as fear increases the possibility of malpractice

After confirming the path to recordkeeping practices, the next thing pharmaceutical companies need to cultivate is a corporate-wide culture centred on data governance. First, management must show a willingness to resolve issues once they are raised, and provide appropriate resources to meet challenges to define priorities as required. Second, when there are problems, management must adopt an open-minded approach and encourage staff at all levels to report errors, omissions, failures, abnormal results, bad practices or even falsification without fear of penalty. Only by establishing a corporate culture that stresses data integrity, openness and transparency, will drug manufacturers be more likely to mitigate data integrity risks. The data govern-

ance system should also be reviewed by management and personnel at all levels to ensure effectiveness as regulatory compliance requirements evolve.

4.Train personnel to operate under regulatory expectations

For pharmaceutical companies, the biggest problem is how to put a quality management programme in place to prevent the company from getting a failed audit due to data integrity. The key is to thoroughly understand regulators’ audit expectations on data integrity and how to assess them for gaps.

Data integrity can be understood as the extent to which all data are complete, consistent and accurate throughout the data lifecycle from a quality perspective.

Abbreviated by regulators as ‘ALCOA’, data should be Attributable, Legible, Contemporaneously recorded, Original or a true copy and Accurate (ALCOA).

ALCOA refers to the capability to maintain and ensure the accuracy and consistency of their data lifecycle from data collection to process, from review to reporting and to archiving. To ensure all personnel are aware of the acute need to meet regulators’ expectations for data integrity, it is important to offer your personnel and laboratories seminars and training on the ALCOA principle.

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Safety and Control

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Strategy

Another key concern discussed in the MHRA guidance is for primary records where the same information might be recorded in different places, information concurrently residing in different systems should be defined as an actual primary record in case of discrepancy.

It also needs to be defined if the data is used to perform regulator activity and make quality decisions. This attribute is a primary record that needs to be defined in the Quality Management System (QMS) and should not be changed on a case by case basis either for convenience or avoiding compliance.

integrity assurance as suggested by the MHRA.

India is now the world’s third largest supplier of generic drugs by volume while its domestic market is expected to grow at 15 per cent to 20 per cent CAGR to reach US$50 to US$74 billion in the next decade, according to PwC.

6.Evolve with future regulatory expectations

5.Assess your data for gaps before the auditors do

In preparation for a regulatory audit, companies should understand the ownership as well as the actual and detailed lifecycle of all their important quality-related data. The data required for regulatory audits comes in different forms–-whether it is a set of results or instructions or in document format, record or report–scattered across different hardware, applications, platforms and systems in the laboratories of a pharmaceutical company.

This regulated data created, reviewed, and approved might be used at some stage, and it may go through archival and retention phase before it is finally disposed of or destroyed. As a result, it is of paramount importance to consider where data resides and who is responsible at each stage of the data lifecycle. These procedural controls on the data lifecycle need to be defined, communicated and understood across the organisation to ensure compliance requirements for data integrity are met.

Another reason why many pharmaceutical companies in Asia fail to meet regulatory requirements is because their quality systems are often separated from the data governance system. Instead, pharmaceutical quality systems should exist within the quality system, and be purpose-built for evolving regulatory compliance. The data governance system should be designed with electronic record 16

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regulations and compliance policies to satisfy regulatory agencies and certification organisations. The overall framework should include specific procedures, technical controls and trainings to manage and achieve data integrity through the quality system in a multi-vendor instrument systems environment.

The data governance system should also have been harmonised and extended to contracted organisations, suppliers, or even service providers along the supply chain to ensure the highest level of data

Warning letters, safety alerts and delayed market entry could easily wipe out significant profits. In light of this, data integrity compliance plays an indispensable role in ensuring the strategic positioning, profitability and time-to-market of pharmaceuticals and ensuring companies are not being damaged by failure to deal with data integrity. To fulfil data integrity expectations, companies are required to overhaul their operations by focusing on several key regulatory concerns — Culture and Governance, the Data Lifecycle and the System Lifecycle.

We cannot stress enough the significance of data integrity in the quality management system that ensures finished medicines are of the required quality.

To prevent product recall and serious reputational damage, companies should build in an integral quality system to ensure accuracy, completeness, content and meaning of the data to be retained throughout its lifecycle. More importantly, data should remain useable and available to the regulatory agencies involved in making quality decisions that can impact the drug and the patient.

A u t h o r BIO

Gary Cameron joined the Asia/Pacific Marketing team as Director of Informatics Sales and Marketing in 2012. Gary has been with Waters for since 1997 in a variety of roles, beginning in field sales and marketing, transitioning to Empower informatics product manager at Waters HQ in the USA, and now taking responsibility for the future direction of Waters informatics products in the Asia/Pacific region. He has worked closely with major companies and government agencies throughout the world, advising them in areas such as laboratory data management, regulatory compliance, multi-vendor integration and enterprise implementations.

www.pharmafocusasia.com

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MEDICAL FAIR THAILAND 2017 Rehabilitative Care & Connected Healthcare

The 8th edition of MEDICAL FAIR THAILAND 2017 is set to reaffirm its place as the leading medical and healthcare exhibition in the region with its upcoming staging from 6 - 8 September 2017 at Queen Sirikit National Convention Center. With an international line-up of 700 exhibitors, 17 national pavilions and country groups that include first time participation from India, Russia, and the European Union, and more than 8,500 qualified trade buyers, MEDICAL FAIR THAILAND 2017 is the premier meeting spot for medical and healthcare professionals.

As Thailand aims to become a high-income country by 2025, and with new development plans in place with

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Thailand 4.0, the country is transforming itself from being industry-driven to innovation and technologydriven. Among the 10 targeted industries are Smart Electronics, High-income Tourism and Medical Tourism, and Biotechnology, as well as additional growth engine sectors such as automation and robotics, digital, medical and healthcare. Against this backdrop, MEDICAL FAIR THAILAND 2017 is the ideal platform to network and source for business opportunities.

The exhibition is supported by some of Thailand and the region’s most prominent government and industry trade associations, including Thailand’s Ministry of Health and the Asian Hospital Federation.

Staying relevant to the changing needs and demands of the Southeast Asian market, which include an ageing population where 46 million people will be over the age of 65 by 2020, alongside a tech-savvy growing middle class population, two special platforms will take centre stage at MEDICAL FAIR THAILAND 2017 -Rehabilitative Care and Connected Healthcare. The extensive showcase will feature a wide range of products and solutions, from patient therapy, exercise and mobility devices to a full suite of smart wearable technologies.

Complementing these two platforms will be the 3rd Advanced Rehab Technology Conference (ARTeC) 2017, with the theme “Robotics for Mobility: Quality of Life for the Ageing World�. Thought-leaders in their

respective fields will cover a spectrum of topics such as robotic rehabilitation, neurological rehabilitation and more.

With a well-established history since 2003, MEDICAL FAIR THAILAND continues to grow from strength to strength as the region's No. 1 medical and health care event. Focused on equipment and supplies for the hospital, diagnostic, pharmaceutical, medical and rehabilitation sectors, the exhibition provides the best business opportunities to navigate the dynamic marketplace of Thailand and Southeast Asia.Plan your visit today!

For more information, log on to: www.medicalfair-thailand.com Advertorial www.pharmafocusasia.com

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Research & Development

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Reviving Pharma R&D Productivity with New Modalities The pharmaceutical industry is facing a decline in R&D productivity. However, genomics, biomarkers and access to human tissue samples are offering a range of well validated, but challenging biological targets. To seize the opportunity, leveraging New Modalities and abolishing silos is a must, and represent a chance to increase productivity.

Eric Valeur, Associate Director, New Modalities, Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, UK

O

ver the past decade, a plethora of comments have highlighted a decline in Pharma R&D productivity. Several causes have been claimed including tighter regulation leading to even higher attrition as well as increasing costs. Another explanation has been that the biological targets against which drugs are designed have become more challenging. In other words the low hanging fruits, or ‘easy’ targets, have already been picked, leaving only ‘harder’ targets. While this may be disputable as classical targets classes continue to represent a significant part of companies pipelines, several major therapeutic areas are clearly facing a paucity of well validated targets.

The biological targets landscape is changing

Before discussing the biological targets landscape, it may actually be pertinent to explain the basic concept of a biological target, for those not familiar with the meaning. The usual metaphor of the ‘key/ lock’ is the simplest way to describe the principle of the majoritydrug approaches: a biological target is the ‘lock’ and a drug, or modality, is the ‘key’. The ‘lock’ is typically a protein whose function is linked to a positive or negative biological effect. Thus, developing a drug usually consists in increasing or decreasing the level of a protein or of its function. In addition, it is important to consider that the ‘lock’ may be located outside (extra-

cellular) or inside (intracellular) a cell.

Typically, accessing intracellular ‘locks’ requires smaller drugs, or ‘keys’.

With the development of genomics and biomarkers, as well as better access to human tissue samples, genetic links between diseases and specific biological targets are getting stronger. However, these targets with strong human validation are in many cases deemed ‘undruggable’.

Put simply, these ‘locks’ typically require larger ‘keys’, but are often intracellular, which is usually not compatible with these larger ‘keys’. Based on this, two main options are then to be considered: avoiding the targets (since these are ‘too hard’ to drug), and therefore indirectly deceiving patients as well as failing the essential mission of the pharmaceutical industry; or novel approaches are to be developed to turn these targets into tractable ones, embracing the associated higher risk.

Silo mentality and ‘classical’ modalities

Beyond risk-aversion, an additional factor stands in the way of addressing these ‘undruggable’ targets. Indeed, from a therapeutic modality point-ofview, the pharmaceutical industry has a heavily silo-biased structure. A stereotype is to consider on one hand www.pharmafocusasia.com

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Figure 1 Strengths and limitations of classical modalities, and positioning of New Modalities

small molecules and on the other hand biologics. Each modality is typically pursued in isolation from others, as is the case of the majority of biotechs, which often do not have the critical mass to have capabilities across modalities. The situation is actually very similar in Big Pharma, with often limited collaboration across small molecules and biologics technologies.A silo-based structure is not per se an impediment to drug discovery.

Indeed ‘classical’ modalities, namely small molecules and biologics are still offering many opportunities.

Small molecules offer the advantage to be an established technology, with a robust drug discovery process, which usually enables oral delivery and potentially broad tissue distribution, including access to intracellular targets.

In addition, costs of good are usually low. However, small molecules are typically less selective, leading sometimes to less optimal safety profiles, and are also less suited to some of the novel target types because they are ‘too small’ to interfere with these.

Biologics, predominantly proteins and antibodies, arguably present the opposite picture: high specificity and potency, long duration of action but typically lower tissue penetration, high production costs, and usually non-oral routes of administration.

In addition, intracellular biological targets are usually not accessible.

Since many challenging biological targets would require larger modalities 22

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than small molecules but also smaller modalities than biologics, novel strategies, or New Modalities, are required (Figure 1).

Addressing challenging targets with new modalities*

Rather than applying theexisting silo mentality to challenging targets, pharmaceutical research is presented with the opportunity to develop New Modalities. In addition, these may be brought together, potentially combining them, to address the challenges associated with the novelty of these targets. New Modalities cover a broad range of molecular entities and representative examplesare presented below.

Figure 2 Simplified categorisation of selected New Modalities

Peptides can be described as tiny proteins, and like their bigger sisters, are constituted of aminoacids. This modality has already resulted in many marketed drugs in a range of therapeutic areas, especially oncology and metabolic diseases.

However, one of the key limitation of peptides is their low stability in blood and their usually low permeability, limiting both oral delivery and access to intracellular targets. Excitingly, a new generation of peptides is now offering novel options leading to several drug candidates. Recent developments include bringing together a small molecule and a peptide to form ‘bicyclic’ motifs.

The new architecture offers antibodylike potency with small molecule-like pharmacokinetics. Another example are the so-called ‘stapled’ peptides, in which, again, small molecules components are merged with a peptide to form a stabilised molecule, with stronger stability, and whose active shape as a drug is locked by the small molecule component.

This specific modification has also been shown to be potentially amenable to intracellular targets, opening a new range of opportunities for this modality.

Several next generation peptides are now being tested in clinical trials, including POL7080 (Polyphor, antibiotic) and ALRN-6924 (Aileron, oncology).

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Research & Development

(Figure 3). While many challenges still have to be addressed, this genome-editing modality is being pursued by several companies.

The Rise of Hybrids

Figure 3 Simplified principle of mode-of-action for ASOs, modRNA and CRISPR

Perhaps in a similar way than peptides mimic proteins, oligonucleotide-based therapies copy the biomolecules at the core of living organisms: DNA and RNA. DNA carries the genetic code, which can be read and transferred to RNA. The RNA carries the message inside the cell to produce a given protein for which the RNA is coding. Interfering with this series of events can therefore regulate the level of a given protein. For example, Antisense Oligonucleotides (ASOs) block a specific code on RNA. This technology is well suited to the cases where a beneficial therapeutic effect is expected to be gained from limiting the amount of a protein.

Interestingly, the same modality can also be used to target another mechanism within cells, leading in this case to an increase in the amount of protein.

Conceptually, oligonucleotide approaches differ from the classical ‘key-lock’ concept: in this case the drug aims at removing or increasing the ‘lock’ rather than blocking or activating it with a ‘key’ (Figure 3).Examples ofmarketed drugs based on these technologies includethe recently approved Etiplirsen (Duchenne 24

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Muscular Dystrophy) and Nusinersen (spinal muscular atrophy).

Modified RNA (modRNA) are a very different type of oligonucleotides: they mimic directly the whole code for a protein. Thus, this modality results in the production of the encoded protein, and is therefore relevant in diseases where absence of a protein is inducing negative events. In this respect, modRNA corrects a deficiency by providing it via another mean: it generates a ‘lock’ that is missing (Figure 3). While this technology is still emerging, several clinical trials have now been initiated, including for AZD8601, a regenerative treatment for patients with heart failure.

With the prospect of correcting genetic defects leading to serious conditions, the ‘CRISPR-CAS9’ technology is gaining a lot traction.

The system utilises an enzyme (CAS9), which acts as ‘molecular scissors’, clipping a portion of DNA selected by an oligonucleotide. A ‘corrected’ DNA sequence can be provided to the system, which then uses the cell machinery to incorporate this ‘right’ sequence

Beyond the examples of bicyclic and ‘stapled’ peptides mentioned before, a whole new range of hybrid modalities is appearing. For example, in the field of biologics, different entities have been merged, or ‘fused’. These include protein fusions and peptide-antibody fusions.

Peptides aimed at different biological targets have also been fused into one single modality, as an “all-in-one” drug.

Examples include MEDI0382, a dual molecule for the treatment of diabetes.

Classical small molecules are also being combined to offer novel ways of addressing biological targets. The so-called PROTAC technology can be applied when the presence of a protein has negative consequences. The approach brings in close proximity a protein regulating degradation with the ‘bad’ protein, which essentially receives a ‘death kiss’, leading to its degradation.

Perhaps the most peculiar example of hybrids is the field of drug-conjugates.

The objective of these modalities is to ‘home’ a drug to a specific site in the body, a concept more broadly known as targeted delivery. Drug conjugates are formed by linking a drug modality to a homing modality, and result in a whole range of new hybrid modalities.

The approach is of particular interest in oncology, where cytotoxic drugs can be specifically directed to tumours, as exemplified by Antibody-Drug-Conjugates (ADCs), and the related two marketed drugs Kadcyla and Adcentris. In addition, in the context of challenging targets, drug conjugates may open therapeutic windows for regenerative medicines.

Indeed, regenerative approaches are typically aimed at inducing proliferation in a tissue needing repair, for example after a heart attack. Since proliferation has obviously to be triggered only in the relevant tissue, homing the drug to that tissue can be seen as a must.

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Research & Development

Leveraging These New Modalities: A Network Approach While New Modalities demonstrate how moving beyond silos can address challenging targets, a question remains on how to achieve this. Indeed, the whole range of New Modalities requires a very diverse set of competences and knowledge. One option is to integrate these within the same company, essentially the strategy that Big Pharma often takes. While this certainly provides the range of skills together with critical mass, the typical heavy bureaucracy and creation of silo mentality, together with the usual appearance of ‘turf wars’ are clear impediments.

Perhaps a more promising strategy is to possess in house critical knowledge,

Summary and Perspective

A u t h o r BIO

By leveraging New Modalities, either individually of by creating new ones through combination, the pharmaceutical industry is presented with the exciting prospect of drugging these challenging targets with strong human target validation. By approaching these targets with a mindset of integration

26

Eric Valeur has over 10 years drug discovery experience gained at Merck, Novartis and AstraZeneca.

He is passionate about science but moreover about how bridges can be built between scientists and business professionals to deliver innovation. He holds a PhD in Organic chemistry from the University of Edinburgh, U.K. and an MBA from Imperial College London, U.K.

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in a selected number of modalities, and to work collaboratively with externals experts in the other modalities. These experts may be either specialist biotechs (e.g. Ionis for ASOs, Moderna for modRNA) or academic groups.

Such a network-based approach brings together different modalities, avoiding silos. To achieve this, an external focus is an obvious prerequisite, and novel collaboration models, especially with academia, need to be designed. For example, the creation of a new type of collaboration is currently being explored between a world leading academic institution, the Max Planck Society in Germany, and a large

of drug modalities rather than silos, and establishing strong networks across biotechs and academic groups, the most suited modality for a given biological target can be developed. Drugging wellvalidated targets, regardless of their complexity, is increasing the chances of success in clinical trials and will therefore revive R&D productivity. To achieve

pharmaceutical company, AstraZeneca.

Thus, a new ‘satellite unit’, composed of AstraZeneca scientists directly embedded in the academic environment at the Max Planck Institute of Molecular Physiology, has been established.

Researchers from industry and from academia are working side-by-side in the same laboratories to address challenging therapeutic targets through novel strategies in the New Modalities area. With this setting, novel innovation can be generated by uniting both industrial and academic strengths.

Such innovative partnerships represent one attractive strategy to drive the field forward.

this New Modalities paradigm, scientists and decision-makers have, however, to be comfortable with exploring novel avenues, rather than desperately pushing ‘classical’ modalities on targets that can be drugged, but where human target validation is weak. Looking beyond the apparent higher risk, at first glance, of some New Modalities is a must: the prospects of much increased probability of success in the clinic, as a result of addressing well validated targets, is much more rewarding. It is time for the pharmaceutical industry to aim at the high hanging fruits. Most importantly, beyond the satisfaction of increased productivity, the most rewarding effect will be to provide life changing medicines to patients. *Reference: New Modalities for Challenging Targets in Drug Discovery, Valeur E, Guéret, S.M., Adihou, H, Gopalakrishnan R., Lemurell M., Waldmann H., Grossmann T.N., Plowright A.T., Angewandte Chemie International Edition2017, in press.

DOI: 10.1002/anie.201611914

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Research & Development

Research and Development of Medical Countermeasures in Asia for Pandemic and Bioterror Threats Medical CounterMeasures (MCMs) are being developed on a global scale to treat and prevent pandemic disease agents as well as chemical and radiological threats, both accidental and intentional. While this field is recognised as a burgeoning biomedical product sub-sector in the USA, China is actually the world’s second largest developer of MCMs and an example of the important contribution of AsiaPacific countries to this evolving business landscape, which we will describe in our forthcoming article.

Zachary Peter Smith, Tufts Center for the Study of Drug Development Tufts University, US Christopher-Paul Milne, Center for the Study of Drug Development (CSDD) Tufts University Medical School, US

B

eginning in the mid-1990s, incidents involving easily weaponised and accessible agents such as anthrax, a commonly occurring bacterium, and sarin, a chemical toxin from a commonly used family of pesticides, demonstrated the growing threat of Chemical, Biological, Radiological and Nuclear (CBRN) agents as weapons for bioterror attacks. At the same time, there was increasing awareness of the broadening scope and frequency of naturally occurring pandemics. Thus the category of biological agents was considered to include: emerging infectious diseases such as Severe Acute Respiratory Syndrome (SARS); re-emerging infectious diseases like measles and pertussis; and, weaponised biological agents such as smallpox and anthrax.

SARS was among the first of the emerging infections of the 21st Century to illustrate two significant characteristics of the new plagues: the first is

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their potential for significant direct (i.e., medical and government program costs) and indirect economic impacts (e.g., Asia-Pacific economy lost nearly US$40 billion); and secondly, that even relatively quick-kill infections can easily become geographically widespread due to the rapidity of modern travel and the global nature of business (i.e., approximately 250 cases of SARS in 10 countries spread within a few days from a professor, who had been treating SARS patients in the Chinese countryside and then traveled to a popular hotel in Hong Kong).1 While these factors are mostly accidental, intentional (mostly illegal) actions have complicated and broadened the threat spectrum for CBRN. Bioterrorists have used the US mail system and the Japanese subways as vehicles for transmission for anthrax and sarin exposure, respectively. Similarly in 2003, monkeypox virus entered the US through imported Gambian rats sold as exotic pets, and international smuggling of birds is thought to be a possible pathway for the bird flu to enter the country.2 Many of the identified threats, even from pathogens known to be highly lethal and transmissible, did not have preventive vaccines or effective treatment options 1 Trust for America’s Health, Germs Go Global: Why Emerging Infectious Diseases are a Threat to America, October 2008 Issue Report, Page 10

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China

2 Trust for America’s Health, Germs Go Global: Why Emerging Infectious Diseases are a Threat to America, October 2008 Issue Report, Page 9

beyond supportive care. In response to these threats, it became imperative to the US Government (USG) that a biodefense system of Medical Counter Measures (collectively, MCMs) had to be developed. (See Box) Consequently, the US is the most active country for MCM R&D, however, nearly half of the global pipeline of MCMs is located outside the US, China, for example, is the world’s second most prolific country in terms of its MCM pipeline, as well as being the most active in this field among Asian countries. The 52 MCMs in development in China make up 49 per cent of the Asian MCM pipeline, and China is developing roughly 2.5 times as many MCMs as the next most active Asian country - South Korea (19).

Following South Korea is India, with 15, and Japan with 9. Development numbers quickly drop off from there with Hong Kong and Singapore each developing 3, Taiwan developing 2, and Thailand and Malaysia each developing 1 (Figure 1).

Data accumulated by Tufts CSDD over the last 10 years from public sources and its own proprietary database indicate that MCM developers in Asia are mainly small to medium sized enterprises, privately owned, and are somewhat more likely to describe themselves as biotech rather than pharma companies.

A look at the top five indications in terms of countermeasures being developed

Malaysia

Thailand

Taiwan

Singapore

10

Hong Kong

20

Japan

30

India

40

South Korea

50

0 Figure 1 Number of MCMs in Development by Each Country www.pharmafocusasia.com

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The MCM Initiative was launched in 2002 by the USG to coordinate product development, preparedness, and response against terrorist attack with CBRN agents, a naturally occurring emerging disease, or a natural disaster. The graphic demonstrates that in terms of the number of products and R&D sponsors comprising the pipeline for one notable disease example, Ebola, the response appears to have been significantly increased by a series of legislative acts as well as the threat posed by other disease agents engendering both real and perceptual public concerns (see graphic).

us za Vir Influen on 22% ti c fe In

Rabies Virus Infection 23%

Salmonella typhi Infection 9% Hepatitis A Virus Infection 9% Japanese Encephalitis Virus Infection 7%

Others 30%

Figure 2 Five Most Common Countermeasures in Development in Asia

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Has the USG's Medical Countermeasure Initiative Worked?

Ebola Pipeline Over the Last Decade 2014

50

# of Products # of Sponsors

40 30

50

2010

55

20 2006

10

21 12

0

18

12

Bioterrorism Act of 2002; Bioshield Act of 2004 (Anthrax, SARS)

PREP Act; PAHPA in 2006 (Swine and Bird Flu)

PAHPRA in 2013 (MERS, Ebola)

*Source: Tufts Center for the study of Drug Development, Outlook 2015

Bioterrorism Act – accelerated approval of priority Medical CounterMeasures (MCMs) against Chemical, Biological, Radiological and Nuclear (CBRN) threats, created animal efficacy rule for when human studies are not feasible, and established the Strategic National Stockpile (SNS).

Project BioShield Act – provided funding to support development and procurement of MCMs and authority to the FDA Commissioner to issue Emergency Use Authorizations (EUAs)of unapproved medical products in emergencies.

Pandemic and All-Hazards Preparedness Act (PAHPA) – improved the nation’s public health and medical preparedness and response capabilities for emergencies, whether deliberate, accidental, or natural, and authorized the establishment of the Biomedical Advanced Research & Development Authority (BARDA), and when reauthorized in 2013, enhanced FDA efforts to review MCMs using advanced tools for regulatory science.

Public Readiness and Emergency Preparedness Act (PREP Act) – provides limited immunity from tort liability and compensation for claims of loss caused, arising out of, relating to, or resulting from administration or use of MCMs.

indicates that while there is some overlap in the priorities among researchers in Asia and in western countries, researchers in Asia are choosing to develop countermeasures for several indications that receive far less resource allocation in other areas of the world. Worldwide, influenza countermeasures are the most common in the MCM pipeline, however in Asia influenza drops to second place behind rabies, which makes up 23 per cent of the total MCM pipeline in Asia. Salmonella typhi, hepatitis A (HAV), and Japanese encephalitis fill out the top five making up 9 per cent, 9 per cent, and 7 per cent of the pipeline respectively (Figure 2).

These five indications alone account for 70 per cent of the entire MCM pipeline in Asia, while the remaining 15 disease indications for which countermeasures are being developed in Asia only make up 30 per cent of the countermeasure pipeline.

Rabies, recognised by the WHO as a re-emerging threat in many Asian countries, is fatal in almost all instances.3 However, it is also considered a highly preventable disease through vaccination programmes, and is among the top five most common countermeasures on a world scale, as well as in Asia.

This position may be largely due to the attention it receives in the Asian pipeline. Currently, there are 40 rabies countermeasures in development around the world, 24 of which are being developed in Asia (60 per cent) (Figure 3).

3 Rabies in the South-East Asia Region. World Health Organization.

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Research & Development

25%

World

20%

Asia

15% 10% 5% 0%

Rabies Virus Infection

Influenza Virus Infection

Salmonella Typhi Infection

Hepatitis A Japanese encephalitis Virus Infection Virus Infection

Figure 3 Per cent of Pipeline by Indication, Around the World and in Asia

Influenza, which periodically causes pandemics that are disruptive socially and economically, especially in Asia, receives a great deal of attention both in Asia and on a world scale. Researchers in Asia are currently developing 18 per cent of the influenza countermeasures in development around the world, and these countermeasures make up 22 per cent of all MCMs in development in Asia, a percentage similar to that of the worldwide pipeline (Figure 3).

Salmonella typhi, hepatitis A, and Japanese encephalitis all have a relatively minor presence in the MCM pipeline globally, and the majority of countermeasures for these indications are in development in Asia. Researchers in Asia are currently developing 59 per cent of all Salmonella typhi countermeasures in development, 82 per cent of all hepatitis A countermeasures, and 78 per cent of all Japanese encephalitis countermeasures (Figure 3).

Unsurprisingly, among MCM developers in Asia, emerging and re-emerging diseases are a top priority.

Eleven of the twenty disease indications for which countermeasures are in development in Asia are for emerging or re-emerging diseases (as opposed to those for food-borne illness or biodefense).In fact, these 11 indications account for 32

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72 per cent of the MCM pipeline in Asia (Figure 4.) In addition to the previously mentioned diseases, researchers are developing countermeasures for threats such as drug-resistant tuberculosis, dengue fever, chikungunya, viral hemorrhagic fever, and Zika.

Emerging and re-emerging diseases pose a particular threat in Asian countries, and are consistently listed among the top non-traditional threats in the region. The WHO is especially watchful of diseases like dengue and avian influenza, which have caused epidemics in the past, and Ebola and MERS-CoV, which have not had outbreaks in the region but could have devastating results if one occurred.4 The reasons these diseases pose such a threat in the region are many, and have been described as the result of “complex, dynamic systems in which biological, social, ecological, and technological processes interconnect.�5 Expanding cities and farmlands allow increased interactions between humans and vectors of these diseases such as bats, and areas 4 Asia Pacific Strategy for Emerging Diseases, Progress Report 2015. World Health Organization.

5 Elin Gursky, Frederick Burkle Jr., David Hamon, Peter Walker, and Georges Benjamin. The Changing Face of Crises and Aid in the Asia-Pacific. Biosecurity and Bioterrorism: Biodefense Strategy, Practice and Science. 2014, Vol.12, Num. 6, p.310-317

of dense populations allow the diseases to be easily transmitted from person to person. Many countries in the region also lack the healthcare infrastructure to treat those affected by these diseases, let alone contain or prevent an outbreak should one begin.

As illustrated by the five most common disease indications within the MCM pipeline, researchers in Asia devote significant attention to food-borne illnesses and the development of countermeasures for these illnesses. There are currently 23 countermeasures in development for six food-borne illnesses in the Asian MCM pipeline, and these countermeasures account for 22 per cent of the pipeline (Figure 4).

Hepatitis A typifies the complexity of the threat posed by food-borne illness due to its somewhat paradoxical nature.

The symptoms and severity of Hepatitis A increase the older the patient is at time of exposure, with infants and children often showing no symptoms when exposed. A study by Nina Barzaga indicated that in the 1980s in many Asian countries like South Korea, China, and Thailand, 85 per cent-95 per cent of the population tested positive for hepatitis A antibodies by age 10. However, likely due to improvements in the quality of drinking water, hygiene, and sanitation, by the 1990’s, this percentage of exposure was not reached until 30 years of age, and in some countries, 50 years of age6.

This meant that while conditions were improving, people were being exposed to the hepatitis A virus at a later age, when it is much more dangerous, and created the potential for outbreaks of the disease. With the increased risk of an outbreak comes the increased need for an effective countermeasure.

Other food-borne illnesses for which countermeasures are in development include clostridium botulinum (botulism), and several forms of Shigella.

Also of note is the relatively scant attention received by biodefense 6 Nina Barzaga. Hepatitis A shifting epidemiology in South-East Asia and China. Vaccine. 2000, 18, S61-S64

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Research & Development

Registered 8% Pre-Registration 5%

Food-Borne Illnesses 22%

Phase III 5%

Biodefense 6%

Phase II 6%

Emerging / Re-Emerging Diseases 72%

Phase I 9% Clinical 1% Discovery 66%

Figure 4 Per cent of MCM Pipeline Devoted to Each Threat Area

7 Masamichi Minehata. ‘Getting the biosecurity architecture right’ in the Asia-Pacific region. Medicine, Conflict, and Survival. 2012, 28:1, p.45-58

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through to later development. Only 11 per cent of countermeasures are in later clinical trials, and only 13 per cent of products are in the Pre-registration or Registration phases. For MCM development to remain viable among Asian countries, more dedicated resources for advanced stages of development must be established.

MCM developers in Asia are largely focused on vaccine development. Of the 105 countermeasures currently in development in Asia, 77 of them are vaccines (73 per cent). Only 28 (27 per cent) of the MCMs currently in development in Asia are non-vaccine, therapeutic agents. This seems to indicate that the focus of Asian MCM development is on prevention, and not treatment.

A u t h o r BIO

countermeasures. Only 6 per cent of the MCM products in development in Asian countries are products with biodefense applications. Bacillus anthracis (Anthrax) has one countermeasure, radiation sickness has two, and variola virus has three in development in Asia. It is worth noting that half of these countermeasures are in development in South Korea, a country which lives under the constant threat of chemical or nuclear attack from North Korea.

While this apparent lack of attention to biodefense countermeasures is likely a complicated issue, a 2012 paper by Masamichi Minhata summarised the attitudes of researchers in Asia quite well.

“The risk that most concerned practicing scientists was the scenario of pathogens under research ‘accidentally infecting people or animals…’more than the risk of theft or advertent use of agents for destructive purposes…”7 Similar to the worldwide MCM pipeline, and the drug pipeline in general, a majority of the Medical Countermeasures in development in Asia are in early development, defined as Phase I or earlier (Figure 5). With 76 per cent of the countermeasures in early development, it is clear that there is a bottleneck for countermeasures to move

Figure 5 Percentage of MCMs in Each Stage of Development

Despite the fact that just over half of the current MCM pipeline is based in the US, even there the legislative scheme is complex, the resulting government infrastructure variable, and the funding stream uncertain. Consequently, the shape of the global industry landscape that has emerged in response has been somewhat changeable and uneven. This daunting reality was evident during the recent Ebola outbreak in which the impact of MCMs on the course of the epidemic was viewed as too little, too late. This betokens urgent questions regarding whether public and private sector investment and coordination worldwide are sufficient to create a R&D sub-sector capable of meeting even the current known public health needs for MCMs, let alone those of an unknown future?

Zachary Peter Smith completed his B.S. at Florida Southern College, and completed his M.A. at Brandeis University. He has worked as a research assistant at a variety of labs including the Etter Lab at the University of Massachusetts, and the Evolutionary Psychology Lab at Harvard University.

Christopher-Paul Milne joined the Center for the Study of Drug Development, Tufts University School of Medicine (TUSM) in 1998, and is currently a TUSM Associate Professor and Directorof Research at the Center. He has published over 75 book chapters and papers on biopharmaceutical regulatory and policy issues worldwide, while serving as an Innogen Center Associate (University of Edinburgh), and recently as Visiting Professor at Kyushu University in Japan.

Elimination of Pharmaceuticals from the Wastewater of a Pharmaceutical Plant Roche AG had commissioned the company EnviroChemie to develop a new procedure for a new production facility in Mexico, which prevents the undesired release of ecotoxicologically contaminating drugs into the environment and eliminates pharmaceuticals in the wastewater directly at the point of origin, even before they enter the general sewage treatment plant.

In the first step, the three different methods UV/H2O2 oxidation, ozone oxidation and adsorption on activated carbon were tested on a laboratory scale, and evaluated with regard to ecological and economical aspects. When comparing the validated procedures, ozonisation in this special case proved to be the most effective method, in order to efficiently destroy the active ingredients in the wastewater safely and completely. Based on these results, EnviroChemie designed a large-scale technical plant in the second step and implemented it.

Figure 3 Pre-assembled pressure reactors for ozonisation

The following article describes the project development and design of the Envochem plant for eliminating active ingredients from the wastewater of the production facility directly at the point of origin.

1. Introduction Pharmaceuticals and their metabolites are detected on an increasing scale in the aquatic environment.

The drugs mostly get into the surface and drinking water through the excretions of humans and animals. However, the wastewater of pharmaceutical production facilities can also be contaminated with active ingredients. If the drugs produced are rated as ecotoxicologically contaminating, the wastewater should be treated directly at the point of origin, to ensure that only biodegradable substances end up in the environment.

This was the challenge faced by Roche when building a new production facility in Mexico. Two highly effective medicaments for the treatment of cancer are formulated in this facility. In-depth analyses have shown that the two agents Capecitabin (Xeloda) and Mycophenolat Mofetil (Cellcept) could be ecologically critical and should therefore not get into the wastewater. During galenic production, approx. 10,000 litres of wastewater are generated daily, which need to be processed. Only one agent is treated per day.

Roche commissioned EnviroChemie to test different procedures for decomposing Mycophenolat Mofetil on a laboratory scale and to implement the results in a large-scale technical plant. The aim was to find a cost-effective and at the same time affordable method with which the drugs can be fully eliminated.

Tests with the Capecitabin were carried out in the Institute for Energy Management and Environmental www.pharmafocusasia.com

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Engineering in Duisburg (IUTA), Germany. Tests for adsorption on activated carbon were performed at Roche Basel in Switzerland.

The specifications for the technology are: • Reliably deliver results • Ensure a very high operational safety • High degree of automation • Compact construction for the processing plant • Little handling of chemicals • Generation of as little waste as possible

2. Laboratory tests For removal of the active ingredients contained in the wastewater, three different procedures were tested on a laboratory scale and evaluated economically.

Apart from the UV/H2O2 oxidation and adsorption on activated carbon, the third method of choice was ozone oxidation. Depending on the product, acid/ base/sodium hypochlorite treatments would also come into consideration, which are used at other locations of the said company. However, these procedures were not suitable here for several reasons.

The results showed that the two agents can basically be removed from the wastewater with all three methods. In the present case, ozone treatment of the wastewater best met the requirements within the scope of the patented Envochem technology by EnviroChemie and proved to be the optimum method.

The results of Capecitabin oxidation are shown in figure 1. For this purpose, a sample with an active agent concentration of 200 mg/l was produced. The oxidation process was completed after 20 minutes and required a total of 18.33 g ozone. Based on the lab results, the production plant would have a maximum daily requirement (24h) of 917 g (18.33 g O3 x 10,000 L/200 L) ozone, 38 g would be required per hour.

For the laboratory tests with regard to breaking down Mycophenolat Mofetil and its hydrolysis products, a sample with an active agent concentration of 25 mg/l was produced. In a first step, the hydrolysis behaviour of Mycophenolat Mofetil was examined. It was shown that after approx. 24 hours, 80 percent of the original substance are still present (see fig. 2). The ozonisation attempts demonstrated that Mycophenolat Mofetil is completely destroyed by ozone within a few minutes. A daily requirement of approx. 460 g/d was calculated. Comparing the Capecitabin results shows that dimensioning of the plant is determined by the usage of ozone for its oxidation.

3. Process description The obtained data were used as a basis to develop an individually adapted wastewater processing plant which meets all requirements. The resulting Envochem system is housed completely in a six metre long container and is designed to run fully automatically 24 hours a day, so that the wastewater can be treated in a continuous process.

The wastewater is supposed to run from the production facility to a storage tank initially, which is equipped with a water gauge and has a volume of 15 cubic metres. The Envochem plant is directly connected to the tank. The flow rate to the processing system is controlled by a pump with frequency converter and inductive flow sensor. Depending on the liquid level in the storage tank, the flow rate can be varied from 0.4 m3/h to 0.8 m3/h. Solids are retained by a filter system.

4. Ozonisation The ozone is produced by an ozone generator, which does not draw the oxygen directly from the ambient Figure 1 Ozonisation of Capecitabin in the pilot facility of the IUTA. (200 l tap water, c0 = 200 mg/L, ozone concentration: 110 g/Nm3, gas flow rate: 0.5 Nm3/h) 36

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from the wastewater, the treated water runs through an activated carbon filter. In order to ensure sufficient safety, an additionally available ozone detector in the container issues an alarm if ozone occurs in the ambient air.

5. Process control

Figure 2 Hydrolysis behaviour over 30 hours.

air, but from an upstream PSA system. An injection system mixes the ozone with the wastewater, which is located in two reactors (see figure 3). There is a slight excess pressure, which ensures an effective reaction of the ozone with the available agents.

Excess foam is separated in a second reactor. As the ozone requirement depends on the chemical properties and the concentration of the respective drugs in the wastewater, the patented system is equipped with sensors for measuring the dissolved remaining ozone concentrations after treatment. The system controls the performance of the ozone generator fully automatically, so that there is always a defined ozone concentration of e.g. 2 mg/l. If the ozone requirement increases, the generator automatically produces more, if it decreases, ozone production is also reduced. In order to remove the remaining ozone Capecitabin

Mycophenolat Mofetil

Maximum concentration of pharmaceuticals in the lab test [mg/l]

200

25

Daily wastewater volume of the production facility [m3/l]

10

10

Ozone requirement per hour (production facility; [gO3/h])

916.5

240

Ozone requirement per 24h (production facility, [g3/d])

38.18

10

Table 1 Concentration of drugs in the lab test and calculated ozone requirement for complete decomposition of pharmaceuticals during routine operation with maximum wastewater contamination

The system is equipped with software, which enables simple operation of all installed elements and allows visualisation of the complete process. The user can access the measurement values and the process runs at any time. The generated data are displayed in a table and can be archived easily. Status signals are fully logged and can be viewed at a later time.

An optional modem enables remote maintenance and control measures by EnviroChemie, so that in case of an emergency, quick action is possible.

6. Commissioning The system was commissioned in Mexico under guidance of EnviroChemie. All measuring instruments and process control systems of the system pre-installed in the container including a breakdown were tested in Germany. In order to verify the functionality of the system, a Factory Acceptance Test (FAT) was performed together with Roche.

7. Conclusion The tests for eliminating the pharmaceuticals on a laboratory scale have shown that a reliable system is available with the patented Envochem technology, which can completely decompose residual drugs in the wastewater. Automatic control of the ozone concentration in the wastewater ensures the needbased application of the ozone.

Elmar Billenkamp EnviroChemie GmbH Germany, JĂźrg Straub, Martin Studer Hoffmann-La Roche AG Switzerland, Jochen TĂźrk, IUTA, Institute for Energy Management and Environmental Engineering, Germany Advertorial www.pharmafocusasia.com

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Added Costs for Added Protections

The impact of implementing safety features in pharmaceutical packaging and labelling The Impact of Implementing Safety Features in Pharmaceutical Packaging and Labelling - Serialization, Unique Device Identification (UDI) and aggregation catalyse a paradigm shift for the entire industry and are already impacting the pharmaceutical supply chain. In some cases, mandated serialization is expediting aggregation implementation.

Jorge Izquierdo, Vice President, Market Development, PMMI, The Association for Packaging and Processing Technologies, US

T

he global pharmaceutical market is a complex and dynamic industry that is continuously evolving in response to a variety of market influencers. The landscape of the pharmaceutical market has changed significantly with the rise of generic drugs and the rapid expansion of mergers and acquisitions.

Many companies are reevaluating the location of their headquarters and rethinking both their development and production processes. Simultaneously, government mandated serialisation has created a scramble amongst pharmaceutical companies to implement tracking solutions to comply with new regulations.

The medical device industry has undergone significant changes in recent years due to the passing of the Affordable Care Act (ACA) and the expansion of government regulations, including the adoption of Unique Device Identification (UDI) numbers. With new purchasing players entering the market because of the ACA, medical device companies have 38

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manufacturing

shifted their marketing to new partners with a focus on value-based solutions.

While they are in different industries, pharmaceutical and medical device companies often face a surprisingly similar array of challenges and market realities. Businesses in both industries are actively addressing new government regulations often resulting in new equipment purchases. Both industries are under increasing pressure to produce more at lower costs while not sacrificing quality. As a result, companies are turning to contract services at an increasing rate. The pair also share a continued increase in mergers and acquisitions. Also, rapid growth can be seen in the pharmaceutical and medical device industries in emerging markets, particularly the Asia-Pacific region.

Faced with the regulatory challenges of serialisation and UDI along with pressure to produce at low cost, healthcare manufacturers are looking at new equipment to replace outdated production lines. Nearly half of healthcare manufacturers interviewed in PMMI’s 2016 Pharmaceutical and Medical Devices: Trends and Opportunities in Packaging Operations1 research report continue to replace legacy equipment and buy new equipment while two-thirds of participating companies predict spending more on capital equipment in the next 12–24 months. (In this report, produced

by PMMI, sixty industry professionals from pharmaceutical, medical device and contract service companies share their experiences in complying with tracking regulations, operational challenges and their future equipment needs.)

With demand for medicines and medical devices growing globally, manufacturers face choices when it comes to which countries they produce their products.

Among the advantages to be gained from locating plants outside the US are: • Lower labour costs • Tax advantages • Overall cost reductions

• Lenient regulatory environment • Cheaper raw materials.

Imports account for at least half of all medical devices used in the US, while about 80 per cent of active pharmaceutical ingredients in medications sold in the US are manufactured elsewhere, according to the Food and Drug Administration (FDA). Over the past decade, the value of imported medical devices has steadily increased, gradually eroding the previous trade surplus. Many imports are lowertech products, such as surgical gloves and instruments. Continuing shifts in trade patterns have resulted in China and Mexico becoming significant exporters of mid to lower-tech equipment and supplies to the US

The 2016 Pharmaceutical and Medical Devices: Trends and Opportunities in Packaging Operations report cites costs at up to $4 million to implement serialisation at one manufacturing site.

Offshore manufacturing is a growing trend. Many of the pharmaceutical products and medical devices produced outside the US by US-based manufacturers are imported back into the country.

Just a decade ago, six million shipments of FDA-regulated goods passed through the nation’s 200 ports of entry, while in 2016 the number of shipments quadrupled to 24 million.

Most Active Pharmaceutical Ingredients (API) are produced offshore, so much so, that many companies bulk produce overseas before shipping back to the US for primary packaging. Because of the massive amount of imports, offshore companies are seeking to buy US operations to get a foothold in the US and vice versa.

Branded drugs are a different animal, however, and are usually manufactured entirely in the US to alleviate risk. The risk lies in the possibility of introducing counterfeit ingredients into the pharma supply chain. Of the top 10 most valuable counterfeit markets, pharmaceuticals rank number one according to PMMI’s 2016 Brand Protection and Product Traceability Market Research report.2 (PMMI compiled the 2016 2 http://www.pmmi.org/Research/ResearchTrends. cfm?ItemNumber=32377

1 https://www.amazon.com/gp/huc/view.html?ie=UTF8& newItems=C3I4K6TCX072UH%252C1 www.pharmafocusasia.com

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Brand Protection and Product Traceability Market Research report from the insights of 75 brand manufacturers, industry experts and technology suppliers who shared their experiences complying with traceability regulations in the food, beverage and pharmaceutical industries.)

The counterfeit drug market is growing rapidly, and Deloitte accountants currently value it between US$75 billion to US$200 billion. The World Health Organization (WHO) reports that over 25 per cent of medicines available in developing countries, and 50 per cent of products ordered online, are counterfeit.

The solutions available in the global anti-counterfeiting market are predicted to witness significant growth in the next five years with CAGRs ranging from 12.8

In the U.S., drug serialisation began in earnest in 2013 with a full programme expected by 2023 (see below) • 2013: Legislation enacted by U.S. Congress, signed into law: Drug Supply Chain Security Act (DSCSA) • 2015: Manufacturers, wholesalers and re-packagers required to provide and/ or receive pedigree for each transaction • 2017: Manufacturers required to include a product identifier number on each package and homogenous case of prescription drug products • 2019: Wholesalers required to accept or distribute only prescription drug products that include a product identifier number • 2020: Dispensers required to accept or distribute only prescription drug

under the Public Health Service Act (PHS Act) must bear a UDI. Must be submitted to the GUDID database • 2016: The labels and packages of implantable, life-supporting and life-sustaining devices must carry a permanent UDI. Must be presented to the GUDID database • 2017: The labels and packages of class II medical devices must bear a UDI. Must be submitted to the GUDID database • 2019: Data for class I devices and devices that have not been classified into class I, class II or class III, but are required to be labeled with a UDI, must be submitted to the GUDID database • 2021: Class I devices and devices that have not been classified into class I,

per cent to 16.1 per cent. In fact, the growth of the global anti-counterfeiting market will outpace the overall market segment growth of food, beverage and pharmaceutical industries by roughly two to three times in the next five years.

The entire supply chain requires checks-and-balances to close the gaps when tracking, authenticating and locating products as custody changes hands during multiple deliveries.

In response to increasing drug integrity concerns, more than 40 countries have introduced track-and-trace laws to help regulate product as it passes through the supply chain. By early 2019, more than 75 per cent of the world’s prescription medications will be protected by legislation.

products that include a product identifier number • 2023: Mandates the full implementation of an electronic system (aggregation) ensuring compatibility throughout all stages of distribution.

For medical devices, the FDA is establishing a UDI system to identify medical devices through their distribution and use.

When fully implemented, the label of most devices will include a UDI in human-readable and machine-readable form. Device labellers must also submit specified information about each device to the FDA’s Global Unique Device Identification Database (GUDID).

• 2014: The labels and packages of class III medical devices and devices licensed

class II or class III, but are required to be labeled with a UDI, must a bear UDI as a permanent marking on the device itself.

No one technology can offer 100 per cent serialisation and ensure product safety. Solutions will go far beyond the idea of a simple fix, creating added layers of supply chain security. Pharmaceutical manufacturers are analysing every step along their supply chains from incoming materials to primary and secondary packaging all the way through palletising and transportation. The use of 1D barcoding throughout each of these stages was the most attractive solution employed by respondents to the 2016 Brand Protection and Product Traceability report. The report also indicated that 30 per cent

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Regulations and traceability

Pharmaceutical companies are struggling with the costs associated of meeting regulations and setting up an internal infrastructure for data collection. With a limited number of industry suppliers able to help implement the complex challenges of serialisation and UDI, understanding the requirements is a significant hurdle and can cause delays.

The cost alone is driving some smaller operations completely out of business.

The 2016 Pharmaceutical and Medical Devices: Trends and Opportunities in Packaging Operations report cites costs at up to $4 million to implement serialisation at one manufacturing site.

Companies struggling with internal infrastructure have found it difficult to determine the best method to capture, manage and transmit data. Defining rules and requirements to meet all regulations has also proved difficult as has acquiring and procuring equipment when 42

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there are a limited number of suppliers.

Machine delivery times can be as high as two years.

Not only is the equipment hard to get, but it is highly expensive with a projected return on investment up to 30 years.

One way equipment manufacturers can help the industry is with modular machine concepts that are compatible with existing lines equipped with matching software.

The number one global event for solutions for serialisation is Healthcare Packaging EXPO (Sept. 25–27; Las Vegas Convention Center), where pharmaceutical manufacturers can find many resources and solutions to meet track-and-trace and anti-counterfeiting demands. Co-located with PACK EXPO Las Vegas, the show will bring together top CPGs from around the world to explore state-of-the-art healthcare and

A u t h o r BIO

used temperature sensors at the palletising and transportation stages, while the use of pallet tags, RFID tags and smart inks may grow as these technologies become more accessible. Additionally, there is a broad range of solutions to help brands track and verify their products. These include holograms and covert techniques like RFID (Radio Frequency Identification) that require specific equipment to test product authenticity. Other sophisticated technologies to enhance brand security include smart inks, covert markings and temp sensors. Temp sensors are thermally sensitive resistors that can communicate whether a product has spoiled or faced exposure to temperatures outside of an acceptable range—all potential indicators that product integrity has been jeopardised.

Pharma companies are looking for ways to recover costs by improving manufacturing, packaging and handling processes – packaging changes are mandatory because all serialisation information can’t fit on some products. Because of this, it is undeniable that serialisation negatively affects overall equipment effectiveness.

packaging technologies, equipment and materials as well as exchange ideas with peers and build professional relationships.

The event boasts an expected 30,000 attendees, including 5,000 international visitors from more than 125 countries, combined with 2,000-plus exhibiting companies spanning 800,000 net square feet of a nearly sold-out show floor.

Beyond the technologies displayed on the show floor, attendees will find tremendous educational opportunities in the Innovation Stage where suppliers present free 30-minute seminars on breakthrough technologies throughout the day.

Registration, which includes access to both Healthcare Packaging EXPO, and PACK EXPO Las Vegas is US$30 until Sept. 1 when the price increases to US$100. For more information and to register online, visit packexpolasvegas. com or hcpelasvegas.com.

Jorge Izquierdo joined PMMI’s Latin America office in 1993. He eventually moved to the U.S headquarters where he oversees PMMI’s market development strategy, research and programs for strengthening the competitiveness of North American suppliers of processing and packaging equipment. He is also responsible for industry engagement initiatives for continuous improvement of processing and packaging operations.

Izquierdo is a Mechanical Engineer from the Universidad Nacional Autonoma de Mexico (UNAM), where he earned an MBA from the Instituto Autonomo de Mexico (ITAM) and has participated in globalization programs at the Thunderbird Graduate School of International Management.

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Falsified Medicines Directive Ready for 2019?

Markku Pietarinen, Business Segment Manager, Pharmaceutical Labelling, UPM Raflatac EMEIA UPM Raflatac has developed a range of pharmaceutical labelling products to support compliance with the Falsified Medicines Directive (2011/62/EU) on packaging for prescription drugs and high-risk, over-thecounter medicines. An estimated 30 billion such drug packs are sold and handled annually in Europe. Few solutions offer the same ease of adoption for meeting the February 2019 deadline.

The Falsified Medicines Directive makes it mandatory for prescription (white list) or high-risk OTC (black list) drug packs to carry a unique serial number to identify and authenticate individual products. In addition, packs should be sealed in a tamper-evident way which visibly exposes attempts to open them.

While the delegated regulation (EU) No 2016/161 stipulates that an anti-tampering device has to enable verification of package tampering, there is no elaboration on specifications. However, the European Commission Directorate-General for Health and Food Safety advises that guidance can be taken from the new CEN standard EN 16679:2014 “Tamper verification features for medicinal product packaging”. This CEN standard

is the route UPM Raflatac pursued in the development of tamper-verification labelling products meeting an urgent market need for Directive-compliant solutions.

Irreparable tamper verification UPM Raflatac’s tamper-verification products are based on the RP62EU adhesive, which exploits the properties of the cardboard with water-based varnish typically used for pharmaceutical packaging. RP62EU works by facilitating cardboard tear between the bleached chemical pulp and BCTMP layers in the cardboard construction; lifting or removing the label causes highly visible and irreversible damage as an indication of package tampering. The labels cannot be smoothed back down.

RP62EU is available with a range of clear film as well as paper-based label faces. Pharmaclear PP Seal visibly stretches on removal, and Pharmaclear PP Tear TC displays the surface torn from tampered packs.

Pharmatight paper label face is relatively fragile and suffers irreversible damage or break when tampered with. Attempted removal of the Pharmatight label will also cause surface damage to cardboard pharmaceutical packs. An RP62EUL adhesive variant enables missing label detection by luminescent detector.

Inherent ease of adoption For many pharmaceutical product lines, these self-adhesive label solutions are the preferred option due to their simplicity of implementation.

Quickly implemented and effective: Tamper-verification solutions based on the RP62 EU adhesive.

Ease of adoption is particularly a strong point when the tamper-evident functionality of the RP62EU is combined with a clear, filmic label face, which has little effect on the graphic design of the package. Pharmaceutical manufacturers achieve the tamper-evidence required by the Falsified Medicines Directive, while continuing with their existing package layouts and packaging stocks.

Advertorial

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Pharmaceutical labelling solutions for tamper-verification UPM Raflatac has developed a range of labelling products to support compliance with the Falsified Medicines Directive on packaging for prescription drugs and high-risk, over-the-counter medicines.

The tamper-verification functionality of the RP62 EU adhesive is available with a range of clear film and paper-based label face materials. Few solutions offer the same ease of adoption for meeting the Falsified Medicines Directive.

UPM Raflatac’s innovative pharma and healthcare labelling solutions are backed by comprehensive support, an established supply network and a worldwide presence you can rely on.

www.upmraflatac.com

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Continuous Manufacturing Are we there yet?

The urgent need to dramatically improve efficiency and productivity within the pharmaceutical manufacturing sector is in the state of flux. With the US FDA’s push for moving the pharmaceutical industry into 21st century, reality of the market place, and innovation of some equipment manufacturers, number of options is being evaluated by the industry. However, number of roadblocks still exists to implement true continuous manufacturing. There are, however, some technology improvements that are available, that could offer the true continuous manufacturing.

Dilip M Parikh, President, DPharma Group Inc., US

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n 2004, US FDA issued guidance document “PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance”. To encourage the pharmaceutical industry to adopt novel manufacturing methods, it cited industry resistance as follows: “the pharmaceutical industry generally has been hesitant to introduce innovative systems into the manufacturing sector for a number of reasons. One reason often cited is regulatory uncertainty,

manufacturing

which may result from the perception that our existing regulatory system is rigid and unfavourable to the introduction of innovative systems.” Since that time, tremendous amount of activity is seen in the pharmaceutical industry with constant encouragement from the FDA to move the industry from 20th century to the 21st century. Pharmaceutical manufacturing continues to evolve with increased emphasis on science and engineering principles. Effective use of the most current pharmaceutical science and engineering principles and knowledge throughout the life cycle of a product can improve the efficiencies of both the manufacturing and regulatory processes.

The general process involved in the manufacture of drug products consists of a series of unit operations, each intended to modulate certain properties of the material being processed. From the standpoint of unit operations involved as practiced today, there are some that are inherently continuous in nature while there are others that are conducted in batch mode. For example, in case of solid dosage manufacturing, good examples could be the unit operations of tablet compression or roller compaction. However, such unit operations do require additional up stream or downstream processing that will require integrating two or three separate unit operations.

Nevertheless, there is definite shift in the mindset of the industry to move from the batch processes to continuous manufacturing. With major universities and major pharmaceutical companies investing millions of dollars towards the continuous manufacturing shift.

To the duplicate food or petrochemical industry’s continuous manufacturing example, the continuous manufacturing plant in pharmaceuticals should be capable of running 24/7 for 50+ weeks/ year, with no significant downtime for major cleaning (except in product or process changeover). While the technologies, and therefore development and manufacturing expertise, needed for the final dosage formulation aspects

True continuous, single pot processing provides significant improvement in building both temporal and spatial control in process engineering through removal of hot spots and dead zones, while maintaining higher level of process continuity.

of continuous processing are different than those needed for chemical synthesis, there are many areas of overlap such as powder handling, drying processing, process safety, and process monitoring and control technologies. Most pharmaceutical companies though are currently developing a hybrid approach, in which continuous manufacturing steps may be incorporated for portions of a drug substance or drug product process, or

for an entire drug substance or drug product process. The most common ones were continuous drug synthesis processes and continuous direct compression process for solid oral drug products. Ideally continuous processing should provide, seamless integration of process quality, reduced capital cost, smaller footprint, reduced inventory, easy scale up and reduced time to market. The current options for the industry are limited in that few, ‘continuous’ granulation for example, are generally, an integration of existing unit operations such as milling, blending, wet granulation, drying, tableting and coating or encapsulation.

Recently, there were two products approved by FDA direct compression formulation was manufactured.

In a true continuous manufacturing process, the input material(s) are continuously and simultaneously fed into and transformed within the process, and the processed output materials are continuously removed from the system—except at the beginning and at the end of the process. The amount of material being processed at any given instance may be relatively small in a continuous manufacturing process, but

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as the process can run over a period of time to generate necessary quantities of finished material with desired quality.

For a continuous manufacturing process, understanding process dynamics of how a material flows through the process is important with respect to the material traceability (the ability to preserve and access the identity and attribute of a material throughout the system) and performance of the unit operation and the integrated system. To manufacture solid dosage product in a continuous manner, several options are employed in the industry. These include multiple fluid bed units integrated to produce fluid bed granulation, roller compaction for dry granulation, or direct compression blending and compression followed by coating of the tablet dosage form.

A combination of twin-screw extruder coupled with fluid bed dryer and the ancillary equipment as a package is utilised to wet granulate, dry, blend and compress solid dosage product.

There are number of limitations in employing the continuous manufacturing approach due to nature of the Active pharmaceutical ingredient (API) characteristics, composition of the formulation, percentages of each ingredient, and Critical Quality Attributes (CQA) of the finished dosage forms among the major ones. There are challenges posed by process analytical tools that are currently available to monitor all the critical process parameters, even though considerable progress has been made to employ NIR, Raman spectroscopy, vision systems etc. However, for continuous manufacturing, the quality of produced pharmaceuticals needs to be assessed in real-time (in-line, on-line, and at-line) and not via the traditional off-line, often destructive and time-consuming analysis methods that supply the desired information only hours after sampling.

Of all the steps in continuous manufacturing of dosage forms, feeding powder remains the most critical.

If the formulation is comprised of a single ingredient, then its flow properties morphology will reflect in the challenges 48

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that it might pose. The multi-ingredient composition of the formulation poses additional challenges like segregation of ingredients, integrity of the composition throughout the process stream and final quality of the product. Powder feeding for a continuous process is currently based on volumetric or gravimetric techniques utilising the screw feeder.

The measurement system with loss in weight using load cells for poorly flowing material is also utilised. Exploring this area is very critical for continuous manufacturing.

Extrusion is an inherently continuous process, which lends itself to a straightforward implementation in a continuous manufacturing environment. Systems include singleand twin-screw extruders with co-rotating twin-screw extruders being the most frequently ones used for pharmaceutical processing. Hot Melt Extruders (HME) has gained wide acceptance over the last three decades and has already established its place in the broad spectrum of manufacturing operations and pharmaceutical research developments. In addition to being an efficient manufacturing process,

HME enhances the quality and efficacy of manufactured products and therefore over the past few years HME has emerged as a novel technique in pharmaceutical applications. HME has received considerable attention from both industry and the academia in a range of applications for pharmaceutical dosage forms, such as tablets, capsules, films, and implants for drug delivery via oral, transdermal, and transmucosal routes.

The main use of HME is to disperse Active Pharmaceutical Ingredients (APIs) in a matrix at the molecular level, thus forming solid solutions. In the pharmaceutical industry, HME has been used for various applications, such as (i) enhancing the dissolution rate and bioavailability of poorly soluble drugs by forming a solid dispersion or solid solution, (ii) controlling or modifying the release of the drug, (iii) taste masking of bitter APIs, and (iv) formulation of various thin films.

Besides HME, the application of Twin screw extruder is increasing in the pharmaceutical industry for continuous wet granulation, because of the advantages it offers including equipment design flexibility, short residence time, wide range of throughputs and intimate mixing of formulation ingredients.

In twin screw extrusion process for wet granulation, understanding the mechanism of liquid distribution inside the granulator as it relates to the screw configuration as well as the functional role of the latter in defining the size of granules produced is essential for optimisation of granule properties obtained. Usually the screws of a twinscrew extruder are built up modularly.

Generally for twin-screw processing, discrete element or a combination of screw elements are assembled on the main shaft with specific functions such as feeding, conveying, mixing or kneading. Classical conveying or forwarding elements are always inserted at cylinder openings, e.g. at barrel holes to convey material away from the feed opening or to discharge processed material at the end of the extruder Kneading elements

CANTEL MEDICAL ĂŶƚĞů DĞĚŝĐĂů ƐŝĂͬWĂĐŝĮ Đ WƚĞ >ƚĚ ƐŝĂ͗ ʞ ƐŝĂ͗ ΀нϲϱ΁ ϲϮϮϳͲϵϲϵϴ &Žƌ ŵŽƌĞ ŝŶĨŽƌŵĂƟ ŽŶ ĞŵĂŝů ƵƐ Ăƚ ŝŶĨŽΛΛĐĂŶƚĞůŵĞĚŝĐĂů͘ĐŽŵ͘ƐŐ Žƌ ǀŝƐŝƚ www.mcpur.com

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built on the principle of a ‘flow stream in continuity’ utilising a twin-screw processor, that has a unique ability to clean itself. The energy transfer is made effective using thermal, mechanical or chemical means at wide-ranging magnitudes with minimal shear or pressure peaks providing specific advantages in handling sensitive input materials that may or may not rely on the use of water or vapour. Granulation process can typically be achieved with residence time as little as 5-15 seconds (including granulating, drying and sizing), and the optimised granules obtained are ready to be compressed into tablets or filled into capsules. True continuous, single pot processing provides significant improvement in building both temporal and spatial control in process engineering through removal of hot spots and dead

A u t h o r BIO

or kneading blocks, the second classical element type, are usually used when material has to be sheared and thoroughly mixed. Combing mixer elements meet the challenge of conveying and mixing simultaneously. Basically they are conveying elements with longitudinal slots. These slots provide more space for distributive mixing without or nearly no loss in forwarding properties. Most of these twin-screw kneading elements are bi-lobe and the impart high shear on the material generating heat, and may cause degradation of the product because of amount time the material is under kneading force. Irrespective of type and complexity of the function and process, the extruder must be capable of rotating the screw at a selected predetermined speed while compensating for the torque and shear generated from both the material being extruded and the screws being used.

With a modification of kneading elements which is in traditional twinscrew units is bi-lobe, a unique fractional lobe element recently developed

by STEERLife company offers ‘Integraal’ technology for the twin screw extruder with the ability to process wet granulation, drying and sizing of the product in one stand-alone equipment. This True continuous, single pot manufacturing is

zones, while maintaining higher level of process continuity.

In summary, the industry has committed to explore and adopt continuous manufacturing paradigm, regulatory authorities are supporting it, businesses would like to see the cost of manufacturing is reduced, hence ready to invest, and patients would like to see reduced cost ofmedicine.The combination of existing technologies into integrated ‘continuous’ package is now available but the newer technologies based on twinscrew extruders has a potential to provide stand-alone equipment that performs number of unit operations for which currently separate unit operations are required thus offering a true continuous manufacturing pathway.

References are available at www.pharmafocusasia.com

As an industrial pharmacist, Dilip has more than 40 years of industrial experience in solid dosage technologies, Good Manufacturing Process compliant facility planning, process engineering and manufacturing, as well as operational management at various major pharma companies in Canada and the US. At STEERLife, Dilip focuses on developing innovative continuous manufacturing technologies for solid dosage products.

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COVER STORY

Pharmaceuticals are in Good Hands with Turkish Cargo Şeref Kazancı, Senior Vice President, Turkish Cargo, Istanbul

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s Turkish Cargo we have been awarded with IATA’s ‘Center of Excellence for Independent Validators’ (CEIV) in Pharmaceutical Logistics at our Istanbul hub. With this strength, we aim to offer our customers

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the most reliable means of transport. As an air freighter; speed of delivery, wide network and safety are some aspects of our efficiency. When it comes to handling in the air cargo sector, there are strict rules that have to be followed.

IATA CEIV Pharma certification is recognised as one of the most important indicators of our process for pharmaceuticals shipments. The successful completion of IATA’s CEIV pharma certification process by an airline company

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reinforces the airline’s commitment to meeting the high standards set by the pharmaceutical industry and the legislators globally in the transportation of delicate, extreme temperature and timecritical consignments such as vaccines, biotechnological products, diagnostic samples, precision healthcare devices, organs and tissues. We have successfully completed the IATA CEIV Pharma Certification. We revised each step of the process in order to ensure high level of reliability and security throughout shipment. By being certified by IATA CEIV Pharma, Istanbul Cargo Hub is fully complied with all applicable pharmaceutical standarts in order to increase transportation of pharmaceutical products by air. Owing to our IATA CEIV Pharma Certified that support this strategy, we expect more than 40%

increase at the end of the 2017 in pharmaceutical transportation.

Geographically, Turkish Cargo hub at Istanbul Ataturk Airport, is located in a very strategic location. The natural hub status of Istanbul enables us to provide rapid connection between the pharmaceuticals producers and consumers in Asia. As Turkish Airlines, we have freighter services to many countries and moreover, every month, we are opening a new passenger routes.

Besides, when we analyze the growth in the cargo types, pharma shipments have the highest growth rate, as twice as general cargo. To fill our increasing capacity, we have to get share from

the growth in the pharma shipments.

Turkish Cargo carries out our cargo operations in line with special schedules established for cool chain logistics and ensures the punctual transport of these supplies, sent via passenger or cargo aircrafts to over 100 countries around the world. Our biggest difference on cargo business is our network that enables our customers to send their pharmaceuticals shipments to more than 100 countries.

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Pharmaceutical industry is a fastgrowing business in the global market.

We are aware of the huge potential in the pharmaceutical market that continues to grow day by day. We made highly promising investments to improve pharmaceuticals shipping services. As Turkish Cargo, we redefined SOP for the pharmaceuticals.

We have inaugurated a new 3.000 m² special cargo storage area and now 42 separate special cargo rooms which have high quality standards, including temperature-controlled storage units designated for drug, vaccine and healthcare shipments. All of our temperature-controlled storage units are monitored for temperature and humidity levels via an online tracking system. Pharmaceuticals are stored safely in storage units which suited for the type of cargo and are stored under the temperature range requested by the sender. Pharmaceuticals and healthcare cargoes containing medicines in our temperature controlled storage units 54

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We will focus more on special cargo transportation for this year. We are planning to bring Turkish Cargo brand at a higher level with our ongoing efforts and so we can focus more on the 3rd airport, which is planned to be the world's biggest airport.

are then transported from storage and enplaned before take-off.

Turkish Cargo’s pharmaceutical logistics are prepared specifically in order to protect the contents and prevent them from deterioration. All medical pharmaceutical and healthcare products requests made to Turkish Airlines verbally or on paper, are handled by our offices, agencies abroad and Cargo Reservation Department.

In the acceptance stage, cargoes are examined and categorised by our Cargo

& Document Acceptance Unit, according to their destinations, types, weight, amount and size. At the acceptance stage, all transportation of pharmaceutical and healthcare products are executed in accordance with the IATA Acceptance Checklist. At the reservation stage, the shipments are assessed for safety, portability and packaging in accordance with aircraft type, country regulations, , international regulations, IATA regulations and IATA Airport Handling Handbook. Later, the cargo that passes these assessments are accepted through special delivery doors dedicated to medical supply shipments and located close to X-ray scanners.

The preparations of flights departing from Turkey are performed on the basis of Preparation Manifest obtained from Cargo Operation System including the cargoes of relevant flight.

Pharmaceutical shipments must be displayed with codes on the manifest. For preparation at international stations, location of pharmaceuticals

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shipments specified in the manifest is determined and after shipments are received from the relevant locations, they are included in Bulk loading or ULD loading. If requested by consignor, temperature of temperature sensitive pharmaceuticals are preserved and they are protected from outside temperature fluctuations in line with Instruction on the Use of Thermal Blankets.

Moreover, with our partnership with active temperature controlled container providers we are able to prevent our cargoes from being exposed to often changing temperatures during flights.

Working together with active temperature controlled container Envirotainer and by using their solution, constant and required temperature throughout the entire cold chain is maintained, even to long-distance destinations. Thanks to the agreements we made with international container suppliers, we can provide shipments between -20°C and +25°C at the requested conditions and capacity. With our data entry log, we also report to our customers about the changes in temperature of their shipments during the whole transportation process. Envirotainer active container demands of our customers are assessed by our expert teams in our Special Cargo Directorate. On request, our containers are installed with a temperature setting by our certified experts and delivered to our clients ready to be loaded to the plane. After the acceptance of the container, it is carried into the active container storage area at our facility. The temperature and battery charge is monitored in designated periods according to instructions given in Container Regulations. The temperature and battery charge of the container is constantly monitored until its delivery to the recipient. To this end, we’ll continue to carry out related training and certification programs to equip our employees and business partners with the knowledge and competence on this project.

Turkish Cargo built local pharma handling expertise and a pharma

mindset training the employees on pharmaceutical handling. All Turkish Cargo staff that are involved in the transporting of cargoes, participate in international and in-house training and certification programs. These trainings are carried out in accordance with the regulations established by the Directorate General of Civil Aviation And standards specified in the IATA Airport Handling Manual. In addition to these trainings provided by related companies, we also provide refresher trainings. For instance, standard operating procedures checks on correct use of IATA pharma label, use of IATA pharma acceptance checklist, service providers

implementing pharma specific SOP’s and dedicated pharma handling.

We started providing thermal dolly service, which is an active temperature controlled dolly used for the transportation of temperature sensitive cargo in between temperature controlled rooms and aircraft, and we will be planning to expand this service through 2017. Furthermore, along with these improvements we are planning to launch new products for pharmaceuticals shipments in 2017.

Turkish Cargo will continue to provide technology-driven logistics solutions to individual customers and major corporations.

A u t h o r BIO

Şeref Kazancı who was born in Istanbul in 1979, was graduated from Istanbul University, after which he started his career in the industrial production sector.

Later, in 2011, he continued his career at Turkish Ground Services, one of the Turkish Airlines’ affiliate, as purchasing supervisor and later assumed the role of purchasing manager. In the early 2016, Kazancı joined Turkish Cargo, the cargo subdivision of Turkish Airlines, as Vice President and on September 2016 he assumed his new role as Senior Vice President of Turkish Cargo.

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The Impact of Implementing Safety Features in Pharmaceutical Packaging and Labelling This article explains what labelling and packaging measures should the manufacturers need to implement and how effectively they can do so with advanced packaging technologies to ensure the patient safety. Besides, it explains how it is going to impact on the outcomes of pharmaceutical companies and the need of an optimally designed labelling solution to meet the Regulatory needs without failure. Decode the end-to-end coverage of packaging and labelling safety features to be implemented.

Sathyanarayanan Krishnamurthy, VP Regulatory Operations, Freyr, India

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very year, over millions of dollars are being spent to develop drugs that not only provide the required patient treatment but are also safe for human consumption in a set of forms.

With huge investments put-in, at the stage of manufacturing, are companies set to take up equivalent responsibility in following safety standards while marketing them? Several mislabelling and mispackaged instances suggest a big NO. There were instances that confirm poorly worded, unclear or ambiguously presented information of a drug has led to adverse reactions, and critically unfortunate incidents.

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To cite a few cases: long ago, a soothing syrup meant for infants had been marketed without prominently labelling ‘morphine,’ led to numerous untoward incidents; the year 1982 saw another major series of incidents in Chicago due to drug tampering; similarly, in the year 2009, a renowned biopharmaceutical company had to recall a staggering number of its products in the US because it was not adhered to child-resistant packaging that met legal requirements. There have been several product recalls in the recent past due to labelling errors. One recall was initiated by a manufacturer of blood

glucose test strips, wherein a labelling error omitted the strips’ model number.

The omission led to the use of these test strips in the wrong glucose meter which resulted to showcase incorrect results. Another renowned organisation voluntarily recalled a mislabeled lot of its injectable anti-seizure medication following confirmed reports of particulate found in a single unit, that could severely harm patients.

Thus, even when the ever-increasing legislative demands for patient information on pharmaceutical labelling often poses a packaging challenge to both manufacturers and brand-owners, patient compliance is increasingly gaining enough importance beyond functional requirements and fulfilling legal obligations. The annual cost to non-adherence in the US healthcare system alone is close to a whopping

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US$100 billion, and there is an even greater responsibility on manufacturers to ensure that drug usage information is presented to the patient in a manner that is easy to understand and easy to refer to, not just when the drug is first used, but throughout the course of time. Fortunately, manufacturers and brand-owners are becoming increasingly aware of the importance of labelling on healthcare products referring to the success rate of a drug.

Today, in most cases, the on-pack information seems to have a direct connection with the patient, helping improve user appeal, and most importantly impacting the direct effect on patient outcomes. Considering the enormous cost of developing, testing and launching an innovative drug in the market, using cheap and potentially less effective packaging that not only

risks patient safety, but also questions the efficacy of the drug is not the right approach. With more scope for impactful labelling and packaging techniques than ever before, the growing realisation is that a given drug is only as efficient as the usage information conveyed to the patient. This has resulted in a massive change in the mindsets of brand-owners and manufacturers who recognise the need for clearly-presented, easy-to-follow labelling and packaging measures that is conducive to positive patient outcomes.

Some of them could be: Types of safety measures for labelling

Even when strict guidelines are in place to ensure that the pharmacist provides the respective patient with accurate strength and quantity of a prescribed drug, under most circum-

stances it is extremely difficult to rest assured that the patient would adhere to the prescribed course. For this reason alone, it is imperative that the guidelines within the labelling make clear the imperative side effects due to incorrect dosage, among several other instructions. Cited below are some of the types of safety labelling measures undertaken by pharmaceutical companies to ensure maximum patient health safety. • Boxed Warnings: A boxed warning consists of a summary of the information that is key for a prescriber to consider, including any restriction on distribution or use. Typically, there is a more detailed discussion of the risk elsewhere in the labelling that must be identified by a cross-reference • Contraindications: These refer to situations in which the medication should not be used. A drug should www.pharmafocusasia.com

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be contraindicated in those clinical situations for which the risk from use clearly outweighs any possible therapeutic benefit. These are not based on theoretical possibilities but on known hazards • Warnings & Precautions: It is intended to identify and describe a discrete set of adverse reactions and other potential safety hazards that are serious or are otherwise clinically significant because they have implications for prescribing decisions or for patient management • Adverse Reactions: This section lists all side effects observed in all studies of the drug and not just the dangerous side effects which are separately listed in 'Warnings’ section. Separate lists are required for adverse reactions identified from clinical trials and those identified from spontaneous reports after a drug has been marketed.

The impact of implementing safety measures

Having taken care of all the safety features to be incorporated with the packages and labels, there is going to be a huge impact on the outcomes for pharmaceutical companies. Right from streamlining procedural hiccups to reducing product recalls to saving costs to companies, safety best practices for packaging and labelling are set to be driving factors for pharma industry.

No scope for product recalls: With the information provided in an accurate manner adhering to HA standards and with products are packed with

Types of Packaging Safety Measures Effective package management is an increasingly critical capability for pharmaceutical companies. Not only does optimal packaging bring benefits to the patient, but also to nurses, pharmacists, doctors and manufacturers alike.

Proper packaging can reinforce brand preference, improve compliance, facilitate consumption, limit dosage errors and help prevent drug counterfeiting. Provided below are measures to ensure maximum patient safety: Unique identifier: A 2D data matrix code and human readable information which will be placed on medical products that can be scanned at fixed points along the supply chain. It comprises of a product code which allows the identification of at least the name of the medicine, the common name, the pharmaceutical form, the strength, the pack size, and the pack type; a serial number which is a numeric or alphanumeric sequence of a maximum of 20 characters randomly generated; a batch number; an expiry date Authenticity seals or tamper-evident labels: Packaging having an indicator or barrier to entry which, if breached or missing, should provide visible or audible evidence to consumers that tampering has occurred. Film wrappers, shrinkable seals and bands, breakable caps, tape seals, blister packs, etc. are few examples of tamper-evident labels Product authentication: Authentication features can be embedded either on the dose or on packaging of the medicines. These may be overt, covert or forensic features Anti-counterfeit measures: Another global challenge for this sector is the problem of product piracy. The worldwide trade in counterfeit medicines is a multi-million business that causes considerable loss for the pharmaceuticals industry and, more importantly, puts the health of numerous people at risk. The following are few measures undertaken jointly by the packaging and pharmaceuticals industry to prevent the distribution of counterfeit medicines • Holograms: Many major drug companies use holograms on at least some of their medicines in the form of labels, seals, hot-stamped patches, and blister-foils. The ability of the hologram to provide effective protection lies in the continuous innovation, invention, and evolution in holographic techniques that have succeeded in creating increasingly complex devices that are easily recognised yet difficult to copy accurately • Track & trace system: Another recent trend is the serialisation of holograms as part of systems that combine authentication with traceability. These systems link on-pack security devices with database management and field-tracking services. Manufacturers can tell where a pharmaceuticals consignment has been, where it is located, and where it is headed. This is particularly important in identifying the source and provenance of products.

• Synthetic DNA and laser codes or special printing inks invisible to the naked eye.

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The Challenges in Implementing Safety Features The global nature of the pharmaceutical industry, with manufacturing sites and markets all around, results in a constantly evolving regulatory landscape. New regulations emerging with increased pace call for frequent label and packaging changes. Moreover, entering new markets means accommodating new languages and country-specific rules.

To consistently meet regulatory compliance standards in terms of both labelling and packaging, an optimally designed labelling solution is the right resort. Pharmaceutical companies also require a solution that is standardised and centralised, to be more operationally efficient and saving on organisational costs, avoiding expensive mistakes, and ensuring that even the most remote facility follows governmental and industry, and health agency regulations, while also meeting overall internal branding standards.

Labelling and artwork pack management is perhaps one of the most challenging functions to be effectively handled, managed and run by most life sciences and Pharma companies. With touch points across most of the major divisions, the function requires implementing a robust Artwork Management System (AMS) that can scale and evolve at the same time to be effective with the growing needs of the pharma companies.

need to comply with the new improved regulations • The highly-debated FDA genericdrug labelling rule, which was due to be passed in mid-2016, has been further delayed and is now expected to be finalised in 2017. If the proposed rule is passed, generic-drug companies across the globe must strengthen their pharmacovigilance operations right from assessing safety signals to ensuring label compliance A u t h o r BIO

contaminant-free packages, companies can obtain approvals in minimal times making the drugs available in the market in quick TAT. Ensuring the patient safety standards are met through with resistance towards external influences like moisture, oxygen, biological contamination, adulteration, and mechanical damage, the quality of the pharmaceutical products maintained as is as in production thus striking off any untoward events and product recalls.

Not only the patient safety, but also the brand identity will be safeguarded with advanced pharmaceutical packaging technology like tamper-evident features and integrated capsule sealing technology. There will be no counterfeits and brand value will stay secured.

Referring to the labelling information, organisations must take care of the medicinal information put out through labels. The information provided on labels should not only ensure the safety and efficacy but should also be clear and accurate.

Emphasising the same, health authorities worldwide released many safety measure guidelines for labelling and packaging best practices which the manufacturers could consider for integrated patient safety and for successful compliance. Some of them include: • Health Canada has released a guidance document for Palin Language Labelling which came in effect from June 13, 2015, for Prescription drugs, and is expected to come in effect from June 13, 2017, for non-prescription drugs • Australian Government Department of Health, the Therapeutic Goods Administration (TGA) followed suit and announced new labelling requirements which went effective from 31st August 2016. With new labelling requirements for Australian Medicines coming after so many years, a four-year transition time has been given to be compliant with the improved standards. That suggests the sponsors will have enough time for transition and from 1 September 2020, their new medicine labels will

• To better protect children from serious risks, the FDA sought label changes for two types of opioid medications, codeine & tramadol with additional contraindications & warnings.

• The motto behind frequent labelling guidelines is to ensure labels should not only convey accurate drug information to the end user, but should also ensure drug safety by making the information easy to understand by the physician as well as patients.

Sathyanarayanan Krishnamurthy is a Regulatory Operations and Strategy specialist with experience across Regulatory Information Services, Packaging, Labelling, Life Cycle Management of Artwork Creation, Systems and Tools implementation.

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Responding to the Needs of an Evolving Industry In the ever-evolving pharma market, pharmaceutical and medical manufacturers need to be experts in understanding the industry’s challenges and opportunities to meet their customers’ needs. To stay ahead, Datwyler identified three main topics for future development: future health care, patient safety and global leadership. A new health care offering and two new facilities in India and the US support the new strategy.

Dan Stefanoiu, Chief Business Officer, Datwyler, Switzerland

I

n today’s competitive healthcare market, pharmaceutical and medical manufacturers rely on partners with a deep understanding of not only the industry’s challenges and requirements, but also of its opportunities and promise for growth. The pharma market is everevolving and ever-changing. Companies have the responsibility to provide the appropriate answers to their clients to meet future challenges. Against this background, Datwyler has identified three main topics on top of its agenda: Shaping the future of healthcare, patient safety and global leadership are the foundation of the company’s road map.

New healthcare offering: Improving patients’ lives

Based on this agenda, Datwyler has introduced a new healthcare offering in March 2017 which consists of the three categories Bio Care, Pharma Care and Med Care to better meet customer needs and expectations. The solutions in the Bio Care category are specially developed and manufactured to address the needs of large molecule pharmaceuticals.

This applies particularly to highly 60

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sensitive drugs such as biosimilars or biologics for which barrier properties alone are no longer enough to meet the packaging needs of the most sensitive pharmaceuticals. Those drugs are at the risk of being rendered ineffective when in contact with extractables and leachables such as subvisible particles in silicone oils. The Pharma Care category is designed to overcome the challenges for small molecule drugs. The elastomer formulations, compounds and coatings offer maximum compatibility with any pharmaceutical, also mitigating silicone related risks as much as possible. The solutions of the Med Care category are designed for medical companies, providing them with highest quality products and eliminating potential regulatory issues. Enhanced machinability and high productivity rates as well as additional backup manufacturing sites ensure a maximum security of supply. Upon request, hydrophobic and hydrophilic silicone oil and chlorination are available as a final treatment, providing medical companies with further options to customize the product they need.

Introducing First Line in key healthcare markets

In an ever-evolving pharma market and industry, quality standards are of the highest importance to meet the demands of the market and for a company to be a reliable partner to customers. The production standard First Line is dedicated to guaranteeing the highest levels of quality and safety for pharmaceutical rubber components. The First Line production operates in a fully integrated Good Manufacturing Practice (GMP) environment using innovative automated processes and conforming to the highest industry standards. Each zone has been meticulously designed and constructed to prevent bio-contamination and is equipped with material airlocks. Stateof-the-art pass-through washing equipment has its automatic loading side in one zone and its automatic unloading side in a zone of even higher cleanliness.

The new clean room also incorporates the latest generation of camera inspection techniques. The entire facility as a whole incorporates rational and lean production flows in accordance with the Six Sigma methodology. The First Line manufacturing concept exceeds the most stringent quality standards of regulatory authorities and is certified to ISO 15378. It is designed to operate under a zero-defect philosophy. The process flow, gowning protocols, personnel and material flow, and state-of-the-art automation all result in the lowest endotoxin, bioburden, particulate, and defect levels available in the industry.

At present, Datwyler is building two additional facilities with First Line standard in the United States and India.

Manufacturing

India: the Hotbed of the Asian pharmaceutical market

India’s pharmaceutical and biotech markets continue to grow and evolve rapidly, catering to a global customer base. The country is also being recognized as one of the global manufacturing destinations. India counts the most FDA approved pharmaceutical production facilities in the world after the USA. Manufacturers that provide safe and effective solutions are an integral part of the country’s path towards growing further into a worldwide aligned successful industry.

In the Indian market, Datwyler is presently focusing on high-end rubber formulations for products like plunger stoppers, Lyo, serum and customised rubber stoppers. Thanks to the introducing of the First Line manufacturing concept, the facility will be able to expand its portfolio by the innovative Omni Flex product line to meet the evolving needs in the healthcare market.

Within the parenteral packaging industry, market trends indicate a growing demand for fluoropolymer coated elastomeric closures, primarily to mitigate risks related to drug stability and compatibility. For a therapeutic protein, the exact chemical make-up and three-dimensional conformation can influence the efficacy of the drug product. Interactions with

leachables, including silicon oil, can present a risk to the safety of therapeutic proteins. Conformational changes, degradation and/or aggregation can lead to the inefficacy or Test immunogenicity of the protein, ultimately impeding or preventing the success of the drug product. Therefore, many manufacturers of biologics or biosimilars are already relying on fluoropolymer coated closure solutions today.

Omni Flex fluoropolymer coated closures not only have barrier properties which enable superior chemical compatibility, but also have the added benefit of eliminating the closure as a source of silicone-oil-based Subvisible Particles (SbVPs). The coating is formed in a two step process. First, the proprietary fluoropolymer film is applied by a tumble spray coating, and second, a post-treatment process provides sufficient thermal energy to bond the coating covalently to the bromobutyl substrate and to form a smooth, continuous fluoropolymer film.

Thanks to the line-of-sight nature of the spray coating, the entire plunger surface is covered except for the interior of the plunger-rod cavity. The total coverage A u t h o r BIO

While Datwyler is a global industrial supplier to the healthcare industry, the company also relies on local expertise and facilities to cater to the respective markets. India as a substantial force in the global pharma market offers a perfect opportunity to introduce the First Line manufacturing standard to the global and local market. The new facility in Pune is the company’s commitment to India and the Asian market. Spread over an area of 24,000 m², the facility will be integrated in the existing premise and will start to operate in September 2017.

Currently, 290 employees are working in the facility, but staff numbers will rise to a total of 350 employees by the time production starts.

by the Omni Flex coating stands in contrast with the partial coverage of most film coatings and therefore offers the benefit of providing a complete barrier. The total coverage of the fixed lubricious coating also eliminates the need for siliconisation of the plunger rills. This eliminates the largest source of subvisible particles and allows Omni Flex coated plungers’ particle levels to be some of the lowest in the industry. In combination with the optimised product design, the elimination of siliconisation results in glide forces for Omni Flex products which are highly consistent down the length of the barrel and from plunger to plunger. Furthermore, the spray-coating process easily lends itself to coating custom designs for innovative drug delivery devices.

The plant in Pune has been delivering commercial supplies to customers worldwide since 2013, including exports to Europe, the USA and South East Asia. However, Datwyler also has a significant market share in India and has been supplying Indian customers from their global plants for the last 20 years.

Currently, the company is catering to more than 50 customers in India.

Dan Stefanoiu, as a member of the Executive Management, is in charge of global business and customer relations for the Datwyler Sealing Solutions Division. He joined the Division in April 2016.

Before joining the Datwyler Group, Dan acted as Director of Sales and Business Development for Dana Corporation. Dan earned a master of engineering degree from the Polytechnical Institute of Bucharest and completed further management studies.

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Experttalk

The Asian Healthcare Market

Rapid growth and accompanying increasing regulations lead to the need for serialisation The Asian market is growing rapidly, and along with this expansion comes the issue of drug counterfeiting. Bernd offers his insight into the key trends affecting this market and what regulatory authorities are expecting manufacturers to do to combat this dangerous and costly problem.

Bernd Stauss, Senior Vice President Production/Engineering, Vetter, Germany

1.Can you briefly inform us what your company does and what its service portfolio offers?

Vetter is an independent, globally operating Contract Development and Manufacturing Organisation (CDMO).

As a solution provider to the pharmaceutical and biotech industry, we specialise in the development, aseptic manufacturing and final packaging of prefilled syringes, cartridges, and vials.

Our facilities, located in Europe and the US provide support for early stage drug products with seamless transfer to our commercial manufacturing operations for large-scale production.

As a CDMO being in business for more than 35 years, we have extensive experience in working with biologics and other complex compounds including monoclonal antibodies, peptides, interferons, and vaccines. As a full-service provider with approximately 4,100 employees, we offer support to our customer’s products throughout their lifecycles from preclinical development through global

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market supply. Our in-depth knowledge in development, clinical trial manufacturing, commercial production, lyophilisation, visual inspection, packaging and labelling technologies, provide our customers with a strategic partnership that can accelerate a compound’s success.

2.How important is the Asian pharma and biotech market in general and especially for Vetter?

The Asian healthcare market is one of the fastest growing markets worldwide.

As such, it offers significant potential for pharmaceutical and biotechnology companies requiring the services that a CDMO can offer. We have observed a distinct shift taking place both in the nature and manner of contract manufacturing in the region and how products are distributed. There are also strong efforts to enlarge the customer base for medicines manufactured within the Asia Pacific region (APAC) through distribution to customers outside of the APAC region.

Experttalk

If we are going to stay abreast of this market, and take advantage of its growth in the injectable drug market, we need to have an increased presence in this region.

Our response was to strengthen our global position by opening our first sales office in Singapore. We made this choice for a variety of reasons not the least of which is the fact that Singapore is considered a global biomedical sciences hub located in the heart of the APAC region. As such, many of the companies doing business in region are already key customers of Vetter. This makes the choice of the geographic location an easy one for us to make.

Our opening of the Japan office in 2015 further underscores the importance of Japan in particular and the APAC region in general to Vetter. It is important to note that Vetter has been working towards a presence in the Japanese market for many years and has been in the position to fill and package drugs for this market. The growth of the Japanese market is expected to further increase due, in part, to the reforms implemented in 2010. In summation, our increased Asian on-site presence underlines the importance of the APAC region for Vetter’s business activities.

3.Are there any market trends or regulatory challenges which are of high importance for your business?

There are, and will always be, new trends and regulations occurring within the (bio-) pharmaceutical industry. One concerning trend that is affecting the industry as a whole and consequently also our company is drug counterfeiting. This has been a worldwide issue for decades and continues to grow unabated for a variety of reasons including internet sales, unsecured supply chains and minimal punishments. Most importantly, drug counterfeiting puts patient’s lives at risk.

For these reasons, regulatory agencies have been seeking and implementing new methods to thwart drug counterfeiters. Serialisation of packaging, which

Due to the importance of eliminating drug counterfeiting, serialisation is already common across most adopted regulations, Which means that by 2019 the majority of the global drug supply will essentially fall under some form of serialisation requirement.

relies on a clear means of authentication and traceability, is today considered to be one of the most popular solutions by many countries.

4.Can you give us greater insight into the important issue of serialisation?

Serialisation involves the process of assigning and applying a unique identification code to a product. The formats of serial number vary widely from global standards to unique versions e.g. in China and Brazil.

The industry uses the term ‘aggregation’ to define the relationship between multiple items within a product shipment, such as cartons, cases, and pallets.

Together, serialisation and aggregation form the foundation of ‘Track-and-Trace’ which can document a product’s current and past locations throughout the supply chain. This ability to track a product’s whereabouts and trace its path is the start of a safer and more efficient drug supply chain.

5. How would you describe the current situation regarding the regulations for serialisation?

In 2017, agencies from many countries will be tightening their guidelines in order to fight drug counterfeiting and are relying on serialisation to do so. In some countries like Turkey, India and Argentina,

regulators are already demanding that drugs be serialised. The European Union will do so in February 2019. The US Food and Drug Administration (FDA) will make serialisation of drugs a requirement beginning November 2017. Drugs will be given a Global Trade Item Number (GTIN) including the National Drug Code (NDC), a serial number, a batch number, and an expiration date. Because serialisation requirements differ among countries, pharmaceutical and biotech companies must find flexible solutions that can easily adapt to the demands of individual regulatory authorities.

6. How is Vetter preparing for serialisation regulations?

Vetter has been preparing for new regulations for quite some time. In fact, back in 2012 prior to official regulatory guidelines, we established the basis for a serialisation program by doing an initial concept study. We began with a systematic process to evaluate aspects such as: what lines were essential to be upgraded, which suppliers we could work with, the costs involved, and the identification of staff members that should be included as part of the project team. After careful analysis and thoroughly answering of these questions we started our serialisation approach. As part of this project we upgraded our systems and implemented our first pilot line. Today, we are compliant with serialisation requirements for different markets and systematically upgrade further lines.

7.Does Vetter have experience with the implementation of customer projects that involve serialisation?

Because we started preparing for serialisation regulations as early as five years ago, we have been in compliance with serialisation requirements for many markets for quite some time. In 2014, we successfully implemented our IT-solution, and that same year we also announced significant progress in our state-of-the-art engineering solution.

After these solutions were implemented, Vetter began offering its customers a

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Experttalk

range of serialisation services designed to support the prevention of product counterfeiting. In 2015, we reported the first commercial batches for South Korea with single-use identification numbers for one of the world’s leading pharmaceutical companies. We continue to work on and prepare for serialisation requirements in the US scheduled for later this year, and the European Union in February 2019. Additionally, we have already implemented serialisation for other regions of the world such as China, Brazil, Columbia and the Netherlands.

8. It is very interesting, that your first serialisation project was for the Asian market. Which APAC regions already have serialisation requirements and what are the timelines for future regulations of Asian authorities?

Due to the importance of eliminating drug counterfeiting to protect the safety of patients and ensure product integrity, serialisation is already common across most adopted regulations. This means that by 2019 the majority of the global drug supply will essentially fall under some form of serialisation requirement.

India has already implemented serialisation for products manufactured within

Bernd Stauss was appointed as Senior Vice President Production/Engineering for Vetter in 2014. In this position he is responsible for all Production at Vetter sites as well as Engineering, Technical project management and Technical Services/EHS. Mr. Stauss joined Vetter, a leading contract development and manufacturing organisation (CDMO), in 1994 as a Manager for Validation. He later moved to Vetter’s Langenargen Plant in 1996 as a Manager of Engineering, and in 2002 was elevated to Head of Production/Engineering. In 2003, Mr. Stauss was promoted to the position of Vice President Engineering and in 2007, Vice President Production/Engineering.

Mr. Stauss earned his MBA in Business Administration from the University Ludwigsburg in 1989, and a MBA in Pharmaceutical Engineering in 1994 from University Sigmaringen, Germany.

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that country. Other APAC countries with implemented serialisation guidelines are China and South Korea. In South Korea, serialisation requirements have been in place since 2016 and cover 100 per cent of pharmaceutical drug products. The current law now requires companies to serialise drug products. In China, any drug products that are on the Essential Drug List (EDL) must already be serialised. This requirement follows unique requirements in that country for serial number acquisition, serial number and product data formatting, and barcode labelling. It was originally intended that all drug products had to be serialised by the end of 2015. However, China has placed a hold on their serialisation regulation due to difficulties in implementation.

9.What effects do changes in regulatory timelines such as in China have on the development of the serialisation program at Vetter? What is Vetter doing to anticipate and meet the future demands of international serialisation regulations?

The problem of drug counterfeiting is a danger to the industry and patients alike and continues to grow. As previously

noted, Vetter has been in the position to support customer and regulatory serialisation demands since quite some time. We already have implemented an IT solution to support serialisation and lines to print and encode serialisation data on packages, as well as the ability to manufacture products that are serialised according to the latest regulatory guidelines. We prepare early in the process, creating partnerships and working as closely as possible with our customers to help ensure that regulatory requirements can be fulfilled according to the defined timeline of the regulatory authority. The investment into serialisation solutions is crucial for the safety of the patient, the integrity of our customer’s products, and to Vetter in its role as a leading CDMO. As such, we will continue to invest in future-oriented techniques and approaches, such as our serialisation program.

10. What are the main aspects Vetter must consider when realizing a successful serialisation project for your customers?

As noted, Vetter takes serialisation seriously and, as such, has a well-defined strategy. For example, we created the position of a Serialisation Process Manager. This function is responsible for certifying that all future requirements arising from different relevant markets will be successfully implemented. We also created a cross-functional team that includes members from departments such as IT, Product and Service Management, Regulatory Affairs, Project Management, Engineering, and Supply Chain. Each member of the team has a strong working knowledge of serialisation, and we continue to make every effort to remain abreast of any new regulatory requirements by building upon the knowledge we have gained in the process.

For our customers it is important that we keep their needs in mind, combining the regulatory requirements with their specific ones. The goal is to be as flexible as possible to implement all regulatory and customer requirements alike.

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Experttalk

Pharmacogenomics Saleem Mohammed, Founder & CEO, Xcode Life Sciences, India Abdur Rub, Co-founder, Xcode Life Sciences, India

What do you think are currently the landmark achievements in pharmacogenomics?

In his 2015 State of the Union address, US President Barack Obama announced the Precision Medicine Initiative. Its “to enable a new era of medicine through research, technology, and policies that empower patients, researchers, and providers to work together toward development of individualised care.�

This was a major initiative undertaken by the White House to bring precision

medicine into clinics. Several other major initiatives are underway to make precision medicine a reality. Currently, more than 150 US FDA approved drugs carry pharmacogenomic information in their labelling. Genomics is now being included in many early stage clinical trials. These developments coupled with the rapidly falling cost of genetic testing are tilting the cost-benefit scales in favour of routine and preemptive pharmacogenetic testing at least in higher age brackets to begin with.

Saleem Mohammed completed his PhD in Bioinformatics from the US and moved back to India to pursue his dream of pioneering in the field of biotechnology. He founded Xcode with a vision to bring India in the forefront of personal genomics. Previously, he worked as a Scientist in Gene Expression Technology at Monsanto, a biotechnology giant.

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What is Pharmacogenomics testing?

Pharmacogenomics (PGx) testing is a genetic assessment carried out to determine whether an individual is a poor, normal or extensive metaboliser of a certain drug. Depending upon the metaboliser status, the physician may prescribe the standard dosage, or adjust dosage or prescribe an alternative drug.

This is in contrast to standard practice of trial and error, where, first the standard dose is prescribed followed by an assessment of whether this dose and drug is effective or not and repeating the process as many times as necessary to get to the optimum dose of the right drug. The current practice of trial and error is a massive drain on healthcare resources at the individual and national level. The objective of pharmacogenetic testing is to give the right drug, to the right patient at the right dose without trial and error. Often PGX is combined with parameters such as drug-drug and drug-food interactions to make it highly effective.

Which individuals might benefit from Pharmacogenomics testing?

Almost all individuals, regardless of age group are prescribed drugs for incidental, chronic and acute medical conditions throughout life. Many commonly prescribed drugs such as pain, allergy and other drugs have PGx information available for them. From this perspective, getting a one-time, low-cost PGX assessment done that has a life long utility can be considered useful. Having this information in advance empowers the physician to prescribe the right medication at the right dosage.

Experttalk

Risks Genetics is one of the factors influencing drug safety and efficacy. So, a physician should also consider other factors such as age, gender, and weight that may influence response to a drug.

Abdur Rub holds a Masters in Engineering from University of Cincinnati and a PhD in Biomedical Sciences from the University of South Florida (USF), USA. He has co-authored over 25 journal papers and has over 50 international conference proceedings in a variety of scientific disciplines.

His main scientific contributions are in the areas of in vitro diagnostics, genetic sequencing and gene amplification technologies.

Pharmacogenomics testing becomes even more important for those patients who are on multiple medications, patients whose current prescriptions are not working, patients who are on complex drug treatment plans, patients who have previously experienced adverse drug reactions to medications, and those prescribed any of the more than 100 FDA-approved drugs where pharmacogenetics information is included in black box warning including the following: Plavix® (clopidogrel), Coumadin® (warfarin), Strattera® (atomoxetine), Lopressor® / Toprol® (metoprolol).

What are the possible test results?

The degree of responsiveness to a drug depends upon the genetic variations present in the patient, resulting in four possible categories that affect drug metabolism and consequently clinical outcome i.e., response and toxicity. These categories include:

• Ultrarapid metaboliser - Standard or Dose adjustment recommended • Extensive or Normal metaboliser Standard dose recommended • Intermediate metaboliser - Dose adjustment recommended • Poor metaboliser - Alternate drug recommended.

In addition to genetic variations, age, gender, disease, etc. also play a vital role in the body’s response towards a drug.

What are the potential benefits and risks for the patient?

Benefits • It improves patient safety by identifying patients at risk for adverse drug reactions • It reduces healthcare costs and improves drug efficiency • It helps in finding appropriate medications and doses more quickly.

What, in your opinion, are some of the major challenges to personalised treatment?

The science of targeted therapies, also referred to as personalised or stratified medicine, has the following challenges: • Limited awareness among patients and medical community • Time taken to deliver results; pointof-care testing is critical in some emergency cases • Treating genetics as a standalone diagnostic tool. A comprehensive assessment of drug-drug, drug-gene, and drug-food interactions needs to be part of the prescription process • Inconsistent standards for evaluating diagnostic and predictive genomic tests • Lack of ethical and regulatory guidelines, and lack of incentives for genomic medicine.

What are the most significant risks or issues that are involved in the incorporation of pharmacogenetics into clinical research or clinical care?

Despite the numerous benefits precision medicine has to offer to medical practice, there are barriers or issues that must be overcome for their integration into clinical practice or research.

• The knowledge gap of professionals • The lack of decision support systems integrated with clinical data • Lack of international collaboration • Study design limitation • Regulatory and ethical concerns • Ethnicity and influence of non-genetic factors • Lack of standardisation and guidelines for test implementation.

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Products & Services Company.........................................................Page No.

Company.........................................................Page No.

STRATEGY CPhI China.............................................................. 09, 13

F.P.S. Food and Pharma Systems Srl........................... 15

DDF Summit.................................................................. 41

Vonlanthen Conferences.............................................. 23

EU Pharmaceutical Law Forum.................................... 25 F.P.S. Food and Pharma Systems Srl........................... 15 Messe Duesseldorf Asia........................................ 17 - 19 NLSDays 2017.............................................................. 43 Siegfried AG.................................................................. 11 Vonlanthen Conferences.............................................. 23 World Courier.............................................................. IBC RESEARCH & DEVELOPMENT Bachem AG............................................................. 03, 27

MANUFACTURING Bachem AG............................................................. 03, 27 Bosch.......................................................................... IFC Cantel Medical.............................................................. 49 Chemspeed Technologies............................................ 31 DDF Summit.................................................................. 41 EnviroChemie GmbH...................................... 35 – 37, 50 NLSDays 2017.............................................................. 43 Siegfried AG.................................................................. 11

EnviroChemie GmbH...................................... 35 – 37, 50

Turkish Cargo................................................. OBC, 52-55

Eppendorf AG............................................................... 33

UPM Raflatac......................................................... 44 - 45

EU Pharmaceutical Law Forum.................................... 25

Vetter Pharma................................................. 05, 62 - 64

Suppliers Guide Company.........................................................Page No.

Company.........................................................Page No.

Bachem AG.......................................................03, 27 www.bachem.com

F.P.S. Food and Pharma Systems Srl.....................15 www.foodpharmasystems.com

Bosch.................................................................... IFC www.boschpackaging.com

Messe Duesseldorf Asia................................. 17 - 19 www.medicalfair-thailand.com

Cantel Medical........................................................49 www.mcpur.com

NLSDays 2017........................................................43 www.nlsdays.com

Chemspeed Technologies......................................31 www.chemspeed.com

Siegfried AG............................................................11 www.siegfried.ch

CPhI China........................................................09, 13 www.cphi.com/china

Turkish Cargo...........................................OBC, 52-55 www.turkishcargo.com

DDF Summit............................................................41 www.ddfsummit.com

UPM Raflatac.................................................. 44 - 45 www.upmraflatac.com

EnviroChemie GmbH................................35 – 37, 50 www.envirochemie.com

Vetter Pharma.......................................... 05, 62 - 64 www.vetter-pharma.com

Eppendorf AG.........................................................33 www.eppendorf.com

Vonlanthen Conferences........................................23 www.vonlanthengroup.com

EU Pharmaceutical Law Forum..............................25 https://lifesciences.knect365.com/pharmalaw/

World Courier........................................................IBC www.worldcourier.com

To receive more information on products & services advertised in this issue, please fill up the "Info Request Form" provided with the magazine and fax it, or fill it online at www.pharmafocusasia.com by clicking "Request Client Info" link.

1.IFC: Inside Front Cover 2.IBC: Inside Back Cove 3.OBC: Outside Back Cover

“The interview titled "Biotechnology A solution or a problem" published in Pharma Focus Asia, Issue 22, July 2015, was erroneously mentioned as 'Advertorial'. Misprint regretted. Appreciate your patience”.

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