Pharma Focus Asia - Issue 11

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Biosimilars taking shape

Biosimilars Succeeding in the market of the future

Global Biogenerics Market Opportunities and Challenges

How Similar are Biosimilars in India?

A blind comparative study

Foreword Biosimilars

A new era in biotech “Biosimilars will eventually bring down the cost of biological medicines and in doing so will expand the market”, Cecil Nick, Principal Consultant, PAREXEL Consulting, UK.

T

he era of generics is all set to hit the biotech industry. Not so long back, the fledgling industry for biosimilars was threatening to not take off due to the lack of proper ground work of regulations. But the strengthening regulatory framework for biosimilars, especially in Europe­—with USA expected to follow suit—might have given biosimilars a fresh lease of life. This is very good news for the industry.

Under the new regulations, biosimilars will undergo an extended procedure for authorisation. However, apart from safety issues and extended post-approval surveillance, similarity of biosimilars when compared with original brands remains the biggest challenge.

In Europe, a specially-adapted approval procedure had been authorised and the first biosimilar was approved back in April 2006. This, however, was an exception as there was a lack of consensus on several issues.

Similarly, unending debates and arguments made things even slower in the USA. The rise of biosimilars is particularly interesting in the Asian context. It is said that depending on legislation, companies in India and China will be able to produce their own versions with 30 per cent lower prices than the originals. This has made Indian and Chinese bitoechs targets for acquisition. Recent news about GSK looking to acquire a stake in Shantha Biotech is being a case in point.

After initial reservations, it is now clear that physicians are gradually getting positive about prescribing biosimilars. Though the argument regarding International Non-proprietary Names (INN) and interchangeability of the products with different INNs remains unresolved, the interest in biosimilars has grown steadily.

Though biopharmaceuticals are considered to be more effective they are also more expensive. Their high prices have played a crucial role in them lagging behind molecule-based drugs. With low cost biosimilars, this situation will change. No wonder then that biopharmaceuticals have been outperforming the market.

Despite opposition from originator companies and delays by the US FDA, the European market continues to grow and biosimilars market is on the threshold of rapid expansion and represents one of the most evolving areas in the biopharmaceutical industry. According to IMS data, the value of generic companies in the biopharmaceutical industry was US$ 85.9 billion in 2007 and is estimated to exceed US$ 135 billion by 2011.

The cover story in this issue of Pharma Focus Asia features three articles with valuable insights from Mateja Urlep, CEO and Founder of TikhePharma, Salah Ahmed, President & CEO at Abon Pharmaceuticals, LLC., Venkatesh Nani, Director for R&D at Barr Laboratories, Rustom Mody, Director for Quality Control Dept at Intas Biopharmaceuticals Limited, Vishakha Goradia, Senior Executive at Intas Biopharmaceuticals Limited, Deepak Gupta, Head of Analytical Quality Control at Intas Biopharmaceuticals Limited. These three articles talk about the importance of biogenerics and differences in biosimilars compared to original brands, opportunities and challenges involved in biosimilars and the future market of biosimilars.

Sujay J Shetty, Associate Director of Pharma Life Sciences Advisory at PriceWaterhouseCoopers and Ganesh Nayak, Executive Director at Zydus Cadila talk about the M&A and Partnerships scenario in India. We also feature challenges in handling of counterfeiting medicines, pharmaceutical theft and dangers of the internet.

Prasanthi Potluri Editor

Contents Research & Development 22 Novel Genetic Vaccines Rational design and standardised evaluation David Klatzmann, Pitié-Salpêtrière Hospital, France

24 Evaluating drug solubility in lipid-based delivery systems Shirlynn Chen, Boehringer Ingelheim Pharm. Inc, USA

32 Biosimilars

Succeeding in the market of the future

Mateja Urlep, TikhePharma, Slovenia

35 Global Biogenerics Market

Opportunities and Challenges

Salah U Ahmed, Abon Pharmaceuticals, LLC. USA Venkatesh Naini, Barr Laboratories, USA

40 How Similar are Biosimilars in India?

A blind comparative study

Rustom Mody, Vishakha Goradia, Deepak Gupta, Intas Biopharmaceuticals Limited, India

28 Can Genomics Provide Blockbuster Drugs in Defiance of ‘Personalised Medicine’?

David W Moskowitz, GenoMed, Inc., USA

Manufacturing 50 The Freeze Drying of Biologicals Recent trends Paul Matejtschuk, Potters Bar, Hertfordshire, UK

58 M&A and Partnerships in Pharma Rising opportunities Sujay J Shetty, PricewaterhouseCoopers, India

60 M&A and Partnerships in Pharma Indian scenario Ganesh Nayak, Zydus Cadila, India

Strategy

04 Rethinking R&D Novel approach to partnering Barbara Yanni, Merck & Co., Inc. USA Jing-Shan Hu, Merck Sharp & Dohme (China) Ltd., China

07 Shaping the Future of Drug Development & Marketing Strategies Payer perspectives Elizabeth L Bewley, Pario Health Institute, USA

12 Twenty-first Century Crime Counterfeit, illegally diverted and stolen pharmaceuticals Thomas T Kubic, Pharmaceutical Security Institute, USA

16 Personalised Genetic Diagnostics Warrants global expansion Dean Sproles, Iverson Genetic Diagnostics, Inc., USA

18 Next Generation Pharmacovigilance For enhanced patient safety John D Balian, Amrit Ray, Andres Gomez, Bristol-Myers Squibb, USA

Clinical trials 62 Managing a Major eCTD Filing An Amgen case study Bryan M Noel, Amgen, USA

Information technology 66 Regulatory Information Management Leveraging standards and efficiencies of eCTDs Donald Palmer, Regulatory Systems Group, USA

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Advisory Board

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

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

Editors Prasanthi Potluri Akhil Tandulwadikar Art Director M A Hannan Senior Designer Ayodhya Pendem Sales Manager Rajkiran Boda

Douglas Meyer Senior Director, Aptuit Informatics Inc., USA

Frank A Jaeger Director, New Business Development Solvay Pharmaceuticals, Inc., USA

Sales Associates Kunal Ahuja Murali Manohar John Milton Amreen Fatema Annie Jones Assistant Manager – Compliance P Bhavani Prasad CRM Yahiya Sultan

Georg C Terstappen Chief Scientific Officer, Siena Biotech S.p.A., Italy

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

Laurence Flint Associate Director, Clinical Research Schering-Plough Research Institute, USA

Neil J Campbell CEO, Mosaigen Inc. and Partner Endeavour Capital Asia Ltd., USA

Subscriptions incharge Vijay Gaddam IT Team Ifthakhar Mohammed Azeemuddin Mohammed Sankar Kodali Thirupathi Botla N Saritha Chief Executive Officer Vijay Chintamaneni Managing Director Ashok Nair

Pharma Focus Asia is published by

A member of

Confederation of Indian Industry

Phil Kaminsky Founder, Center for Biopharmaceutical Operations University of California, Berkeley, USA

Rustom Mody Director, Quality and Strategic Research Intas Biopharmaceuticals Limited, India

Sanjoy Ray Director, Technology Innovation Merck Research Laboratories, USA

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Sasikant Mishra Business, Policy and Network Strategist Pharmaceutical Industry, India

Strategy

Rethinking R&D

Novel approach to partnering

With a decrease in R&D productivity, increase in the cost of late-phase drug development and a greater competition for licensing opportunities, the stakes are high for the major players in the pharmaceutical industry.

Barbara Yanni

Vice President and Chief Licensing Officer Merck & Co., Inc., USA

Jing-Shan Hu

Director Worldwide Licensing & External Research Merck Sharp & Dohme (China) Ltd. China

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ISSUE - 11 2009

Strategy

L

ike the majority of industries in today’s economy, the pharmaceutical industry faces a range of business challenges. The number of new drug approvals in 2007 was the lowest in almost a quarter-century and 2008 was only slightly higher. A continuing increase in patent expirations would result in a projected US$ 50 billion loss in revenue by 2011.

With a decrease in R&D productivity, increase in the cost of late-phase drug development and a greater competition for licensing opportunities, the stakes are high for the major players in the pharmaceutical industry. While Merck is optimistic—three new product FDA filings are anticipated this year with nine Phase III programmes continuing

(including one product being developed by the Merck / Schering Plough joint venture)—we know that finding a gamewinning strategy that is innovative from both a scientific and business perspective is critical to our future success. We believe that the best way to address these challenges is through redefining our approach to drug discovery and development. Global collaborations are a key component of this new strategy.

The benefits of partnering are not new to Merck. For years we have recognised that biotechnology companies, smaller drug companies and universities are generating promising scientific leads. We have reached out to researchers all over the world in our quest for novel science. Our regional network of

worldwide licensing scientific experts are currently meeting with companies around the world to look at their discoveries—from early stage to late stage (Phase III)—that have the potential to address unmet medical needs.

In the last five years, Merck has entered into approximately 250 significant new alliances. In 2008, approximately 65 per cent of our revenue was derived from our alliance products and patents . GARDASIL™, a cervical cancer vaccine that helps guard against four types of HPV, is just one example of what happens when we combine our innovation and expertise with that of our partners.

External Basic Research – Embracing partnerships

A key element of Merck’s global research strategy is External Basic Research (EBR), a newly created research team that was formed last year to focus explicitly on external sources of science and innovation. EBR’s mission is to develop and implement a strategy to expand the scope and size of Merck’s early pipeline with science from multiple sources. The group has already developed an impressive portfolio of external partnerships and is delivering compounds for the Merck pipeline. EBR is an integral part of the basic research team within Merck Research Laboratories (MRL) and is aligned with MRL franchise strategies and pipeline priorities.

Headed by Dr. Catherine Strader, EBR comprises a team of senior and accomplished Merck scientists who are focussed on external science. Together they are developing close long-term strategic relationships with Merck’s collaborators. Each day, EBR scientists work with our partners to address strategic and tactical issues and move the collaborations towards our shared goals.

Through EBR, our partners are linked to Merck’s strong internal science Total includes 50 per cent of JV revenue for MSP, Merial, Sanofi-Pasteur and J&J/Merck

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Strategy

At Merck, approximately 250 significant alliances have been formed over the past five years 60

# of alliances formed

50

47

53

50 44

55 46

38

40 30 22

23

20 10 0

10

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 Figure 1

base and have access to all appropriate MRL resources across all therapeutic and technology areas. The EBR team applies Merck’s industry-leading drug development expertise to ensure that drug candidates are IND-ready as quickly and carefully as possible. It is this scientific leadership that we expect will deliver 25 per cent of Merck’s early pipeline from external partnerships within the next three to five years.

From validated targets, new technologies and biomarkers to product candidates for the early pipeline, EBR’s current collaborations span all stages of drug discovery and early development.

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ISSUE - 11 2009

Building a balanced portfolio of partnerships is a key part of the EBR strategy, as well as bringing in external expertise from our academic, biotech and contract collaborations in order to achieve the best results for each programme. Our partners benefit through access to scientific synergies, increased opportunities to collaborate and financial rewards for creativity and innovation. In turn, Merck is strengthening its pipeline, using a flexible scientific base and rapid access to emerging science.

A global footprint

The External Basic Research group

recognises that outstanding science comes from sources worldwide. They manage partnerships in more than 20 countries—eight of those countries are in Asia.

Merck has a history of close working relationships with our Asian partners and has great respects for the state-ofthe-art chemistry, manufacturing and R&D infrastructure available there. We have worked with WuXi AppTec and other contract partners to accelerate our chemistry programmes efficiently and cost- effectively, further enhancing Merck’s long-term competitive position among the industry leaders in drug discovery.

Another type of innovative deal we have entered into in Asia is the early stage risk-sharing partnership. Merck has signed agreements with four separate companies headquartered in India, an emerging market recognised for its research capabilities, to share the risks and the potential rewards of drug development. Advinus is working with us to develop clinically validated drug candidates for metabolic disorders. Based on selected oncology targets provided

by Merck, our partner Piramal Life Sciences, is conducting a drug discovery programme through proof-of-concept in oncology. In the antibiotic and antifungal area, Ranbaxy is working with us to focus on two target programmes with the ability to expand. And Orchid, the most recent of the four partnerships, is working with us to develop novel agents for treatment of bacterial and fungal infections.

Embracing partnerships

What we want most for our partners and potential partners to know about Merck is that we are dedicated in finding the best science—wherever it is. Through combining our strengths and sharing our successes, Merck is focussed on integrating innovative external science with our innovative internal science and together delivering a pipeline that meets unmet medical needs for patients worldwide.

Strategy

Shaping the Future of Drug Development & Marketing Strategies Payer perspectives

Two questions from patients about drug therapy—does it fix my problem? does it cause other problems?—suggest three new pharma strategies to address payers’ priorities for improved results.

These strategies are affected by payer perspectives as they shape the future of drug development and marketing strategies.

Elizabeth L Bewley President & CEO Pario Health Institute, USA

T

he US ranks 50th in the world in life expectancy and 46th in infant survival rates. Virtually all the statistics point in the same direction. Compared to other developed nations, health outcomes in the US are worse and costs are higher. US health outcomes and costs are unacceptable.

For example, the US ranked last out of 19 developed nations in a study of preventable deaths. Additionally, the US spends more than twice as much per person on healthcare as other developed nations do. In 2009, healthcare costs in the US will total about US$ 8,160 per person.

caused by Adverse Drug Events (ADE).

Total deaths from selected causes are 424,000 deaths.

This is equivalent to killing the entire population of the city of Miami every year. These numbers do not include all deaths caused by medical care. For example, they do not include deaths resulting from misdiagnoses. Additionally, many more people are injured by medical care than are killed outright. For example, a typical study concluded that ADE alone lead to 17 million trips to the emergency room each year, and 3 million admissions to long term care.

Medical Care Causes One of Every Six Deaths

Purchasers of healthcare have limited interest in the outcomes of clinical trials. They are paying for real people in real life, including people with multiple diseases. They expect medical care to enable these people to perform significantly better in day-to-day activities.

Medical care is the direct cause of at least 17 per cent of all deaths in the US each year. These include 200,000 deaths caused by medical errors in hospitals, 99,000 deaths caused by Infections acquired in hospitals and 125,000 deaths

Payers want better results

Healthcare is not individual-centric

Why doesn’t the excellent medical research in the US result in better quality of care and longer life expectancy? The answer is deceptively simple.

Healthcare in the US is not individualcentric (patient-centric). That is, care decisions often do not take into account whether they improve or degrade the patient’s long-term well-being.

Four outcomes of treatment are common

As an example, consider what happens when a doctor prescribes a drug for a chronic condition. People are likely to have two questions about its impact on their health: • Does it fix my problem • Does it cause other problems?

These two concerns are mapped on the chart in Figure 1 and yield four possible outcomes. The first outcome appears in the upper right hand quadrant: the drug solves the original problem and

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ISSUE - 11 2009

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Strategy

Not effective

Drug work; also causes troublesome side effects

Very effective

Four outcomes are common

Drug doesn't work; also causes troublesome side effects Side effects

does not create any others. However, on average, 50 per cent of the people given a typical drug will fall in the bottom two quadrants—the drug does not work for them.

The second outcome appears in the bottom right-hand quadrant. Here, the drug does not solve the original problem.

It also does not cause people any new problems. However, if their condition warrants treatment, and the treatment is not working for them, then presumably their health is likely to deteriorate. In addition, money spent here is wasted.

It is not a desirable quadrant.

The third outcome appears in the bottom left-hand quadrant. Here, the drug does not solve the original problem. However, it does create new health problems. For example, more than 50 common drugs are known to cause significant weight gain in many people.

The fourth outcome appears in the upper left-hand quadrant. Here, the drug solves the original problem, but also creates new problems. It is a challenge to decide if gaining the benefits justifies tolerating the problems.

It is no longer acceptable to payers for pharmaceutical companies simply to develop a drug that is very helpful for, say, 48 per cent of the people with a certain disease. It is also necessary to be able to tell if any given individual is one of the 48 per cent who will be helped, or one of the 52 per cent who will not. Purchasers do not want to pay

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Drug works

Drug doesn't work

No side effects

for the drug for the 52 per cent in this example who will not benefit from it and they do not want to expose those people to potential side effects.

Healthcare focuses on one quadrant

There are four well-populated quadrants on the chart. However, it is typical across the healthcare industry for professionals to talk and act as if the only quadrant is the one in the upper right: drug works, no serious side effects.

Thus, when they talk about engaging individuals more in their own care, they focus on coming up with the right incentives and penalties to drive ‘compliance’ or ‘adherence’. That approach is not in the patients’ best interests. The people who fall in the bottom two quadrants should not take the drug and many people in the upper left-hand quadrant should not either. Generally, well over half the people will be worse off if they simply do as they are told.

Better health would be achieved not by driving people to follow orders, but instead by helping them be better CEOs of their own health and healthcare.

CEOs do not know everything. They rely heavily on experts. But what they do know is what questions to ask. In this case, these might include: • What is this drug intended to do?

• How will we know if it is working for me?

• When will we know if it is working for me?

It is hard to be a successful CEO without good information. A logical question to ask is whether individuals get the information they need.

Doctors omit key facts when prescribing drugs

Archives of Internal Medicine reported on a study in which doctors agreed to be recorded during patient visits, prescribing drugs new to those individuals. Here are the percents of the visits in which doctors mentioned important information: The reason for taking the drug

87 %

The name of the drug

74 %

Side effects

35 %

Given the volume of ADE, the failure to provide these facts consistently is disturbing. The person who is present 100 per cent of the time when a drug is administered is not the doctor. It is the patient. How can individuals help prevent ADE that can kill them if they are not even told the name of the drug they are supposed to be getting?

Healthcare often appears to be focussed on delivering treatments—e.g. writing prescriptions—rather than on improving health. Payers are increasingly intolerant of this disconnect.

Prescribing multiple drugs multiplies the problem

The problem of prescribing drugs without providing basic information gets significantly worse when there are more doctors and more drugs in the equation.

This situation arises frequently. More than 45 per cent of the people in the US have a chronic condition, and 81 per cent of people with serious chronic conditions see two or more doctors. About 20 per cent of people over age 65 take 10 or more different drugs each week.

Prevention provides the following example of healthcare’s focus on delivering treatments instead of on improving health.

A woman in her sixties was prescribed several drugs. After she started taking them, she developed new symptoms,

Strategy

Identify in which quadrant an individual falls

Here are three ways a pharmaceutical company can help identify into which quadrant an individual falls when the doctor prescribes a drug they sell. These approaches range from pre-emptive to corrective.

First, many companies are already working to find genetic markers to identify which people are good candidates for a particular therapy and which are not.

Second, because companies cannot possibly do clinical trials to check every combination of real-world conditions, it may be very useful to work with

Pharmaceutical companies have a key role Better results are likely if all players act as if the purpose of healthcare is to enable people to lead the lives they want.

Three strategies for pharma companies to respond to payers’ priorities are: • One, help identify into which quadrant an individual falls • Two, help address polypharmacy (the over-prescribing of multiple drugs) • Three, help individuals be better CEOs of their own health and healthcare.

integrated care systems (organisations that are responsible for providing everything from primary care to hospitalisation for their roster of patients) to mine their data about their patients. For example, while the drug treats one condition, it may be possible to tell whether people with specific co-morbidities (additional diseases) do especially well or especially poorly when they take it. While this data is not as pristine as clinical trial data, it is often a great deal better than nothing.

Third, it would be useful to apply the research concept of ‘fast failure’ to prescribing. That is, once individuals are taking a drug, how can it be determined very quickly whether it is actually helping them or hurting them?

Address polypharmacy

Polypharmacy, the overprescribing of multiple drugs, resulting in drug

Author

so more drugs were prescribed. Then she developed more symptoms, so yet more drugs were added, and so forth, until she was taking thirteen drugs. She deteriorated significantly. She felt that she would be better off dead.

A pharmacist analysed her drug regimen and identified a number of drug interactions and potential side effects that were probably causing most of her symptoms. When she took this analysis to her doctor, he ‘fired’ her as a patient.

The next eight doctors she went to refused to consider that the treatments might be causing many of her problems.

Stories like this are very common and usually end very badly. She was lucky: the tenth doctor agreed to change her treatment plan, based on the pharmacist’s analysis. Several years later, she is healthy and active, and taking just three prescription drugs.

Payers are upset about the high costs and damaged lives that result when healthcare professionals act as if the only quadrant is the one in the upper right: drug works no serious side effects.

Pharmaceutical companies face lawsuits, bad publicity, fines and restrictive regulations. It is possible that many of these arise because people feel that the pharma company should have made it clearer that their drug results in four heavily-populated quadrants.

interactions and side effects, is very pervasive. In fact, one researcher concluded that it works best to assume that every symptom in the elderly is a side effect of drugs until conclusively proven otherwise. An industry-wide initiative could address polypharmacy.

A first step might be an awareness campaign directed towards doctors and patients. This initiative would need to go far beyond the usual admonitions to ‘bring all your pill bottles to your doctor once a year.’ It would need to provide practical recommendations for preventing, recognising and addressing polypharmacy as it is happening.

A second step might be a toll-free number and a website run by pharmacists. Individuals could list the drugs they are taking and the symptoms they are experiencing. A computer programme could analyse that particular drug regimen and highlight potentially serious drug interactions and known side effects that could be causing their symptoms. The output would be a printout individuals could discuss with their doctors.

Help individuals be better CEOs

The third strategy for pharma companies to meet the needs of payers is to help individuals be better CEOs of their own health and healthcare.

Industry-wide efforts would be helpful, and so would checklists for doctors and patients specific to individual drugs. These could address such questions as, “How will I know if this drug is working for me?” This strategy means giving individuals the information they need to take more responsibility for the care they receive. Their lives may depend on it.

Elizabeth L Bewley has joined Pario Health Institute in 2008 after 20 years at healthcare icon Johnson & Johnson. Her work focusses on catalysing change so that healthcare becomes more individual-centric, and its goal becomes to enable people to lead the lives they want.

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Strategy

Twenty-first Century

Crime

Counterfeit, illegally diverted and stolen pharmaceuticals

The rise in counterfeit medicines worldwide, with concomitant problems of toxicity, instability and ineffectiveness, is often underestimated. It is a hidden risk because counterfeit medicines are largely overlooked in the official public health statistics.

Thomas T Kubic Executive Director Pharmaceutical Security Institute, USA

T

he worldwide markets for pharmaceutical products are generally well regulated, efficient and profitable. It is their profitability that attracts many individual criminals and criminal organisations anxious to peddle counterfeit, illegally diverted and stolen pharmaceuticals.

Through the systematic collection, analysis and dissemination of information concerning the incidence of counterfeiting by the Pharmaceutical Security Institute (PSI) and its member companies, drug regulatory agencies, pharmaceutical manufacturers, international organisations and law enforcement officials are beginning to more clearly understand the extent of this problem.

Documenting the problem

The Institute manages a unique database,

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the Counterfeiting Incident System (CIS), which is used to document incidents of counterfeiting, theft and diversion around the world. On a daily basis, incidents are identified by the careful work of a multi-lingual analytical team. Team members gather the facts from news accounts, police reports and drug regulatory authorities.

Incident reports from PSI member companies complete the collection activity. Comprehensive research produces a detailed picture of the individuals involved, their businesses, and their methods of operation as well as key identifying information.

The ‘2008 Situation Report’ identified 1,834 incidents as having occurred last year. This represented an increase of slightly less than 5 per cent over the total reported incidents in 2007.

Figure 1 illustrates the number of counterfeiting, illegal diversion and theft incidents recorded in CIS since 2002.

The following examples of incidents are provided to illustrate the types of incidents PSI documented during 2008.

These prominent incidents illustrate

Definitions of critical terms Counterfeit Medicine: Is a medicine deliberately and fraudulently produced and / or mislabelled with respect to identify and / or source to make it appear to be a genuine product. lllegal Diversion: This occurs when a genuine pharmaceutical product is approved and intended for sale in one market, but is illegally intercepted and sold in another market; these schemes are often accomplished through the use of false statements or declarations.

Pharmaceutical Theft: Is an illegal taking of medicines by robbery, burglary or theft; thefts are included as incidents when the value exceeds US$ 100,000.’ Incident: Is a discrete event triggered by the discovery of counterfeit, illegally diverted or stolen pharmaceuticals.

the seriousness and potential danger involved with counterfeit pharmaceuticals.

According to the Vietnam Drugs Administration, more and more fake drugs are being discovered by drug inspectors each year, posing a serious threat to public health. Many kinds of drugs, including domestically and foreign manufactured medicines, are counterfeited and sold with counterfeit trademarks. Vietnam has 54 pharmaceutical and cosmetic testing centres but a lack of strict management over drugs circulated in the market has made it difficult to discover fake drugs.

The Health Secretary of Mexico has recognised that in the northern border region of the country many counterfeit medicines are detected. In August 2008, 20 tons of spurious medicines were seized in Guadalajara, Jalisco. Additionally,

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Strategy

Figure 2 illustrates the geographic location and the Total number of incidents by year CY 2002 - CY 2008 corresponding number of incidents experienced in 2008.

Developing countries have been consistently linked to pharmaceutical crime incidents. In 2005, 76 per cent of incidents were linked to developing countries. An analysis of the 115 countries linked to incidents in 2008 reveals that this statistic has remained steady at Figure 1 seventy-six percent. This means that three out of the FDA claimed that pharmaceuticals sold every four incidents reported involved a in neighboring countries could be dangerdeveloping country as a source, transit ous and ineffective because medicines are point or point of seizure / discovery of not manufactured with quality control or illegal pharmaceuticals. appropriate storage procedures.

The rise in counterfeit medicines In September 2008, Belgian Customs worldwide, with concomitant probofficers at Zaventem Airport, near Brussels, lems of toxicity, instability and inefseized a total of 2,134,000 fake pain killfectiveness, is often underestimated. ers and anti-malaria pills. The counterfeit It is a hidden risk because counterfeit medicines were found hidden in large medicines are largely overlooked in the bags in air cargo at the airport. They were official public health statistics. In cases sent in three shipments by a company where deleterious adverse reactions are based in Mumbai and were bound for not self-evident the problem often goes two companies in Togo after transiting undetected. The patient is unknowingly through Casablanca, Morocco. Customs taking ineffective medicines that fail to officers’ suspicions were aroused by spellrestore his / her health. ing errors on the boxes the pills were The following representative cases packaged in. illustrate the potential harm to public health.

The dimensions of counterfeiting In June 2008, two young people in are global Singapore suffered hallucinations, anxiThough the incidents may vary from ety and adverse reactions after taking country to country, counterfeit pharthe herbal supplement Relacore, which maceuticals are found in every region of they bought over the Internet. According the world. Over the past year, PSI has to the HSA, the product was marketed observed an increase in the number of legitimately as an herbal slimming prodcountries affected by this problem. uct, but contained a prescription slimIn the ‘2008 Situation Report,’ ming ingredient that exceeded the atic incidents of counterfeiting, illedose. The HSA was trying to establish if gal diversion and theft were linked the patients bought a counterfeit version to 115 different countries. This was of Relacore. an increase of 3 per cent over the In July 2008, the Jordan Food and countries experiencing the problem Drug Administration (JFDA) issued a last year. warning concerning the use of illegal

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sexual performance enhancers, cautioning that the drugs may contain toxic materials, such as yohimbine and strychnine, which could lead to death. The counterfeit medicines are sold in the form of pills for men and eye drops or gum for women.

In April 2008, Commissioner Andrew von Eschenbach told Congress that a blood-thinning drug was contaminated ‘by virtue of economic fraud.’

These statements followed a far-ranging investigation by FDA scientists. Up to 875 individuals were injured and 81 deaths may have been due to use of this contaminated drug. The adverse events included allergic or hypersensitivity-type reactions. In addition to the US, ten other countries were impacted.

According to the Health Sciences Authority, Singapore authorities seized more than 75,000 illegal products, including some sold as sexual-enhancement pills, after receiving reports of life-threatening reactions. The pills, manufactured in China, had more than five times the normal amount of active ingredient used to treat diabetes. The HSA confirmed that the total number of deaths associated with the use of these products in 2008 is ten.

Following the death of a young woman in Seine St Denis, health authorities analysed the ‘Best life’ capsules taken by this woman. The results of the analyses showed the presence of Sibutramine, a drug substance contained in a prescription only medicinal product and requiring regular patient follow-up due to the risk of cardiovascular adverse effects. The ‘Best life’ capsules also contained phenolphthalein, a substance banned in medicinal products in France since 1999, and other plant derived substances that had laxative properties.

Three arrests were made.

Dangers of the Internet

The Internet is an attractive environment for criminals since there are neither cyber police nor drug regulators on duty. Rogue internet

Strategy

Incidents - Regions of the World

Arrests by region CY 2008

Figure 2

pharmacies sell medications without prescriptions and supply counterfeit, stolen or unapproved products. They are based beyond the reach of the authorities as they carefully establish their operations in distant countries.

According to the WHO, medicines purchased over the Internet from sites that conceal their physical address are counterfeit in over 50 per cent of cases.

Despite this fact, increasing numbers of countries have witnessed a significant increase of medicines ordered over the internet and shipped by mail. The latest figures show an increase in the number of pharmaceuticals being seized by customs agencies. Ease, discreetness, attractive prices and celerity are arguments used by internet drug seller to lure the unsuspecting into putting themselves in jeopardy.

Supporting investigations

While strategic analysis is important to policy makers, most often the investigator needs specific information to support an investigation. The Institute and its members help the authorities identify counterfeiters and their illegal operations. The following categories of information may be of value to investigators in initiating or focussing their inquiries.

During 2008, the Institute identified 766 new suspects living in 71 different countries.

PSI documented the arrest of 917 people involved in counterfeiting, illegal diversion and theft of pharmaceuticals.

Asia and Latin America were the two regions recording the most arrests. See figure 3.

In 2008, 705 businesses were identified in relation to pharmaceutical counterfeiting incidents. The types of businesses recorded include pharmacies, distributors, websites, doctor’s offices and printing companies.

Training is a top priority

While sharing information is critical to successfully disrupting and dismantling criminal groups, it is particularly important to ensure that law enforcement officials are aware of the seriousness and pervasiveness of counterfeiting.

PSI and its members offer a variety of specialised training opportunities for law enforcement officers. Working with international organisations such as INTERPOL and the World Customs Organisation, PSI along with its members has provided training to representatives from more than forty different countries last year. Many of these representatives are critical to the anti-counterfeiting effort.

Figure 3

The pharmaceutical industry is strongly committed to assisting law enforcement and has set training as a top priority program for PSI. Cooperation is the key to success

PSI is dedicated to working cooperatively with law enforcement agencies, drug control authorities and international organisations throughout the world to address the threat to public health and safety. Ultimately, only by working together and sharing information will these criminal organisations be successfully disrupted and dismantled.

All concerned government officials and business leaders are encouraged to: • Use all appropriate opportunities to increase the general public’s awareness and understanding of the risks of counterfeit medicines • Exchange relevant information on counterfeit, stolen and diverted medicines in a timely fashion; and • Increase the number of international investigations of criminal organisations and prosecute their members to the fullest extent of the law in order to maintain the safety of all consumers.

Full references are available at www.pharmafocusasia.com/magazine/

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15

Strategy

Personalised Genetic Diagnostics Warrants global expansion Direct-to-consumer genetic tests should be advertised as ‘genomic art’ to avoid the increase in general anxiety that they will introduce without including a properly informed healthcare provider.

Dean Sproles President & CEO Iverson Genetic Diagnostics, Inc., USA

I

was at the ‘Burrill Personalised Medicine in the Clinic: Beyond Canceræ’ panel, where G Steven Burrill invited me to explain for the audience, ‘Why don’t you take your company and products to China?’

My response at the moment was fairly succinct and addressed our need to focus on domestic (United States) production and follow with a launch of our products during the last half of 2009 throughout the entire Asian Pacific Rim. Our goal is to translate the operational model to Asia and determine which nation would provide a most functional international headquarters. Corporate distribution channels and ‘trusted relationships’ are essential in the effective development of an ‘International Brand.’

Physician interaction and feedback on clinical relevance has been integral in advancing the utilisation and acceptance of our products. Over the past year, our

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corporate resources have been committed to building a substantial sales team (we expect >200 trained sales representatives

by May) and refining the operational requirements (expansion to 19 regional facilities to optimise turnaround time) for providing personalised medical genetic diagnostics that impact clinical ‘decision making.’ Gaining the physician’s acceptance of our products and optimising the clinical utility is our primary focus.

Our initial product launch has been the Warfarin (brand name, Coumadin) sensitivity panel (FDA approved our panel in January 2008), where our primary market consists of mainstream clinicians. I feel, our acceptance among cardiologists, hematologists, and all other mainstream specialists, is a crucial element to our international launch.

With our Warfarin sensitivity panel, we are able to provide a viable product that addresses a real problem in standardising

the dosing based on an individual’s genes.

Penetrating this market and establishing an optimal service component will enable a commercialisation pathway for future and more progressive DNA / RNA-based healthcare products.

Managing risk through gene testing

In August, 2007, the FDA updated labelling on warfarin. This oral anticoagulant is most frequently used to control and prevent thromboembolic disorders, indicating that people with variations of the genes CYP2C9 and VKORC1 may respond differently to the drug. FDA black box warnings notify physicians that patients over 65 years of age using this drug carry a higher risk for bleeding and require special vigilance. This information, combined with numerous clinical studies, has encouraged physicians to recommend genetic testing to better support determining a patient’s

The oral anticoagulant of warfarin is most frequently used to control and prevent thromboembolic disorders, indicating that people with variations of the genes CYP2C9 and VKORC1 may respond differently to the drug. we are actively seeking corporate partners in the Asian market to affect a transfer of technology that will be prepared to address the need of millions of the Asian population on Warfarin that will benefit from receiving a personalised dose.

Gaining clinical acceptance

Our company’s strategy has been to follow the FDA guidance in gaining subtle acceptance and implementation through the re-labeling of several widely prescribed medications to gain clinical acceptance. We have focussed our entire

effort on complying with the recommendations of the regulatory agencies.

Iverson has also expressed an extreme concern over the direct-to-consumer approach taken by several whole genome DNA testing companies. Our position is that direct-to-consumer genetic tests should be advertised as ‘genomic art’ to avoid the increase in general anxiety that they will introduce without including a properly informed healthcare provider.

This approach will allow our organisation to establish a sound reputation and a corporate brand that can readily translate into the global marketplace.

Like other leading researchers and scientists, Iverson is committed to its goal of expanding the use of genetic diagnostics by moving the healthcare model towards a more informational model based on preventative, personalised and predictive medicine. Iverson tests will provide a ‘genetic roadmap’ for both patients and physicians allowing them to better understand healthcare options and shape healthcare decisions within targeted populations.

In the interim, as I’m physically writing this and listening on a conference call to a coalition of companies discussing the pending ‘battles’ with legislation to receive payment for more advanced personalised medicine applications, I find myself placing a considerable amount of thought into Mr Burrill’s question, “Why don’t you take your company and products to China?” Given time to reflect over this and considering the tremendous need in the region, I am enthusiastic about moving forward with the right political or corporate partner that will work with us in a technology transfer to make personalised medicine a present-day application in Asia.

CaseStudy

retaining hospital credentialing. Many retired physicians (who have prescribed Warfarin and understand the issues with dosing) are approaching Iverson and volunteering to assist in our efforts; while most practicing medical professionals are cautious about affiliating with the company due to strict and highly regulated US Stark Laws. As we burgeon through the obstacles in the US healthcare reimbursement system, we continue to provide the test as a service for physicians initiating Warfarin. In the interim,

Author

optimal dose, since too high of a dose contributes to life-threatening bleeding, and too low places the patient at risk for life-threatening blood clots. Studies have indicated that 89 per cent of Asians carry at least one sensitive version of the VKORC1 gene, placing this population at an increased risk for ‘bleeding out’, when consuming higher concentrations of the drug. We utilise software that incorporates the growing number of variations into a dosing algorithm that automates the reporting process and more effectively supports the dosing evaluation and continued maintenance of the patient.

Gene testing and close monitoring is critical to millions of patients who are prescribed Warfarin (Coumadin) due to the high incidence of side-effects, many that are life-threatening. Warfarin is the second most common drug, after insulin, implicated in emergency room visits for adverse drug reactions. The Wall Street Journal reports that 85,000 serious bleeding events and 17,000 strokes a year could be prevented using genetic testing, saving US$ 1.1 billion a year in the US alone. However, the complexity of the US multi-payer system and the perceived lack of coordination between the regulatory agencies has yielded a slower than anticipated rate of acceptance in the US market. The process of implementing Warfarin sensitivity DNA testing as a standard of care has been extremely slow.

Today, there are four FDA-approved platforms for Warfarin sensitivity genotyping, with each receiving approval over the course of this past year (2008). CMS (Centers for Medicare and Medicaid Services), however, has postponed making a decision on payment for the FDA-approved tests until later this year. Progressive hospital networks have adopted our ‘pilot testing’ programme, while many other networks await JCAHO’s (The Joint Commission on the Accreditation of Healthcare Organizations) decision to mandate the testing as a requirement for

Dean Sproles is the Founder, President, Chief Executive Officer, and Chairman of the Board for Iverson Genetic Diagnostics, Inc. Sproles is an entrepreneur and scientist specialising in gene expression and protein sequencing. He is the innovator of the Company’s genetic diagnostic technology.

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17

Strategy

Next Generation Pharmacovigilanc For enhanced patient safety

e

The pharmaceutical industry is facing a tough road ahead in the future marketplace. Though pharmaceuticals remain the most costeffective healthcare intervention, they should bring about a significant transformation in their organisations to realise the glorious future.

John D Balian, Senior Vice President Amrit Ray, Vice President Andres Gomez, Executive Director-Epidemiology Global Pharmacovigilance and Epidemiology, Bristol-Myers Squibb, USA

I

n an environment where development costs have increased exponentially while filings and launches have dropped drastically, the pharmaceutical industry and drug regulators face numerous challenges in Pharmacovigilance (PV), patient safety and in addressing areas of unmet medical needs.

This combination of issues not only adds unsustainable access restrictions and costs in the long term, but also creates an urgent demand for investments in new, enhanced PV capabilities.

These enhanced capabilities will allow companies to improve the processing of safety data with the goal of providing analyses rapidly and transparently to regulators, healthcare providers and patients.

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Existing PV systems need to be reviewed in order to improve the availability, evaluation and communication of the information. This fact is pushing companies to collaborate with local / national and international government agencies, regulators and healthcare delivery systems to create a model that will ensure operational efficiencies and meet the needs of physicians, patients and payers by automating a large portion of the event reporting and processing.

For a true breakthrough, first and foremost, the status of PV must change to one that creates value for the industry, regulators, and patients. To achieve this paradigm, we present some key aspects to be considered for a comprehensive PV transformation.

Innovative partnerships

Traditionally, the tendency has been to maintain the status quo until an event occurs that highlights drug safety issues.

Due to these responsibilities, the pharmaceutical industry has long viewed PV as a sacrosanct dominion, in which the sole intent is adherence to established data collection and reporting obligations. We have applied temporary and ad hoc solutions to address PV issues and employed right methods to address the new problems and challenges that involved more complex, burdensome, and resource-intensive solutions.

Changes in the regulatory environment both in the USA and EU have also accelerated an organisational transformation for PV. The need for new adverse event reporting, and safety monitoring

requirements as well as risk management, have made the usual approach of signal detection and evaluation through existing PV strategies a non-workable paradigm. Therefore, the development of an agile and efficient “next generation” PV solution will not only require internally dictated transformational leaps but also innovative external partnerships to be successful.

The new PV model that is more effective and agile should display the attributes required for the delivery of efficient signal detection, proactive risk-benefit assessment and the timely transactional components of PV, such as receiving and processing of adverse events and authoring of aggregate reports cost-efficiently. These changes will depend on a number of factors such

as mature technologies, superior methods of exchanging safety information, and visionary leadership leading to new collaborations between different partners and disciplines. These new approaches will ease the transition from a historically reactive discipline to a proactive paradigm of sustainable and productive models designed to continuously enhance the patients’ safety.

The success of this proactive system depends on external and innovative partners for the identification and assessment of risks as well and risk management.

Continually monitoring risk-benefit throughout the product life cycle is a central theme for improving drug safety systems. This is particularly true post launch, when the ongoing assessment of risk-benefit is required as new data

is available. As such, PV departments will have to proactively develop their science through the integration of already existing PV methods with methodologies from epidemiology, health services research and health economics. This integration of disciplines will provide PV departments with a synergistic advantage on detection and management, and risks by combining different data, scientific disciplines and methodological expertise.

This supplementation of already existing PV methods with new disciplines will only be feasible by the partnering of industry, regulators, academic centres and healthcare delivery systems. The creation of sentinel observation networks by the Food and Drug Administration as well as PhRMA’s Observational Medical Outcomes Partnership initiative

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are initial approaches to a new proactive paradigm of signal detection, and risk management; where consortiums of academic, government and industry centres of excellence will work on developing new methodologies to be incorporated into the proactive practice of drug safety.

Globalisation

Cost reductions have pushed the development of global sourcing from a trend to a relatively standard practice among multinational companies. However, global sourcing is not a mere cost reduction tool. For PV, global sourcing will mean the integration of onsite, and offshore capabilities, and establishment of overseas centres of excellence for the development and implementation of surveillance methods. Thus, the success of global outsourcing will depend not only on the reduction of PV expenses but on the integration of these capabilities and the improvement of methods with direct impact on risk communication and risk management.

Early and proactive safety launches

The launch of a product is a critical point in drug development, and represents the culmination of discussions between industry, regulatory agencies, payers and patients. The launch presents a determining opportunity to educate healthcare providers, regulators and patients on the safety profile of the product. However, the new vision for PV should encompass earlier education of stakeholders even before the commercial launch. As such, the possibility of “conditional marketing authorisations” would allow for the proactive implementation of earlier active surveillance and education practices prior to the market release of the drug. In addition, the proactive safety advertising will improve and increase the reporting of adverse events. Moreover, it would lead to optimal use of the product, and optimisation of the benefit-risk profile of the drug.

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This would open the door for PV to educate on safety issues and take the opportunity to gather more robust safety data during early usage of the drug.

This approach would create a reasonable hybrid alternative, combining standard methods used in safety surveillance and the assessment of post-marketing safety through the use of large mortality and morbidity trials prior to the approval and launch of the drug.

Transparency

The new paradigm of an enhanced and proactive pharmacovigilance system will only be viable if safety findings are communicated in a clear, concise

The pharmaceutical industry has long viewed pharmacovigilance as a sacrosanct dominion, in which the sole intent is adherence to established data collection and reporting obligations.

and timely fashion. This will require the creation of a unified adverse event reporting system, including a storage database and analytical tool, which would be shared by sponsors, thus, guaranteeing that all available safety data are used in the risk assessment of potential signals. New advances in technology permit the creation of such a cross-company safety data tool that would allow for robust determination of background rates and more reliable signal detection.

In addition, transparency around the transmission of safety data will create an established process for addressing safety concerns during the life cycle of

the drug (e.g. observational data assessments, registries, epidemiological studies, safety studies). The establishment of such processes will also allow the industry to potentially avoid regulatory and commercial pitfalls associated with ad hoc or improperly communicated safety signals.

An industry-wide objective

Current changes in the pricing and reimbursement of new drugs, the regulatory environment, and the impact of worldwide financial changes on the pharmaceutical industry will play a defining role in the establishment of a ‘Next generation PV’ model. Now, more than ever, pharmaceutical companies are being asked to reinvent themselves by reducing development times, through agility, and efficiency, and by addressing existing unmet medical needs while improving the value for patients. PV departments will have to establish collaborative partnerships with existing and new stakeholders to transform existing systems into highperforming organisations where new signal detection technologies, emerging markets, world-class talent on safety assessment and cost-efficiencies will be consistently integrated. However, these organisational changes will require the company to bring about philosophical changes at the business level. These changes will encompass the establishment of proactive ‘Safety launches’, and ‘PV branding’ to precede commercial launches and DTC efforts in order to ensure the best value for patients by truly optimising the benefit-risk profile of new medicines. The creation of a new and innovative PV system based on transparency, collaborative partnerships and optimisation of resources through global sourcing will improve the way signals are evaluated and managed and will add value to the pharmaceutical industry by delivering on regulatory obligations, and pricing and reimbursement decisions, ultimately improving the safety of patients.

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Research & Development

Novel Genetic Vaccines Rational design and standardised evaluation

Vaccines play a central role in health protection and advances in biotechnologies now offers numerous novel approaches for vaccine development. The goal of developing new vaccines to immunise people against infectious diseases has long been a key priority for the world’s medical authorities.

David Klatzmann Professor, Immunology Director, Immunology-Immunopathology-Immunotherapy Research Laboratory Pitié-Salpêtrière Hospital, France

E

dward Jenner’s work in developing the world’s first smallpox vaccine in the 1790s demonstrated that it was possible to protect the general population from major threats to public health, and vaccine development aimed at combating the major concerns of the day has continued ever since.

There have been many successes, and vaccines are now available to immunise people against a wide range of diseases, including measles, polyomyelitis, smallpox and tetanus. However, the pace of vaccine development over time has been extremely uneven a situation that, given the severity of the health threats currently facing the world, demands to be addressed. The resulting need for a more systematic method of vaccine development has led directly to the development of the CompuVac (Rational Design and Standardized Evaluation of Novel Genetic Vaccines) project.

Our initiative which brings together 19 mainly European institutions in the search for a more effective approach to the issue is pursuing an ambitious set

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of objectives very much in line with the pressing nature of the problem. Indeed, this project aims to develop methodologies and tools to improve vaccine development, notably through standardisation of vaccine evaluation.

What the process comprised

(i) a large panel of vaccine vectors representing various vector platforms and all expressing the same model antigens; (ii) standardised methodologies for the evaluation of T- and B-cell responses and of molecular signatures relevant to safety and efficacy; (iii) a database for data storage and analysis of large data sets; (iv) intelligent algorithms for the rational development of prime boost vaccination.

As things stand researchers who want to develop a vaccine platform—or to improve their existing vaccine—usually take their own vector and introduce their own antigen of choice into it. Typically researchers then test it with their own methodologies. While the initial response to this kind of work may well be extremely enthusiastic, the long-term picture is rather

more complex. In particular, the absence of standardised procedures mitigates against the accurate, effective evaluation of vaccines. The problem is that people rarely, if ever, compare what they are obtaining with the results of others obtained with different types of vectors. This means the direct comparison of vaccines’ potential is extremely difficult. In order to allow for the comparison of results you have to first establish methods that will provide significant grounds for it.

The idea here is first to have people use the same antigens to measure immune responses. Within the project we choose two so-called ‘model antigens’—one for testing cellular immune responses and the other for testing humoral immune responses—which are the two halves of the human immune response to vaccines.

The next step was then to standardised procedures to evaluate immune responses to these two antigens. The need for sophisticated new methods is made even more pressing by the modern advances in medical science, which have established new parameters in vaccine development. Great

Research & Development

are two very contrasting disciplines has added another layer of difficulty. It was very challenging for us to bring computer scientists together with immunologists, because these really are two very different worlds. Computer scientists are often not very well-informed about immunology, and many immunologists don’t know much about databases and all the specific things surrounding that.

The real challenge was to get these people to work together and really understand each other. We did this by also recruiting some scientists with training in both aspects ­—biomathematics and immunology—who acted as ‘translators’ so as to help us discuss the relevant issues. If

A conference in Paris will be held on the June 29th of 2009, with international experts in vaccine development. This will be the occasion to present the results of such an evaluation and how it was translated into the development of an HCV vaccine, but also to donate the database and tools to our sponsor(s), and to organise the final communication which should help the CompuVac approach to become an accepted standard in vaccine development.

there has been a breakthrough then this is it—it brings together people from two different worlds and makes them work together to generate a meaningful database. By our commitment to making their results publicly available, the CompuVac project has added another dimension to this initiative. Indeed, their data provides an extremely solid foundation for further research, and as such the project’s work

Author

advances have been made over recent times, advances which prompt us to say that we are living through a particularly important period in the history of vaccine development. There are so many potential vectors out there. Nowadays, people are realising that they can use virtually any type of virus or even bacteria to establish a platform for the expression of heterologous antigens and turn this into a vaccine. They can likewise use the ability of our body to respond to a certain virus or bacteria to make it respond to something else.

So there is, in theory, an almost infinite number of potential vaccine platforms. In addition, for each such platform, you have many different possible engineering that could lead to different vaccine properties.

So, how are you going to compare these?

The answer in part lies in standardisation of the process.

Developing a standardised means of comparison is clearly no easy task, and a number of significant questions remain unanswered. However, it is a task that CompuVac’s advanced technical expertise undoubtedly makes the project well-suited to. Two so-called model antigens that are very well-known have been selected; these are antigens for which there are extremely good, well-known methodologies for immune response evaluation. We have put great efforts into standardising methods for evaluating immune responses against these antigens. There is no magic wand here—it’s just standardisation. The challenge is to get the people developing vaccines to agree to use these methods and then to compare their vectors with those of others.

One of our main goals is to make publicly available this whole system and a database of results obtained with it.

People will be able to test their vaccine design with the gold standard antigens and standardised methodologies, go into the database and compare their results to those already there. Establishing this kind of database has proved to be a complex undertaking. Quite apart from the technical complexity involved, the fact that information technology and immunology

has already attracted the attention of a number of other interested parties.

The first three years of the project were really devoted to building our own vaccines, testing them and developing the database. All this preliminary work has been done and it’s provided us with proof of concept and really showed us that we can generate a meaningful comparison. We’re just starting to publicise our efforts and have already met with some success. For example, we have had contact with academic researchers, non-profit organisation as well as biotech companies. They are extremely interested in using our methodologies to advance the development of their products. This kind of response gives some idea of the potential of the CompuVac project. While such interest is of course welcome, it will not distract him from the day-to-day concerns of pursuing the project’s primary objectives. The next goal for the coming year is to present our results. A couple of meetings have already been planned to present and promote CompuVac, and we will try to get the vaccine community to accept this standard and then encourage them to contribute to its further development. We need to find sponsors for the sustainability of the project. They will agree to maintain the database available on the web for free access by researchers. Sponsors could comprise a charity, a company, or an academic institution.

A unique set of vaccines of different classes has now been assembled and compared, from viral vector derived vaccines to inert VLPs. The validated database and the tool box will be made freely available to the scientific community at the end of the project in June 2009.

David Klatzmann is a professor of Immunology at the Pierre & Marie Curie medical school. He is the Director of the ImmunologyImmunopathology-Immunotherapy Lab and the head of the Biotherapy department at the Pitié-salpêtrière hospital and medical school. His main activities have been to develop translational research in Immunology, he built-up a global organisation – research unit and hospital department – which is one of the rare structure capable of developing biotherapies from bench to bedside.

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Research & Development

Evaluating drug solubility in lipid-based delivery systems Understanding the solubility behaviour of the drugexcipient complex in a lipid-based drug delivery system will help formulation scientists in rational selection of the appropriate excipients and in the determination of the optimum excipient levels to ensure drug remains solublised.

Shirlynn Chen Senior Research Fellow Pharmaceutics Department Boehringer Ingelheim Pharm. Inc., USA

P

oorly soluble drugs are often formulated in lipid-based Self Emulsifying Drug Delivery Systems (SEDDS) to improve their oral bioavailability. These SEDDS are multi-component formulations containing lipids, surfactants, and polar organic solvents necessary to solubilise the drug. One key factor affecting the performance of these formulations is the solubility of the drug in the excipient mixture. Traditionally drug solubility in the excipient mixture is assessed by equilibrating excess drug in the mixture and then the final formulation is prepared at sub-saturation concentration of the drug. Interactions between the drug and lipid excipient in the formulation could lead to formation of molecular complexes that may be less soluble than the drug itself. In such cases, determination of drug solubility is complicated due to the presence

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of the complexing excipients and the solubility of the drug will depend on the equilibrium relationships among those species involved and the concentration of the species in the excipient mixture. Because of the drug-excipient interactions and consequently, the precipitation of the complex during a solubility experiment, the equilibrium drug concentration will vary depending on the relative amounts of drug and the complexing excipient initially added to the solubility samples.

Although it is preferred to avoid using any complex-forming excipients, they may often have to be considered due to their unique functionality necessary for the performance of the SEDDS formulation.

Currently, information is not available with regard to understanding the solubility properties of poorly soluble drug-excipient complexes in lipid-based

SEDDS. Such information would be important since many lipid-based formulations consist of multiple excipients, raising the chances that drug-excipient interactions resulting in complexation may occur. Understanding of the solubility behaviour of the drug-excipient complex in such a system will help formulation scientists in rational selection of the appropriate excipients and in the determination of the optimum excipient levels to ensure drug remains solublised.

The purpose of this report is to describe the solubility properties of a poorly soluble drug-excipient complex in a SEDDS formulation and to introduce an approach for evaluating the equilibrium drug concentration in such a system. Tipranavir (TPV) was used as a model compound. TPV is a novel non-peptidic protease inhibitor that is currently on the market for treating

Research & Development

Equilibration consideration of TPV -DOG complex in the SEDDS vehicles

equilibrating excess amount of TPVDOG complex in the SEDDS vehicles containing various amount of DOG at 25°C. Samples were ultracentrifuged, filtered through a 0.45 um filter and then analyzed by HPLC for total TPV concentration. Characterization of the solid materials isolated at the end of the solubility study indicates that the complex did not change form during the solubility study.

The experimental data of total TVP solubility shown in Figure 1 are fitted to Eq. 7 by non-linear fitting using Micromath Scientist Version 3.0. Values of So and K41 are simultaneously estimated to be 0.0186 ±0.0025 (M) and 21.97±7.19 (1/M4), respectively. The fitted curves are in good agreement with the experimental data, as shown in Figure 1. This result indicates that the proposed equilibrium relationships in Scheme 1 are appropriate for describing the solubility properties of the complex.

Prediction of equilibrium TPV concentrations and precipitation of the complex in SEDDS formulations

HIV positive patients. The compound is a weak acid (pKa 5.5), having very low aqueous solubility (0.1 ug/mL in pH 2 and 17 ug/mL in pH 7.5). It is highly lipophilic (log P = 6.0) and has high solubility in various polar organic solvents, surfactants and lipidic excipeints. TPV was found to form a poorly soluble complex with 1,3 dioctanoylglycerol (DOG), a component of Capmul MCM® which is a widely used lipid excipient. The TPV-DOG complex has a 4:1 TPV-to-DOG molar ratio.

Preparation, characterisation of TPV-DOG complex crystals and solubility determination

Sufficient amount of the TPV-DOG complex was prepared by dissolving TPV and DOG in ethanol at 60°C followed by evaporation of ethanol. The formation of the complex with a 4:1 TPV-toDOG molar ratio has been confirmed by XRPD, DSC, and NMR. The complex is a crystalline material and has a different melting point from the TPV itself.

Total TPV solubility was measured by

With the known values of So and K41, the equilibrium concentration profiles of the total and free TPV, and free DOG as a function of the total DOG in the SEDDS solution can be calculated using Eqs. 5-7, respectively. The predicted concentration profiles are shown in Figure 2. These concentration profiles provide an insight in understanding the solubility properties of the complex and the relationships among the various complexing species in the system.

DOG is a component of Capmul MCM and the weight fraction of the DOG in Capmul can be determined by NMR. Therefore, Eq. 7 can be used to predict the equilibrium TPV concentration at any given level of Capmul MCM. This prediction provides a useful tool in selection of appropriate level of Capmul MCM in the SEDDS to avoid precipitation of the TPV-DOG complex.

In the case where the drug content is above its equilibrium concentration in

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Figure 1

Total TPV solubility as a function of total DOG concentration at 25°C in SEDDS vehicles.

The symbols are experimental data and the line is the curve-fitting according to Eq. 7.

Figure 2

Predicted equilibrium concentration profiles of total and free TPV, and free DOG (right Y axis) as a function of total DOG in the SEDDS formulation at 25°C.

Figure 3

Predicted maximum precipitation of the complex and the dependence of precipitation on the initial TPV concentration in the SEDDS formulation

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the SEDDS containing a given amount of DOG, precipitation of TPV-DOG complex will occur. The amount of precipitation can be predicted based on Eq. 7. When precipitation occurs, both TPV and DOG will decrease from the solution in a 4 to 1 molar ratio.

As a result, this concentration decrease should stop when a new equilibrium is established where the concentrations of TPV and DOG satisfy the solution complex constant (K41) and the solution complex concentration ([TPV4: DOG]soln) is So. Assume the maximum loss of TPV as a result of TPV-DOG complex precipitation is Xp (molar concentration), we have,

(Eq. 8) Where [TPV]int and [DOG]int are the initial molar concentrations of TPV and DOG in the SEDDS, respectively. Given the known values of So and K41 and the initial TPV and DOG concentrations, the value of Xp can be calculated using Eq. 8. As an example shown in Figure 3, in a SEDDS vehicle containing initial [DOG] = 0.15 M, the TPV concentration at [TPV]int,1 = 0.60 M is above the saturation line (supersaturated) and will precipitate out as the TPV-DOG complex. As a result, the TPV concentration will drop to reach the new equilibrium at [TPV]eq,1 = 0.39 M, with a maximum precipitation of Xp1 = 0.21 M. At this new equilibration, the DOG in the SEDDS is consumed by (1/4 Xp1) = 0.05 M. The drug concentration -dependent solubility of TPV observed when the solubility was performed starting with the TPV powder in the Capmul containing SEDDS vehicle, as mentioned in earlier sections, can now be further explained using the examples in Figure 3. In a SEDDS vehicle containing 0.15 M of DOG, if the TPV powder added to the solubility sample is targeted

Research & Development

curve-fitting the solubility data into the model equation. The model was in good agreement with experimental results.

The model equation can successfully predict the concentrations of total and free TPV at any given level of DOG in the formulation. The approach developed provides a useful tool for rationale selection of excipients and their levels to avoid drug precipitation in lipid-based drug delivery systems.

Acknowledgements

Mayur S. Dudhedia, Zeren Wang, Richard

Author

at 0.60 M ([TPV]int,1), the measured final equilibrium concentration of TPV will be 0.39 M ([TPV]eq,1). However, if the initial TPV powder added is 0.39 M ([TPV]int,2) (still above the saturation line, but with a less excess amount of TPV powder), the final equilibrium concentration of TPV will be 0.36 M ([TPV]eq,2). This is because at the end of equilibration, the solid in equilibration with the solution will be converted from the initial TPV to the TPV-DOG complex. The higher initial amount of TPV, which depletes more DOG from the solution, results in a higher final equilibrium concentration of TPV. In conclusion, the solubility properties of the TPV-DOG complex in the SEDDS can be described by two equilibria: a liquid-solid phase equilibrium of the complex and a species equilibrium in the liquid phase. The two parameters, So and K41, can be determined by

T. Darrington, Toby Tamblyn, John A. Smoliga, Paul-James Jones, and Steven L. Krill are acknowledged for contributions to this work. Fernanda Villagra and Francisco Gel are thanked for providing the reference complex material, Rosalie Ferrillo and Corrine Jankovsky for generating the XRPD and DSC data, and Maimoona Chinwala for generating some of the HPLC data.

Nair Rodriguez-Hornedo and Bradley D. Anderson are acknowledged for helpful discussions regarding this research project.

Shirlynn Chen is a Senior Research Fellow in Pharmaceutics department of Boehringer Ingelheim Pharm. Inc. She received her Ph.D. from the University of Connecticut. Chen is currently a group leader responsible for developing oral dosage forms of NCEs for clinical studies and commercialization.

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Research & Development

Can Genomics Provide Blockbuster Drugs in Defiance of ‘Personalised Medicine’?

It has become dogma that the era of genomics will require extensive genotyping of each patient ‘personalised medicine’, and that this will carve up the pharmaceutical marketplace, making blockbuster drugs a thing of the past. In the extreme, each patient will require their own unique, customdesigned drug. Put differently, every patient’s disease will be an orphan disease. Let us use cancer genomics as an example, to refute this dogma.

David W Moskowitz Chairman, CEO & Chief Medical Officer GenoMed, Inc., USA

D

espite 60 years of chemotherapy, there is still no effective treatment for stage IV (metastatic) disease. If there were, cancer would lose its terror.

The current treatment, first popularised by Emil Frei in 1950s, involves the use of cytocidal, or at least cytotoxic, drugs. Cancer cells are treated as if they were viral or bacterial microorganisms. Drugs that exploit the difference between the host and the alien cell type are used.

Although this works reasonably well for bacteria, which have peptidoglycan cell walls, and thus resemble plants more than animals, it hasn’t worked terribly well for cancer or viruses. Both cancer cells and viruses are too much like rapidly proliferating host cells, e.g.

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bone marrow cells, the gut lining, and hair follicles. Drugs that interfere with DNA synthesis not only kill tumour cells but also rapidly proliferating (but normal) host cells. Cytotoxic agents like adriamycin cause heart damage. Vinca alkaloids that disrupt microtubules cause neuropathy, since neurons rely heavily on microtubular transport for their function.

Rather than regarding the tumour as completely alien, it might be more productive to think of cancer as just one more example of rapid proliferation. There are many examples of rapid but controlled proliferation that occur during any host’s lifetime, beginning with the explosive growth of the embryo, extending to wound repair, and involving the daily renewal of the epithelial

linings of the gut, lung, and skin, for example. Breast ducts proliferate prior to lactation. In fact, controlled proliferation is the rule in biology, rather than the exception.

Is it too much to hope that the growth of cancer cells could be controlled, if only we knew what signals to use?

Tumour-expressed genes

Currently, the tumour is the only place that people are looking for drug targets.

Microarrays became technically feasible around 15 years ago, and have since become quite sophisticated. From 60 cDNAs on a nitrocellulose membrane, the entire human genome of 25,000 genes can now be interrogated with an Affymetrix chip.

Research & Development

Unfortunately, gene expression by tumours tends to be quite variable and fairly useless clinically. Inhibiting single tumour-expressed genes by siRNA, for example, has not yet resulted in any dramatic ‘cures’ in animal models of human cancer. Perhaps inhibiting combinations of tumour-expressed genes will be more fruitful, but that work is only just beginning.

Although patients are now being treated based on the gene expression profile of their tumour, the clinical results have been disappointing. Breast cancers expressing the EGF receptor, for example, are being treated with antiEGFr antibodies, with only marginal extension of life (~2 months), despite great expense (US$ 30,000).

Even 30 minutes after an initiating event, the ‘signature’ of tissue-expressed genes fails to reveal the actual triggers.

Tissue-expressed genes confirmed the overall pathway (in the case of compensatory renal growth after uninephrectomy, protein kinase C), and suggested an additional pathway (protein kinase A). But they did not reveal which of the many PKC or PKA agonists were involved. The genes expressed in a tumour, decades after it forms, are even less likely to reveal the trigger for tumour formation.

Why find the trigger?

Because of the enormous amplification cascades inherent in biological signaling, the best clinical strategy is to inhibit the earliest steps in a disease pathway, not steps farther downstream. Despite a very modest odds ratio of 1.2 for the ACE deletion / deletion genotype and chronic kidney disease (CKD), we were able to arrest stage 1 chronic kidney failure due to type 2 diabetes or hypertension, and reverse stage 2 diabetic or hypertensive CKD using a single agent albeit at a higher than conventional dose.

Previously, CKD had been thought to be irreversible.

Presumably, ACE functions at the very beginning of the pathway

for compensatory renal growth and progressive kidney failure (a form of apoptosis).

This experience gives us hope that we might be able to arrest, or at least slow down, the progression of cancer, provided that we can uncover the genes that trigger tumour formation.

Do the triggers reside in tumour or host genomic SNPs?

The National Institutes of Health recently announced a program to sequence 1000 cancer genomes, at a cost well above US$ 100 million. The goal is to find the single nucleotide polymorphisms (SNPs) that change the amino acid sequence of key proteins, such as p53, a critical tumour suppressor.

The tumour genome is thought to be bizarre, and the proximate cause of the tumour’s uncontrolled proliferation.

Pathologists recognise cancer cells by their bizarre nuclei and prominent nucleoli (sites of RNA transcription). Tumours are supposed to be highly mutable.

Yet Ley et al. recently found an AML patient’s tumour genome to be 98 per cent the same as the genome of normal skin cells from the same patient. Indeed, her AML tumour was found to contain relatively few mutations and no chromosome instability.

Both cell types had close to 3 million SNPs, as expected (1 SNP per 1000 bases; the human genome contains 3 billion bases in all). The AML myeloblasts had only 60,000 additional SNPs. Only 9 of these affected a protein’s amino acid sequence. These mutations were heterozygous, meaning that a normal copy of the gene was still present in the tumour.

None involved p53.

More importantly, 8 of these 9 mutations were absent in 187 other AML patients. It’s likely that the 8 coding sequence changes found had nothing to do with AML. Since the tumour had 60,000 new SNPs not present in the skin cells’ genome, these were most likely random mutations. If tumour mutations contributed to the AML phenotype, as

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Research & Development

Host tumourigenesis ‘trigger’ SNPs can be found

In a proof-of-concept experiment, we recently identified about 5,000 germline SNPs, in about half as many genes (2,500), associated with each of the following common cancers in Caucasians: breast, colon, lung, ovary, pancreas, and prostate. We found these in the patient’s white blood cells. Note that these patients, unlike Ley et al.’s AML patient, had normal white blood cells. Thus, the SNPs expressed in their white blood cells were in their so-called ‘germline’; every cell in their body started out with these same SNPs. We used a ‘fishing net’ of SNPs intended to be functional rather than neutral (unlike classical genetic approaches), which may explain our success. But since our SNPnet™ covered only one third of the genome, to find the approximate number of host genes associated with the tumour, one has to multiply by 3. This yields a figure of around 7,500 host genes involved in tumour formation.

Such a large number suggests that the host contributes a great deal to the tumour. Ley’s data suggests that the host’s genome may contribute as much as 98 per cent, and the tumour genome only 2 per cent, to the tumour’s eventual behaviour.

Could host tumourigenesis genes still be driving the tumour decades later?

Presumably, every cell in the AML patient’s body could have become a cancerous cell. The AML patient’s family had several different late-onset cancers, including AML. Her sister had essential thrombocythemia (too many megakaryocytes and platelets). So why did the patient develop AML instead of another cancer?

Put differently, the patient was going to get a cancer somewhere, based on her

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predisposition genes. Why did she get it in a myeloblast (early white cell) like her uncle, instead of the more differentiated megakaryocyte like her sister, or in another cell type altogether, like her mother and her mother’s siblings?

To answer this question, we would need to understand the systems biology of the roughly 7,500 host genes contributing to AML (which we haven’t looked for yet), as well as the 60,000 additional tumour SNPs discovered by Ley et al. but not yet reported.

In this view, blocking the patient’s inherited ‘germline’ genes might be just as useful as blocking her tumour-expressed genes. Clinical success may only be achieved when enough steps

Drugs that interfere with DNA synthesis not only kill tumour cells but also rapidly proliferating (but normal) host cells. are blocked to limit the overall flux through the tumuorigenesis pathway to 1 per cent or less. If 98 per cent of the tumuorigenesis pathway is already carried in every cell of the host, then it might be possible to produce effective chemotherapy based on these genes without having to consult the tumour at all. Even genotyping the patient may be unnecessary.

The clinical diagnosis alone, e.g. ovarian cancer, may be enough to recommend an appropriate cocktail of one or two dozen non-toxic drugs.

Author

is still likely, then they were probably non-coding mutations that changed the levels of the protein made, rather than the structure of the protein itself.

We’ve found so many predisposition genes (thousands), that we should be able to throw most of them away and still be left with efficacious drugs. This means we can screen first for toxicity, which removes 99.9 per cent of drug leads. The conventional method of drug discovery is first to establish efficacy and only later, and grudgingly, to screen for toxicity. The FDA hates this latter approach, however, as do clinicians who must first of all do no harm (primum non nocere).

Since the genes we found with the highest odds ratios (a statistical measure of association) figured in most of the six cancers we looked at, blockbuster chemotherapy drugs seem feasible.

In summary, we’ve found evidence for a single giant pathway involving roughly 7,500 genes, i.e. at least one quarter of the genome, in two-thirds of human cancers. Different cancers use many of the same genes. For each cancer, though, the genes (SNPs, really) have different odds ratios, meaning that the flux through that step varies with each cancer. It’s also possible that the order of the steps could vary in different cancers.

Although a complete understanding of cancer may lie decades hence, we may be able to treat it effectively within the next few years.

I do believe in personalised medicine, within reason. Genotyping will allow for pre-symptomatic diagnosis and early detection of cancer, allowing for curative surgical resection of stage I nodules. This will remain the most effective approach to this dreaded disease.

Full references are available at www.pharmafocusasia.com/magazine/

David W Moskowitz is MD, Chairman, Chief Executive Officer, and Chief Medical Officer of GenoMed, Inc. Moskowitz majored in Chemistry (Harvard), Biochemistry (Oxford Univ), and received an MD from Harvard Medical School. He trained for 7 years in Internal Medicine, Biochemistry, and Nephrology at Washington University in St. Louis before spending 11 years on the faculty of St. Louis University School of Medicine. GenoMed is the second company he founded.

s eric n n e i s gic e biog cted ness o l e i io h s p n b s to t es ex e bus bodie i h t l h f e i t y d o w n r , r gro mpa d hu ucts ulato roval e o d n v reg app ssi ac s a pro pre harm t cost such . The y for for m i a e p n r d The p-tier nifica val fo tractiv pathw ahea t g o o y i pr sa the wa dt es cte ite th ing ap emain aying the . a r t g ket l at esp sr ain in din has na. D and g eneric iative e lea e mar t are ping r biog g ini henc ing th n o i d l o f n e w nd dev nosis n sho ilars a expa g e pro ve be Biosim ha

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31

Biosimilars

Succeeding in the market of the future Translating the pharmacoeconomic potential of biosimilars into real improvements in access to expensive cuttingedge medicines remains a challenge that must be urgently addressed by healthcare authorities and policy makers.

Mateja Urlep CEO and Founder TikhePharma, Slovenia

B

iosimilars are promising remarkable cost-savings for booming healthcare budgets. Yet the full potential can only be harvested when a number of significant market, regulatory and clinical hurdles have been overcome globally.

Biosimilars as cost-savers and improved versions of originator, biopharmaceutical products could provide significant benefits for all involved in the process of providing better healthcare.

Translating the pharmacoeconomic potential of biosimilars into real improvements in access to expensive life-saving medicinal care remains a remarkable challenge that must be urgently addressed by healthcare authorities and policy makers.

Biosimilars today

Generic medicines have been successful in making healthcare more affordable and accessible. Ability to enforce generic substitution by many governments worldwide has helped contain the costs of prescription drugs. On a global level,

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generics are accounted for reducing the health costs for over 20 years, saving upto US$100 billion annually.

Biopharmaceutical medicines account for around 10-15 per cent of the current pharmaceutical market, and the sector is outperforming the market as a whole in terms of growth.

The European Union (EU) and its medicines agency, the EMEA, have successfully addressed the regulatory challenges needed to fulfil the promise of biosimilars in Europe.

Three years ago, in April 2006, the first breakthrough biosimilar marketing authorisation was issued to the human growth hormone OmnitropeÂŽ followed by 12 additional approvals to date.

In the US alone, the most lucrative biopharmaceuticals market by far, protein drug therapies today account for about 16 per cent of spending on prescription drugs, furthermore, the biologics are growing at a much faster rate than their small-molecule counterparts. The lack of availability of lower-cost competitors (i.e. biosimilars, follow-ons) in the US is one of the factors contributing to the rapid growth in spending for these drugs.

Many of the patents for biopharmaceutical products developed in the last three decades of the twentieth century have already expired, thus offering the opportunity for the follow-on versions to be developed and introduced to the market, increasing the treatment choices for patients, physicians and payers.

Scientific developments and achievements in the field of genomics, proteomics and biomarker research are paving the path for new biologic therapies, promising to be significantly more effective compared to current treatment choices. The most recent findings suggest that approximately 30-40 per cent of drugs in the near future

(2009-2012) are likely to be speciality drugs, their most significant component being biopharmaceuticals. It is becoming more and more obvious that the future of the pharmaceutical industry lies with biotechnology hence the expenditures for biopharmaceuticals are predicted to continue to expand by 15-20 per cent annually.

In the US, healthcare costs have reached an alarming level that makes most people see the need for change. At the annual BIO conference just recently held in Atlanta, the US healthcare reforms were addressed by the industry leaders.

Among other issues, they were particularly concerned about biosimilar legislation that is heating the current political debate in the Congress.

However, the discussion so far has produced many more questions than answers about safety, clinical effectiveness and clinical data package required for biosimilars or follow-ons, the term most used in the US. Despite the complexity of surrounding scientific questions and issues, data exclusivity period gains most attention of the industry lobbying today.

However, the EMEA, our pioneer in developing the legal as well as the regulatory framework for biosimilars, has already successfully addressed and answered these questions. To date, the European Commission has granted market authorisation for as many as thirteen biosimilar products from various companies and under a wide range of different brand names. Biosimilar products have been successfully put into clinical practice across European Union Member States in the last three years.

Since the EU regulatory pathway was put in place in 2005, just three biological molecules have been approved, growth hormone, erythropoietin and colony stimulating factor namely. An impressive number of thirteen biosimilar marketing authorisations granted so far is thus based on six biosimilar development programmes for just three different substances, see Table 1.

EU Biosimilar Landscape 3 substances, 6 development programmes, 13 approvals

Substance

Development Programme

Somatropin Epoetin

alfa

EC approval Date

Brand name

Sandoz

April 12, 2006

Omnitrope®

BioPartners

April 24 2006

Valtropin®

Sandoz Hexal

Binocrit® August 28, 2007

Epoetin Alfa Hexal®

Medice

zeta

Stada Hospira

Filgrastim

Abseamed® December 18, 2007

Ratiopharm Teva

September 15, 2008

CT Sandoz Hexal

Silapo® Retacrit® Filgrastim ratiopharm®, Ratiograstim® Tevagrastim® Biograstim®

February 6, 2009

Zarzio® Filgrastim Hexal® Table 1

This did not happen overnight.

European debate leading to the present regulatory approach took more than five years of discussions and consolidations of all stakeholders interested in biosimilars – the EMEA and its Working Parties, biological science, medical science, legal and regulatory experts, as well as pharmaceutical industry.

Pitfalls in European biosimilar developments so far? yes...

Three biosimilar development programmes have been either rejected by the EMEA or applications withdrawn from further evaluation process by the respective applicants. Developments of a biosimilar interferon alfa-2a, interferon beta-1a and human insulin have not yet delivered the expected result, an approval of a biosimilar product to compete in this ever more lucrative market.

Biosimilar legislation is evolving rapidly in other countries as well.

Other national authorities have already successfully addressed the biosimilar regulatory and legal framework, among them Australia, Canada, Malaysia and Japan.

However, progress in the US, the most lucrative biopharmacueticals market

with two thirds of global biological sales, is still painfully slow.

The science is proven and interesting

Biopharmaceuticals are medicines whose active substances are made by or derived from a living organism therefore these medicines are produced using biotechnology. They are proteins (including antibodies), nucleic acids (DNA, RNA or antisense oligonucleotides) used for therapeutic or in vivo diagnostic purposes, and are produced by means other than direct extraction from a native (non-engineered) biological source.

Biological medicinal products with patents already expired are all proteins of recombinant DNA origin. Proteins are generally large, complex molecules that mostly show heterogeniety which is a result of so-called posttranslational changes. Moreover, the biological activity of proteins usually depends on the 3-dimensional structure that must be maintained throughout manufacturing process, fill-finish as well as storage over the shelf-life of the final product dispensed to the patient.

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Why is this?

All biopharmaceuticals are inherently variable due to the fact that they are produced from a living organism.

Variability therefore exists within batches, batch-to-batch, after changes have been implemented to the previous production process, as well as between different manufacturers.

Current analytical techniques coupled with ‘quality by design’ approach in development and manufacture of a biosimilar medicine allow for a thorough comparability exercise and very close match of the quality parameters of the biosimilar compared to the reference. Yet all potentially clinically relevant differences between the biosimilar and the reference may not be detected during in-vitro physicochemical and biological comparability, therefore additional PK/PD studies as well as pivotal clinical trials in patients providing data on similar efficacy and safety profiles, are required in Europe.

For all biopharmaceuticals, originator and biosimilars, additional post-approval requirements such as pharmacovigillance as well as presentation of post-marketing safety data collected in respective surveillance studies, are mandated by the EMEA. Market of the future

Most generic manufacturers are actively involved, either directly or indirectly, in the development of biosimilars, the alternatives of the original brand which should provide remarkable cost savings and better accessibility to state-of-the-art biopharmaceutical medicines.

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But, will physicians use them? Ideally for generic manufacturers they will regard them as therapeutically equivalent and therefore substitutable by pharmacists, in countries where this is an option. The overarching question for physicians is going to be safety and efficacy; they need to be confident about a new alternative’s capabilities in order to switch.

For developers of biosimilars, the issue of interchangeability becomes a key point. In Europe, the biosimilar pathway leading to biosimilar approvals, speaks of ‘therapeutic similarity’ and leaves it at that. There is neither a claim on therapeutic equivalence nor on interchangeability. Therapeutic equivalence is going to be a hard nut to crack in regulated markets. Many of the biosimilar bills before congress in the US already encompass specific provisions which allow applicants to try to demonstrate this, but a clear view from the FDA is currently not yet available.

Another challenge ahead of us is substitutability i.e. can the pharmacist provide a biosimilar version if the physician has prescribed the original brand?

What could be the future role of the insurers, payers, could they mandate substitution to manage their available budgets?

Currently, access for patients to biosimilar medicines in the EU is not automatic, it still requires proactive steps to be taken by all relevant stakeholders, including calling on the physicians to obtain prescription. Issues of reimbursement are left to each individual Member State. There is little public sign that governments have begun to address the market pathway for biosimilars to enable access to these medicines

Author

Generic medicines must prove bioequivalence with the reference product in addition to showing chemical identity of the active substance to be considered therapeutically equivalent.

Authorised biosimilars have been compared to and have demonstrated that they match the reference product in terms of quality, efficacy and safety albeit they are not automatically considered as therapeutically equivalent.

as soon as possible after their marketing approval. Quite the contrary, countries such as France, Italy, the Netherlands and Spain, for example, have explicitly stated that biosimilars will not be substitutable, while the UK government has indicated that it does not expect substitution to occur as brand prescription is mandated for all biopharmaceuticals including biosimilars.

Conclusions

Research and development investment in new medicines by the biopharmaceutical industry stood at US$ 65.2 billion in 2008. Branded biologics have, until recently, been immune to generics competition. However, the breakthrough approval of biosimilars in Europe marks a changing landscape in the realm of biopharma. Through the collective effort of all stakeholders important scientific and legal questions of biosimilars have been successfully addressed in the EU. Biopharmaceuticals still remain some of the world’s most expensive medicines.

Many of them providing significantly improved outcomes in difficult-to-treat diseases such as cancer and autoimmune disorders, or successfully replacing and supplementing a protein normally produced by the healthy body.

Biosimilars are, therefore, vital to ensuring the sustainability of healthcare systems. Where available today, they increase choice in access to stateof-the-art biopharmaceuticals, providing benefits to all stakeholders including patients, physicians and healthcare providers.

Full references are available at www.pharmafocusasia.com/magazine/

Mateja Urlep, is the founder and CEO of TikhePharma, specialised in biosimilars and biopharmaceuticals. Formerly, she held the position of Global Head Marketing and Medical, Sandoz Biopharmaceuticals, Sandoz Int.

Global Biogenerics Market Opportunities and Challenges The number of new biotechnology therapeutics makeup a significant proportion of all new drug development programmes. However, some of these new therapies are prohibitively expensive. Many toptier generic firms today have developed scientific and technological competencies to develop biogenerics, based on comparability guidances applicable to branded companies themselves.

Salah U Ahmed, President & CEO, Abon Pharmaceuticals, LLC. USA Venkatesh Naini, Director, Research & Development, Barr Laboratories, USA

B

iopharmaceuticals can be broadly defined as drug substances obtained from a living organism using biotechnology. Typically, biopharmaceuticals are large molecules with complex structural features and conformations, compared to small molecule drugs. In 2005, biologic drug sales were about US$ 32 billion comprising 14 per cent of total drug sales, and this number is expected to climb to 20 per cent by 2010. This translates to a 17 per cent growth year to year for biopharmaceuticals, compared to 5.7 per cent increase for small molecule drugs.

Projected sales of biotechnology derived products are expected to reach US$ 90 billion this year alone. There are currently about 125 biopharmaceuticals marketed worldwide and approximately 633 new products are in the pipeline, making up over 19 per cent of all new drug development programmes. Twenty per cent of currently marketed blockbuster drugs (sales > US$ 1 billion) are biotechnology-derived.

Number of biologic blockbuster medicines has increased over the years. There

were 20 products of over US$ 1 billion sales in 2006 compared to only 3 products in 2000. The 19 top selling biologicals account for about US$ 50 billion of the total market (Table 1). Remarkable performance growth is expected in the coming years from biotechnology-based companies as seen from Figure 1, which depicts an index of biotech stocks outpacing the broader market indices in 2007.

The same trend is shown in Figure 2 for Europe with market share of major EU countries and their growth potential.

The current anticipated global markets for biopharmaceuticals is shown in Table 2, and as expected North America and Europe are expected to garner a combined market share of over 67 per cent.

This impressive growth in biologics has attracted top-tier generic industries to the biogenerics arena. Despite the significant costs and hurdles expected in developing and gaining approval for such products, the business prognosis for biogenerics remains attractive. The leading generic companies with significant biologic portfolios include Teva,

Sandoz, Barr / Pliva, Stada, Mayne, Ratiopharm, Biocon, Cangene, BTG and Wockhardt. Attractive features for investing in biogenerics include higher profit margins, lower price erosion, longer market share retention and lower competition through high barrier to entry. On the other hand, development of biogenerics entails several risk factors, including high development costs and uncertain regulatory and legal landscape. Several of the top selling biopharmaceuticals (Table 2) have already lost their patent protection, and several more are expected to lose their exclusivity in the coming years. In many instances the reasons for non-approval of off-patent biogenerics is regulatory or legal and not scientific. Although biologics have revolutionised disease treatment, some of these therapies are prohibitively expensive. For instance, treatment with Avastin for colon cancer costs about US$ 100,000 per year per patient and the life-threatening enzyme deficiency Gaucher’s disease treated with Cerezyme, can cost up to a staggering US$ 300,000 per patient for a single year.

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Generic biologics offer significant cost advantages and make life saving therapies more affordable to greater number of patients. For example, it is expected that a 20 per cent price reduction for just six off-patent biopharmaceuticals in Europe could save 1.6 billion Euros a year. Based on information from Express Scripts, American consumers could save over US$ 71 billion over ten years, with generic biological products. The push for biogenerics has gained further impetus with recent approval of first product in the US—Omnitrope (Sandoz), similar to branded growth hormone (Genotropin / Pfizer), but not interchangeable. Also several products have been approved as biosimialrs in Europe.

Development considerations

Complexity of biogenerics is exemplified with the controversy surrounding the basic issue of naming such products. Several labels have been used to describe generic biopharmaceuticals including biogenerics, biosimilars, follow-on proteins / biologics and multi-source biopharmaceuticals.

The concept of “biosimilars” has gained acceptance in Europe as discussed later in this article. Proteins and other biotechnology-derived products are inherently more complex molecules compared to chemically synthesised drugs.

The complexity is enhanced based on host cell (bacterial vs. mammalian) employed to produce these therapeutics and is related to molecular size, possible conformations, number of subunits and post-translational modifications. In addition, inherent heterogeneity of these macromolecules and levels of impurities and contaminants adds to the complexity. The manufacturing processes used to produce biopharmaceuticals are also complex and lend themselves to the often quoted paradigm of ‘product equals process’. This has been extensively used by branded biopharmaceutical companies to raise an alarm for not approving biogenerics. Their concern is that alternative processes for the same drug could potentially lead to dissimilar products.

Typically, more complicated structures such as glycosylated proteins are produced in mammalian cells and the simpler nonglycosylated products use bacterial cells.

In addition, some biopharmaceuticals may be chemically modified (PEGylated) to enhance therapeutic outcomes.

Biosimilar product development usually involves several comparative studies performed between the generic and reference products. Development programme for biogenerics should address the following items for demonstrating high assurance of safety and equivalence (biosimilarity) with the corresponding branded biologic: 1. Quality Attributes – Comparability of molecular structures of biogenerics and

branded products using a battery of analytical techniques 2. Comparability of biological activity using various in vitro and in vivo tests 3. Comparative preclinical safety and immunogenicity trials 4. Comparative abbreviated pharmacokinetics, pharmacodynamics and clinical studies, including bioequivalence, therapeutic equivalence, safety and immunogenicity 5. Post-approval pharmacovigilance studies and reporting as part of a broad risk management system.

Another aspect of development of biogenerics involves the formulation itself, use of any patented

Nineteen “Blockbuster” biopharmaceuticals with total sales of over US$ 50 billion* Product (Company)

Compound

Sales (US$ Billion)

1

Aranesp (Amgen)

Darbepoetin alpha

5.0

2

Enbrel (Amgen / Wyeth)

Etanercept

4.5

3

Eprex / Procrit (J&J)

Epoetin alpha

3.7

4

Remicade (J&J / Schering Plough)

Infliximab

3.6

5

Neulasta (Amgen)

PEG-Filgrastim

3.2

6

Mabthera / Rituxan (Roche)

Rituximab

3.2

7

Epogen (Amgen)

Epoetin alpha

3.1

8

Herceptin (Roche / Genentech)

Trastuzumab

2.5

9

Lantus (Sanofi-Aventis)

Insulin glargine

2.0

10

Avastin (Roche / Genentech)

Bevacizumab

2.0

11

Humira (Abbott)

Adalimumab

1.8

12

Avonex (Biogen Idec)

Interferon beta-1a

1.7

13

Neorecormon (Roche)

Epoetin beta

1.5

14

Neupogen (Amgen)

Filgrastim

1.4

15

Rebif (Serono)

Interferon beta-1a

1.3

16

Novorapid (Novo Nordisk)

Insulin aspart

1.0

17

Humalog (Lilly)

Insulin lispro

1.0

18

Betaferon (Bayer / Schering AG)

Interferon beta-1b

1.0

19

Synagis (Abbott)

Palivizumab

1.0

* Source: IMS Health, MAT Dec2006.

Table 1

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ingredients, stability profile and the primary packaging. In many instances the branded product is packaged along with the delivery system (cartridges, injector pens etc.), which may be protected by additional patents. This is an additional challenge to demonstrate biosimilarity of the drug-device combination with the marketed brand product. Controls on manufacturing and fill-finish operations via Process Analytical Technologies (PAT) will ensure product Quality by Design (QbD) at all steps. As often quoted by leading authorities, the science of developing and approving biogenerics exist today. What is needed is a scientifically rational regulatory and socio-economically favourable legal pathway for their approval and marketing, especially in the United States and Japan.

Tale of two approval pathways (US vs. EU)

The regulatory bodies in Europe (EMEA,

Top selling biopharmaceuticals whose patents have expired Product

Compound

Company

Patent Expired

Neupogen

Filgrastim (GCSF)

Amgen

2006

Novolin

Insulin

Novo Nordisk

2005

Protropin

Human Growth Hormone

Genentech

2005

Activase

Tissue Plasminogen Activator (tPA)

Genentech

2005

Epogen / Procrit

Erythropoetin

Amgen / J&J

2004

Nutropin

Growth Hormone

Genentech

2003

Humatrope

Growth Hormone

Eli Lilly

2003

Avonex

Interferon beta-1a

Biogen Idec

2003

Intron A

Interferon a2b

Schering Plough

2002

Humulin

Insulin

Eli Lilly

2001 Table 3

CHMP and EC) have taken a significant lead in laying the pathway for approval of biosimilars. An overarching guideline for biosimilar was issued by EMEA in 2004. Since then several product specific

guidelines have been issued for insulins, growth hormones, erythropoietins and colony stimulating factors. These guidelines lay out specific details for clinical and non-clinical requirements for

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Biopharmaceutical market by region* Region

2006 (US$ million)

% (Percent)

2011 (US$ million)

% (Percent)

North America

29,628

44.1

44,803

38.1

Europe

18,901

28.2

34,389

29.2

Japan

6,724

10.0

8,686

7.4

Latin America

2,676

4.0

10,366

8.8

Pacific Rim, Africa

5,174

7.7

11,557

9.8

ROW

4,026

6.0

7,822

6.7

Total

67,129

100.0

117,623

100.0

* Source: Scrip Reports, September 2007 Table 2

Index of biotechnology stocks outpacing the broader US market (1Q of 2007)* 16 14 12 10 Avg. % change

comparing products, including comparability assessment of safety and immunogenicity. The European regulatory authorities have taken a path of balancing cost and safety risk, while considering approval of biosimilars, starting with molecules of moderate complexity. Since issuance of these guidances, several biosimilars have received approval in EU countries, including somatotropins, epoetins (alpha and zeta) and filgrastim.

In the US the pathway for biogenerics / biosimilars has not progressed to the level of its European counterparts. This is partly due to competing business interests at stake and the slow pace of regulatory and legislative reforms. Traditionally new drugs in the US have been approved under Section 505(b)1 of the Food, Drug and Cosmetic (FD&C) Act by the pathway of New Drug Application (NDA). Passage of the Hatch-Waxman amendment in 1984 clearly established a legal authority with the FDA for approving generic drugs under Section 505(j) of the FD&C Act. However, the FDA has deemed that this process is unsuitable for approving generic versions of complex biologics. In addition, several years ago new drugs and some older biologics, such as insulins and growth hormones were reviewed and approved by the Center for Drug Evaluation and Research (CDER) division of the FDA, using the NDA route.

In 1990s the approval of all biologics including rDNA derived products was transferred from CDER to Center for Biologics Evaluation and Research (CBER) at the FDA. This agency approved biologics using a Biological License Application (BLA) route, under the purview of Section 351 of the Public Health Service (PHS) Act. CBER does not have a regulatory mandate for approving generic biologics approved by the BLA route under the PHS Act. In recent years there has been a push towards approving some follow-on biologics, using Section

NASDAQ DOW Bio World

8 6 4 2 0 -2 -4 -6 Nov-06

Dec-06

Jan-07

Feb-07

* Source: BioWorld Financial Watch, Volume 15, #28.

505(b)2 approach. In this approach the generic company uses safety and efficacy data generated by the innovator in requesting approval of their product. This mechanism is currently available for those biologic drugs that were originally approved by CDER using the NDA route. However, products approved under this mechanism may not be considered interchangeable with the marketed reference product.

The recent approval of growth hormone Omnitrope (Sandoz) by the US FDA falls under this category. However, the FDA has issued comparability guid-

Mar-07

Apr-07 Figure 1

ances in past for biologics undergoing manufacturing, process or site changes implemented by innovator companies.

At least one branded company (Biogen) successfully argued with the agency that major manufacturing changes to its originally licensed process for Interferon (Avonex), did not warrant additional clinical and safety trials.

The legislative push for biogenerics in the US is aimed at implementing such comparability standards that are allowed for innovator companies.

Due to rising healthcare costs, there is tremendous public pressure to control

Market share and growth of biopharmaceuticals in major European markets* 40

Growth

20

Share %

45

Share

35 30

15

25 20

10

Growth %

25

15 10

5

5

*Source: IMS Health, MAT Dec 2006

Poland

Denmark

Austria

Swizerland

Figure 2

standing of the regulatory pathway for approvals of biogenerics in the US. In the meantime, products approved under the older NDA regime, such as insulin, growth hormones, aprotinin, calcitonin, imigucerase, hyaluronidase may be prime targets for follow-on biologic development in the US. Such products may not be interchangeable with currently marketed formulations.

Other issues with biogenerics yet to be resolved include the use of International Non-Proprietary Names (INNs), legal and patent challenges to

Authors

costs of all therapies, including biologics. US Congress has taken the initiative to create a regulatory pathway for biogenerics, with introduction of “Access to Life Saving Medicines Act”

by Representative Waxman and Senator Schumer. This law aims at providing FDA with the authority to approve “follow-on biologics” based on abbreviated clinical studies and extensive preclinical testing and in vitro characterisation. It also provides for significant incentives to generic companies for investing in research and development of such products. For example, it grants market exclusivity based on first approval and not first to file. It also provides tax incentives for performing additional studies to demonstrate interchangeability with the branded product.

The law also addresses several loopholes with the current system of patent listing in Orange Book for conventional small molecule drugs. It calls for the generic company to request relevant patents from the innovator and notify about any potential challenges to those patents. Patents which are not disclosed at the time of this notification may not be enforced. Once this law is enacted, it is expected to provide a clearer under-

New Zealand

Turkey

Sweden

Belgium

Spain

Italy

Germany

France

0 Germany

0

biosimilars, strategic business alliances thwarting competition, use of countryspecific reference products and timing of data and market exclusivities for the branded product.

While Biotechnology Industry Organization (BIO), a consortium of branded biopharmaceutical companies has raised scientific, technological and safety issues as major concerns for biogenerics, it appears more of a business tactic than scientific. As quoted below by a leading generic company executive, use of comparability protocols intended for branded companies themselves is a viable option for approving biogenerics: “The science to create affordable generic biotech drugs exists today… It is being done every time a brand manufacturer changes a manufacturing process or location and uses comparability to ensure the biotech drug will provide the same safety and efficacy. [B]iotech firms routinely justify process and site changes via comparability studies. For example, if an innovator biotech company seeks changes in process supporting the manufacture of their products, or seeks to change the manufacturing location of a product, comparability is the process by which the amended product is judged to provide the same clinical effect and safety profile”.

Salah U Ahmed is the President & CEO of Abon Pharmaceuticals, LLC. Until recently he was the Executive Vice President of Global Research and Development and Chief Scientific Officer at Barr Laboratories, Inc. He is responsible for the development of generic and proprietary pharmaceuticals as well as API and biotechnology products. Ahmed received his MS in industrial Pharmacy and PhD in Pharmaceutical Sciences from St. Johns University, New York. He has more than a quarter century of pharmaceutical experience.

Venkatesh Naini is the Director of Research and Development at Barr Laboratories. He received his M.Pharm from Jadavpur University, Kolkata, India and PhD in Pharmaceutics from Virginia Commonwealth University, Richmond, VA. He currently leads multiple product development teams at Barr. His research interests include physicochemical characterisation, drug solubility and bioavailability enhancement, biogenerics, drug delivery systems and controlled release formulations. He is the author of four book chapters, over ten research articles and numerous presentations / abstracts.

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39

How Similar are Biosimilars in India?

A blind comparative study It is important to show that biogeneric drugs are comparable in structure and function to that of the innovator and any differences have to be supported with data showing no influence on these parameters.

List of Indian Biogeneric Companies & their Biogeneric Products Company

EPO

HGH

Bharat Biotech

INSULIN

A

A

Cadila Pharma

*

*

Claris

A

A

Dabur

A

A

Intas Biopharmaceuticals Limited, India

Nicholas Piramid

P h a r m a F o c u s A s iiA a

ISSUE - 11 2009

IFN Beta

A

A

Gland Pharma

A

Intas Biopharmaceuticals

A

Microlabs

A

*

A

A

A

* *

GM-CSF

Reliance Life sciences

A

Scigen (Emcure)

*

Serum Institute of India

*

Shantha Biotechnics

A

*

*

A

A

*

*

*

* A

Shashun

*

*

USV VHB

FSH

*

Panacea

40

PEG IFN

*

Biocon

Dr. Reddy’s Labs

I

IFN alpha

Bharat Serum

Rustom Mody Director, Quality and Strategic Research Vishakha Goradia Senior Executive Quality Control Department Deepak Gupta Head, Analytical Quality Control

ndia’s rising prominence in the field of biogeneric products (off-patent biopharmaceuticals) also known as Biosimilars (in Europe) or Follow-onbiologics (in US) is evident from the large number of biogeneric products getting marketing approval. A number of biopharmaceutical protein-based products are due to go off-patent in the next few years which will bring more biogeneric brands to the market.

Usually biopharmaceuticals are manufactured through a complex process of fermentation and multiple purification

G-CSF

* A

Virchow

*

Wockhardt

A

Zenotech / Ranbaxy

A

Zydus

A

Approved Biosimilars =

12

* A

*

*

A

A

*

*

A

3

9

*

*

2

*

1

A = Approved; * = Under Development Note: Under development as per public information. Table may not be comprehensive.

Table 1

Sample details of PEG-Granulocyte Colony Stimulating Factor (rHu-PEG-GCSF) Brand name

Manufactured by

Marketed By

Neupeg

IBPL

IBPL

Neulastim

F. Hoffmann La – Roche Ltd.

Taksal Pharma Pvt. Ltd.

Strength

Batch no.

Expiry date

6.0 mg / ml

600M007

January 2010

6.0 mg / 0.6 ml

B1000B01

Aug. 2009

Sample Details of Recombinant-Human Granulocyte Colony Stimulating Factor (rHu-GCSF) Brand name

Manufactured by

Marketed By

Neukine

IBPL

IBPL

Strength

Batch no.

Expiry date

300 mcg / ml

30M015

Feb. 2010

Grafeel

Dr. Reddy’s

Dr. Reddy’s

Nugraf

Zenotech Laboratories Ltd

Zenotech Laboratories Ltd

300 mcg / ml

GFAV0407

July 2009

300 mcg/ 0.5 ml

CF0107A

Dec. 2008

Fegrast

Bio-pharmaceuticals Co. Ltd China

Claris Life Sciences

300 mcg / 0.9 ml

20070702

July 2009

Xphil

Xiamen Amoytop Biotech Co. Ltd China

Ranbaxy

300 mcg / ml

200801B02

Jan. 2010

Neupogen

F. Hoffmann La – Roche Ltd.

Taksal Pharma Pvt. Ltd.

300 mcg / ml

B1036

May 2009

Colstim

Bio Sudus S.A.

Zydus Biogen

300 mcg / ml

V302061K01

Jan. 2010

Brand name

Manufactured by

Marketed By

Strength

Batch No.

Expiry date

Ceriton

CJ Corp. Korea

Ranbaxy Labs. Ltd.

10000 IU/ml

77007

June 2009

Eprex

CILAG AG, Switzerland

Johnson & Johnson Ltd.

10000 IU/ml

7KST300

April 2009

Epofit

IBPL

IBPL

4000 IU/ml

04K021

May 2010

Espogen

LG Life Sciences Ltd., Korea

LG Life Sciences India Pvt. Ltd.

10000 IU/ml

EPG06004

Oct. 2008

Shanpoietin

Shantha Biotechnics Ltd.

Shantha Biotechnics Ltd.

4000 IU/ml

EP07507

Nov. 2009

Vintor

Gennova Biopharmaceuticals Ltd.

Data not available

Zyrop

BIO SIDUS S.A.

Cadila Healthcare Ltd.

Sample Details of Recombinant Human Erythropoietin - (rHu-EPO)

4000 IU/ml

060802

Jan. 2010

10000 IU/ml

H10-4115H01

August 2010 Table 2

Parameters and analytical methods considered for study GCSF

PEG GCSF

EPO

Physical appearance

√

√

√

UV absorbance (at 280 nm)

√

√

In vitro bioassay (cell proliferation assay)

√

√

√

√

Parameters Physical properties Biological Activity

Analytical method

In vivo bioassay Identity Tests

Reverse Phase High Performance Liquid Chromatography (RP – HPLC)

√

SDS – PAGE (By Gradient Non Reducing)

√

SDS-PAGE (Non Reducing & Reducing)

√

Size Exclusion Chromatography (SEC)

√

Peptide Mapping Immunoblotting Product Related Impurities

√ √

√

SDS – PAGE (By Gradient Non Reducing)

√ √

SDS-PAGE (Non Reducing & Reducing)

√

Reverse Phase High Performance Liquid Chromatography (RP – HPLC)

√

√

Size Exclusion Chromatography (SEC)

√

√

IEF-WB SDS PAGE followed by western blot

√

steps; making them more complex and susceptible to alterations as a result of variations in the process. These alterations, even if small, can influence its structure and function significantly. Product quality, safety and efficacy of biopharmaceuticals are highly dependent on the process of production, purification and formulation and subtle differences are often observed between the innovator’s product and biogenerics. Even seemingly small changes in the structure can have significant effect on the drug’s safety and efficacy parameters. Therefore, it is important to show that biogeneric drugs are comparable in structure and function to that of the innovator and any differences have to be supported with data showing no influence on these parameters.

Competition amongst biosimilar players in India

√ √ Table 3

India has, by far, demonstrated the greatest acceptance of biosimilars which

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41

The coded samples were blind tested simultaneously by a qualified analyst using validated test methods and instruments.

Comparison between Peptide map of P5/CA/01 and P5/CA/02 (Overlap of graph)

Total 16 brands of 3 different Biosimilars were analysed after blinding.

Different quality parameters such as Identity, purity and efficacy were studied. Analytical methods were selected keeping in mind the interference of matrix buffer, etc.

Blinding of all samples was carried out prior to analysis.

Figure 1

Non-reducing SDS-PAGE (By gradient gel) of P5/CA/01 and P5/CA/02 Mol Wt. KDa

Analysis was carried by trained and qualified analyst using validated instruments and using validated methods. National Institute of Biological Standard & Control (NIBSC), UK or inhouse reference standards, calibrated against the innovator’s product were used in all analysis.

250 150 100 75 50 37 25 20

Raw data generated during analysis was recorded.

15 10

After completion of analysis decoding of the samples was done.

is reflected from over 50 biopharmaceutical brands getting marketing approval (Table 1). Biosimilars have established a good reputation among healthcare professionals. Doctors and hospitals are prescribing biogenerics immediately after their launch with interchangeability and substitution among brands being freely practiced.

In recent years the focus within the Indian biopharmaceutical sector has been mainly directed towards the development of biogenerics. This is primarily because it requires much lower R&D spends and time to market coupled with the capability of Indian biopharmaceutical companies to reverse-engineer the drug development process.

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Figure 2

Immunoblot of P5/CA/01and P5/CA/02

Figure 3

Size exclusion chromatography of P5/CA/01and P5/CA/02

Figure 4

RP-HPLC chromatogram of P5/CA/01and P5/CA/02

Figure 5

The lower price of biogeneric compared to the innovator’s drug remains one of the key marketing forces. There is a fierce market competition; forcing these companies to drop their prices too fast and too soon, within two to three years of market launch. This price-sensitivity has led to companies not fully observing quality parameters that are essential for biogeneric products. The comparability with the innovator drug is often poor.

There are differences in the physicochemical properties of the protein, use of different host cells for manufacturing, the process used for purification and formulation are different, composition, strength and the level of impurities and container-closure systems. These differ-

ences (form the innovator’s product) cannot guarantee that the product will be bioequivalent to the innovator’s product as such differences are known to have serious implications on the drug safety and efficacy.

This article is based on a blind study carried out under careful conditions to look at the differences among various biogeneric brands in comparison to the innovator’s product used as a reference.

Blind comparative study

A comparative blind study was carried out at Intas Biopharmaceuticals Ltd. (IBPL) with the objective of comparing quality parameters such as identity, purity,

content and efficacy of various biogeneric brands taken from the Indian market and comparing them with those of the innovators’ drug products. The study was carried out on sixteen commercial brands covering three different biopharmaceuticals, viz. two brands of rHu PEG G-CSF, seven brands of rHu G-CSF and seven brands of rHu Erythropoietin (Table 2) picked from the market. IBPL products were also picked from the market to harmonise any shipment-induced effects and to bring all samples on parity. Precaution was taken at the time of procurement that the age difference between different samples should not be significant. All brands were collected from a single Clearing & Forwarding (C&F) agent to preclude any effects of variation in storage conditions. Samples (including that of IBPL) were shipped using a validated cold-box and a validated cold chain. On receipt at the testing centre, they were verified free of any physical damage. Before analysing them in the laboratory, all samples including the innovator’s product were transferred to sterile microfuge tubes and labelled with a unique code to conceal its true identity. Data was interpreted by comparing all quality parameters with the innovator’s product after decoding.

During the analysis, in-house reference standards made for NIBSC or innovator’s product were also used.

The coded samples were blind tested simultaneously by a qualified analyst using validated test methods and instruments.

Comparison among different brands of rHu-PEG-GCSF

This part of the study focusses on the comparison between Neupeg (Manufactured and marketed by IBPL) and Neulastim (innovator’s product marketed by Roche India) with respect to identity, purity and efficacy. The active ingredient of Neupeg and Neulastim is Pegylated Filgrastim [Granulocyte-Colony Stimulating Factor (PEG-GCSF)], which is a 175 amino acid protein conjugated to polyethylene glycol for a total

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43

molecular weight of ~39 KDa. The protein is produced by recombinant DNA technology in Escherichia coli. Both the products consist of similar excipients i.e.

Sodium acetate, Sorbitol, Polysorbate 20, Sodium hydroxide and WFI except that Neupeg has a drug concentration of 6.0 mg / ml compared to Neulastim, which has 6.0 mg / 0.6 ml. Before analysis Neulastim was diluted to 6.0 mg / ml with the same formulation buffer before assigning codes and testing blind. The quality parameters analysed and the analytical methods used are given in Table 3.

SDS PAGE of rHu-GCSF in Non Reducing condition

Analytical findings

• P5/CA/01 and P5/CA/02 were found to be similar with respect to Specific Activity (P5/CA/01 =1.39 x 108 IU / mg and P5/CA/02 = 1.44 x 108 IU / mg); this value represents the average of five independent replicates performed over a period of three days, identity by Peptide map (Figure 1), SDS-PAGE (Figure 2) and Western blot (Figure 3).

• Both products were also similar with respect to retention time of main peak on Size Exclusion Chromatography (SEC) (Figure 4) and Reverse Phase High Performance Liquid Chromatography (RP– HPLC) (Figure 5).

• P5/CA/02 contains higher percentage (1.6 per cent) of aggregates than P5/CA/01 which shows (0.7 per cent) when analysed by SE-HPLC (Figure 4), the high level of aggregates were also observed on a non-reducing gradient SDS-PAGE, which shows more number of high molecular weight bands, (although all three bands were within the in-house specification (i.e. less then 0.2 per cent of main band of reference standard).

• RP-HPLC analysis of product-related impurities (oxidised and reduced) also shows that the percentage of individual impurities are higher in P5/CA/02 (1.3 per cent) as compared to P5/CA/01 (0.6 per cent) although total impurities found in both products are within the acceptable limits (not more than

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Figure 6

SDS PAGE of rHu-GCSF in Reducing condition

Figure 7

3.0 per cent). These differences may be attributed to some age difference between P5/CA/02 and P5/CA/01, with the former having spent additional six months of shelf-life.

Immunoblot of different brands of rHu-GCSF

Comparison among different brands of rHu-GCSF

The active ingredient of Filgrastim is a 175 amino acid protein (human Granulocyte-Colony Stimulating Factor) with a molecular weight of ~18.8 KDa, which is produced by recombinant DNA technology in Escherichia coli. All brands had the same strength (i.e. 300 mcg / ml) but some had lower fill volumes. Volume was made up to 1 ml with formulation buffer prior to coding of samples and blind testing.

Analytical findings

Figure 8

Chromatogram of SEC-HPLC of different brands of rHu-GCSF

Figure 9A

1. Each sample of rHu G-CSF was visually tested. All samples appeared clear and colourless consistent with the specification except sample P1/CA/04 which showed white fibre like particle in one vial out of three vials.

2. Product identity was tested

by SDS PAGE (Non Reducing & Reducing) (Figure 6 and 7) and western blot analysis (Figure 8). All samples complied with the specifications i.e. principal band of all brands matched the expected molecular weight of rHuGCSF (~18.8 kDa) and was matching in position with the principal band of the reference standard. Identity of rHu G-CSF was also verified by size exclusion chromatography (Figure 09A & 09B) and RP-HPLC (Figure 10A & 10B) by comparing retention time of the main peak with that of the reference standard.

All samples showed similar retention time on size exclusion chromatography and RP-HPLC. 3. There were significant differences in the protein concentration among brands. Only four brands out of seven were found within Âą 10 per cent of label claim. Variation in the protein concentrations among various brands is shown below.

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4. During determination of biological activity by cell proliferation assay, significant variation in the specific activity was observed as shown below.

Note: Specific activity was calculated by labelled protein concentration.

5. Relative impurity level of all

products with respect to high molecular weight impurities was determined by size exclusion chromatography (Quantitative) results obtained (on percentage impurities scale) are as follows 6. Levels of low molecular weight impurities were determined by semi-quan-

PROTEIN CONCENTRATION OF FILGRASTIM (mcg/ml)

SPECIFIC ACTIVITY OF FILGRASTIM (IU/mg x 108)

titative reducing SDS-PAGE (Figures 6 & 7) and results are as follows: Comparative analysis

Erythropoietin is a 165 amino acid protein with a molecular weight of ~30.3 KDa, produced by recombinant DNA technology in Chinese Hamster Ovary cells with 40 per cent of the molecular weight contributed by the sugars.

Erythropoietin is heterogeneous glycoprotein hormone, consisting of several different isoforms, primarily due to variation in the type and extent of glycosylation and sialic acid content. The structure of carbohydrate in Erythropoietin plays an important role in determining the circulatory half-life of the drug. The presence of more basic or more acidic isoforms has been shown to reduce specific activity.

Additional basic isoforms are also associated with a shorter high life.

Analytical findings

HIGH MOLECULAR WEIGHT IMPURITY OF FILGRASTIM (% OF IMPURITY)

P1/CA/08 > P1/CA/03 > P1/CA/S09 > P1/CA/S07 >

P1/CA/S05 > P1/CA/S04 >

P1/CA/S06

Increasing percentage of low molecular weight impurities

Chromatogram of SEC-HPLC of different brands of rHu-GCSF

Figure 9B

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• All EPO samples when tested for visual appearance showed clear, colourless solution, consistent with the specification.

• Samples P9/CA/01 and P9/CA/07 showed more than 0.5 per cent high molecular weight impurities while all others showed less than 0.5 per cent aggregates (Figure 11).

• Isoelectric focusing (IEF) followed by Western blot analysis (IEF-WB) was used to compare the isoform distribution of various biogeneric brands with that of the Innovator’s product (Figure 12).

Four major and two minor isoforms were identified in the innovator’s product (P9/CA/06) as well as in two biogeneric brands P9/CA/02 and P9/CA/04. Two additional basic isoforms were identified in sample P9/CA/01, while four additional basic isoforms were observed in sample P9/CA/03. One additional acidic and one basic isoforms were observed in sample P9/CA/05, whereas sample P9/CA/07 showed one acidic and two basic isoforms.

P9/CA/06 > P9/CA/02 > P9/CA/04 > P9/CA/05 > P9/CA/01 > P9/CA/07 > P9/CA/03

• The in vivo bioassay was done using reticulocytes method given in Pharm.

Eur. All products were within the specification limits of 80 to 125 per cent as shown in table 4A

Chromatogram of RP-HPLC of different brands of rHu-GCSF

Results and Discussion

Figure 10A

Sr. No.

Product Code

Label potency

In-vivo Potency assay

1

P9/CA/S04

10000 IU/ml

8221.9 IU/ml

82.2%

2

P9/CA/S06

10000 IU/ml

8360.2 IU/ml

83.6%

3

P9/CA/S02

4000 IU/ml

3545.7 IU/ml

88.6%

4

P9/CA/S05

10000 IU/ml

9323.7 IU/ml

93.2%

5

P9/CA/S01

4000 IU/ml

3644.1 IU/ml

91.1%

6

P9/CA/S03

4000 IU/ml

7 P9/CA/S07 10000 IU/ml Detail summary of analytical findings of comparative analysis of all products is provided in Table 4B

Potency % of label

3906.8 IU/ml

97.7%

10510.0 IU/ml

105.1% Table 4A

Summary of Analytical Results Results of rHu G-CSF Biogeneric product of EPO #P1/CA/03 P1/CA/04 P1/CA/05 P1/CA/06 P1/CA/07 * P1/CA/08 P1/CA/09 Results of rHu PEG G-CSF Biogeneric product of EPO #P5/CA/01 * P5/CA/02 Results of rHu EPO Biogeneric product of EPO P9/CA/01 #P9/CA/02 P9/CA/03 P9/CA/04 P9/CA/05 * P9/CA/06 P9/CA/07

Protein conc. (mcg/ml) 323 267 324 369 319 297 255

In-vitro activity (IU/mg) 1.78 x 108 2.21 x 108 1.72 x 108 2.50 x 108 2.08 x 108 1.62 x 108 2.06 x 108

RP-HPLC (% of Total impurity) 0.7% 7.1% 1.1% 1.8% 1.4% 0.6% 3.4%

% Aggregates (SEC) 0.3% 1.8% 1.1% 2.4% 0.4% 0% 0.8%

Protein conc. (mg/ml) 6.1 6.4

In vitro activity (IU/mg) 1.39 x 108 1.44 x 108

RP-HPLC (% impurity) 0.6% 1.3%

% Aggregates (SEC) 0.7% 1.6%

In-vivo potency (Mouse) 91.1% 88.6% 97.7% 82.2% 93.2% 83.6% 105.1%

No. of Isoforms 8 6 10 6 8 6 9

Extra isoforms

% Aggregates (SDS-PAGE) >0.5% N.D. N.D. N.D. N.D. <0.5% >0.5%

2 basic 0 4 basic 0 1 Acidic1 Basic 0 2 basic 1 acidic

* Innovator’s product # IBPL product

N.D. = Not Detected

Given the complex nature of biopharmaceutical products, there can be differences in the quality, safety and efficacy among various brands of biogeneric products. However, these differences can be titrated to a low level by using appropriate analytical tools, applying the concept of Quality by Design, use of orthogonal methods for analysis of in-process material, drug substance and finished product, risk-based approach to product development and characterisation of the process and the product through extended comparability testing using innovator’s product as the reference standard.

In absence of any overarching regulatory guidelines for biogeneric products, Indian biogeneric companies are not following uniform measures to establish comparability with the innovator’s product. With the recent introduction of product-specific monograph for six recombinant proteins (viz. EPO, GCSF, HBsAg, Interferon-alfa, Factor VIII and Streptokinase) in the Indian Pharmacopoeia, any company marketing these products in India shall be required to meet the quality parameters as laid down in the pharmacopoeia.

Although physico-chemical comparability is not sufficient to establish bioequivalence and identical safety and efficacy profile, it is the least a biogeneric company must adhere to in order to ensure that their products have comparable efficacy and safety as that of the innovator’s product. An interesting observation was that all biogeneric samples of EPO had potency values higher than the innovator’s product, partly attributable to higher amounts of protein content, presumably because overages are permitted in India. Two samples (P9/CA/01 and P9/CA/07) showed greater than

Table 4B

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Chromatogram of RP-HPLC of different brands of rHu-GCSF

Figure 10B

SDS PAGE followed by Immunoblot of various brands of rHu EPO

Figure 11

0.5 per cent aggregates. Higher levels of product-related impurities (such as aggregates) are highly undesirable as they are known to be immunogenic. Similarly non-comparative isoform profile (e.g. in the case of EPO) can affect in vivo efficacy and immunogenic response.

Worldwide, there have been over 188 cases of Pure Red Cell Aplasia (PRCA)—a rare adverse event known to occur in patients receiving EPO, many of which were subsequent to the manufacturing changes introduced by Johnson and Johnson for its product EprexTM, (which included a formulation change that was free of Human Serum Albumin (HSA), use of uncoated rubber stoppers and change in the route of administration from intravenous to subcutaneous). This adverse event was attributed to impurities which were leached from the rubber stoppers.

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It is now widely known that impurities present in biopharmaceuticals (including protein aggregates) are known to induce immunogenic response to a therapeutic protein. Therefore, it is absolutely important for biogeneric products to have comparable (or lower) levels of impurities as well as a similar impurity profile as compared to the innovator’s product.

There are reports citing various factors which confer risk to the patients and have emphasised the need to control them. Yet many biogeneric companies in India seem to be oblivious of these risk-factors or not doing enough to control them. It is, therefore, necessary that Indian regulatory agencies make it mandatory for biogeneric companies to comply with standards laid in Indian Pharmacopoeia for at least six drug substances. It is also necessary for the National Drug Control Laboratory to maintain vigilance on the quality of

various marketed products from time to time to ensure that certain standards of quality are maintained for all biogeneric products. It is necessary for companies to maintain comparability of their product to the innovator’s drug at all times.

Biopharmaceuticals are susceptible to degradation and aggregation at elevated temperatures and have to be maintained at +2 to +8oC. Failure to maintain this temperature either during shipment or storage can easily accelerate generation of impurities such as aggregates and oxidised forms. This could well be the reason for such impurities as seen in this study. In a country like India, where in the peak of summer, temperatures can reach above 45oC, a robust cold chain is absolutely required. In Thailand, after the incidence of Eprex-associated PRCA peaked in 2002, there were additional 15 non-Eprex PRCA cases reported with biogenerics, some of which have HAS in the formulation. This has been attributed to poor cold chain maintenance. Similar case of PRCA has been reported with the use of a biogeneric EPO in India.

Extreme caution is exercised by the Indian regulatory agencies before granting marketing authorisation of biogeneric products. Prior to the approval for preclinical and clinical studies, it is mandatory for biogeneric companies to provide proof of physico-chemical comparability of the product made from five consecutive batches to the innovator’s drug. It is clear from this current study that in spite of such scrutiny exercised by the regulatory agencies, biogeneric products in India are not comparable to the innovator’s products. It is not known whether the lack of comparability is a result of batch-to-batch variation or a systemic failure to maintain them comparable or a breach in the cold chain affecting their quality. Consistent with our observation, similar comparative study has reported high variability of epoetin products launched in Korea, Argentina, China and India. Although this does not necessarily mean that these products are clinically inferior, maintenance of appropriate

IEF followed by Immunoblot of various brands of rHu EPO

Figure 12

Conclusion

Significant difference in the level of purity has been observed among

various brands of biogenerics of G-CSF and EPO. The degree of purity for some brands was below the Pharm. Eur. and Indian Pharmacopoeia standards. It is time that the Indian regulators should raise the expectation bar. This can be achieved once it will become mandatory

Acknowledgement We wish to thank Vijay Anand, Alkesh Ajameri and Snehal Roy for their valuable contributions to this investigation. We sincerely acknowledge the contribution of Dhananjay Patankar towards helpful discussion and valuable suggestions offered during the manuscript preparation.

Rustom Mody completed his PhD from Department of Microbiology, MS University of Baroda, India. He was a Research Associate for six years at the University of Nebraska Medical Center at Omaha, USA, where he worked in diverse research areas such as immunochemistry, molecular immunology and cancer biology. Currently, He is heading R&D and Quality divisions of Intas Biopharmaceuticals Ltd., with a focus on developing products and intellectual property that could give the company a strategic advantage and global reach.

Authors

internationally accepted quality standards can help to safeguard the interest of biogeneric industry on the long run.

Intas Biopharmaceuticals Ltd. was the only Indian company whose all three biogeneric products were found to be comparable to the innovator brands. All three products (Neupeg, Neukine and Erykine) of Intas Biopharmaceuticals were found to be biosimilar to the innovatorsâ&#x20AC;&#x2122; products (Neulastim, Neupogen, Eprex) with respect to all quality parameters used in the study.

We monitored storage temperatures of various warehouses across India of Clearing and Forwarding agents (who distribute the products in local geographic regions). As a revelation, it was found that many of them did not meet the specified storage conditions. As a corrective and preventive measure, temperatures at all clearing and Forwarding warehouses are now being monitored on a continuous basis. Such measures play a vital role in ensuring patient safety.

for biosimilar companies to comply with the quality standards as given in the product-specific monographs in the Indian Pharmacopoeia. However, the Reference Standards required for comparison are not available till date. Introduction of National Reference Standards should be done on priority.

In the long run, it will be in the interest of Indian biogeneric companies to observe biogeneric guidelines as per the standards laid down by EMEA, if Indian companies have to emerge as global suppliers of biogeneric products. This is because many regulators are now focussing on EMEA guidelines as a benchmark. It is time for the Indian biogeneric players to go beyond Pharmacopoeia quality standards and also ensure stricter monitoring of temperatures during post-manufacturing storage and distribution.

Vishakha Goradia is working as Senior Executive in Quality Control Department of Intas Biopharmaceuticals Ltd. She is postgraduate in Microbiology from Bhavnagar University and having six years of professional experience in biotech Industry. She joined IBPL in 2003 and is associated with analysis of cell culture based products.

Deepak Gupta is currently heading analytical Quality Control department of Indiaâ&#x20AC;&#x2122;s only EU-GMP approved biopharmaceutical plant at Intas Biopharmaceuticals Ltd. Being associated with the Indian biotechnology industry for the past eight years, he has been responsible for quality control of several bio-therapeutics products.

He joined Intas in 2007 and prior to this he worked for Panacea Biotec Ltd and Biological E. Ltd. He received his MSc in microbiology from Gurukul University.

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49

Manufacturing

The Freeze Drying of Biologicals Recent trends

Although conventional freeze drying in vials is still the predominant format, lyophilisation in alternative formats, such as pre-filled syringes, and alternate technologies such as spray freeze drying are becoming more popular.

Paul Matejtschuk Principal Scientist Standardization Science, National Institute for Biological Standards & Control Health Protection Agency, UK

L

yophilisation or freeze drying is a process widely used in the preparation of biopharmaceuticals and biologicals (Rey & May 2004) because it allows greater storage stability for otherwise labile biomolecules, provides a convenient storage and shippage format and following reconstitution rapidly delivers the product in its original formulation, ready for use.

The worldwide biopharmaceuticals market may well be worth US$ 40 billion annually and comprises over 100 licensed products with many more in the development pipeline. A large proportion of these products are lyophilised and whereas this includes more traditional products such as coagulation factors, cellular-derived vaccines and immunoglobulins, it also is a popular format for the products of the biotechnology industry, monoclonal antibodies growth factors, cytokines and recombinant vaccines (Constantino & Pikal 2004). Although conventional freeze drying in vials is still the predominant format, lyophilisation in alternative

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formats, such as pre-filled syringes (Hottot et al. 2009), and alternate technologies such as spray freeze drying especially where inhaled formats are envisaged (Misra et al. 2009) are becoming more popular.

Lyophilisation as a commercial process has been in existence for over 50 years and it was once a poorly understood technology, often thought to be more art than science. It is now increasingly guided by developmental design, based on information derived from analytical studies and optimised by means of high technology process monitoring methods.

Recent trends â&#x20AC;&#x201C; Thermal methods

In lyophilisation a usually aqueous solution of the active component is dried at sub-ambient temperatures, removing the majority of the constituent water but maintaining the biological activity. Lyophilisation is composed of three basic stages preceded by a number of enabling technologies. A product is firstly formulated, sterile filtered (at least for

therapeutic applications) and dispensed into appropriate containers. It is then transferred to the freeze dryer and the process begun by a freezing step, then a period of sublimation under vacuum at sub-ambient temperatures, and finally a further drying period at ambient or elevated temperatures to deliver a product of suitable residual water content. At this point, the atmospheric headspace pressure is adjusted according to process and the containers sealed by stoppering down of the halobutyl or similar closures.

The product is then removed for crimping or sealing, labeling and assessment, for compliance with pre-defined quality attributes, before release.

In order to maintain a homogeneous and robust macroscopic appearance in the dried state both the process conditions and formulation should be appropriate.

By lowering the temperature of the sample the majority of the water is crystallized as ice, any crystallisable salts may have crystallised and the biologically active material is trapped in a glassy state where the

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Manufacturing

Modulated Differential Scanning Calorimetry of heparin sample showing Tg’ at -22°C

Figure 1A

Freeze drying microscopy of heparin under plane polarized light, showing (left to right) freezing (-50°C), drying (-20°C 100µbar) and eventual collapse (-14°C)

Figure 1B

Dynamic mechanical analysis of heparin sample (at 1Hz of frozen sample in a steel powder pocket) showing a change in Tan Delta corresponding to the Tg’ at -18°C

Figure 1C

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biological material, together with excipient molecules and associated water become effectively immobilised, this is termed the glass transition point. Only at this point can drying begin, if the macroscopic structure of the freeze drying material is to be maintained. If this temperature is exceeded then collapse results and this collapsed state may trap higher levels of residual water and possibly result in reduced stability, though the generality of this concept has been challenged by some recent examples (Wang et al. 2004). It is possible to prevent macroscopic collapse and to deliver an acceptable appearance by generating a crystalline structure using excipients such as mannitol or glycine, but if the biological material is trapped in a collapsed amorphous state surrounded by this structure there may still be impaired stability (Passot et al. 2007). This may be similar to the phenomenon described by some workers as micro-collapse where some shrinkage results but the overall structure is maintained.

The determination then of the glass transition temperature is very important and there now exist a number of powerful techniques for its determination (Kett et al. 2005). Historically, eutectic or electrical resistivity monitors were developed, which were simple to use and gave broad indication of the gross transition temperature, though these techniques were less appropriate where mainly non-ionic formulations were used.

More powerful techniques such as modulated differential scanning calorimetry can identify glass transitions but these must be well separated from the energetically far larger eutectic or melt events for them to be adequately resolved. Other techniques such as dynamic mechanical analysis, which are less influenced by the melt of ice, may give useful information, as may techniques such as electrical impedence (Rey in Rey & May 2004, Ward & Matejtschuk 2007). Freeze drying microscopy, though it is not a thermal analysis method as such, is an extremely valuable tool in determining the temperature at which collapse is observed

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Manufacturing

(Fleck et al. 2003). Samples of volume as little as 2-5 ÎźL may generate useful data as the freezing, thermal tempering and finally sublimation are modelled at a microscopic scale. Figure 1 gives examples for heparin, comparing some of these techniques. The comparison of glass transition and collapse temperature data and their interpretation has been recently discussed (Meister & Geiseler 2008) Recent trends â&#x20AC;&#x201C; PAT

Once such temperatures are established, pilot trial studies can be performed in laboratory-scale freeze dryers and the cycle to be used designed based on the results obtained and allow for formulations to be compared and biological activity and its stability assessed (Matejtschuk et al.

2009).The scale up from these laboratory studies to production scale is however a challenge and one which requires an understanding not only of the physical properties of the material to be dried (Nail et al. 2002), but also the influence of the container and the freeze dryer on the drying process (Geiseler & Lee 2008).

This issue is increasing being addressed

by Process AnalyticalTechnology (PAT) where a combination of non-invasive sensory methods are allowing crucial parameters such as the shelf temperature, vacuum applied and length of primary drying and secondary drying to be determined. Once, such parameters had to be studied by series of pilot scale trials, followed by post-run Quality Control analysis. Now the information gained by non-invasive monitoring can streamline the scale up process and even be used in real time to define the run cycle used.

Among these monitoring techniques are manometric pressure rise testing (Geiseler et al. 2007a), changes in water vapour flux generation (using laser light absorption in the spool inter connecting chamber and condenser (Geiseler et al. 2007b) and cold plasma desorption (Mayersese et al.

2007) which look at the overall sublimative properties of a batch. There are other techniques based on gravimetric methods which measure mass loss over primary drying in individual vials (Schmid and Geiseler 2008) and the use of non invasive NIR and Raman Spectroscopy (De Beer

et al. 2009) to study water loss. Some of these technologies are applicable only in laboratory or pilot scale equipment whereas others can be fitted in production scale machines also.

Recent trends â&#x20AC;&#x201C; Formulation & stability

Lyophilisation can result in the loss of biological activity, thought to be due often to the effects of dehydration and stripping away of the water associated with the three dimensional structure of a biopharmaceutical drug. For this reason water-replacing excipients such as non-reducing sugars are particularly good lyoprotectants though whether this is due to their ability to replace water in the dried state (Allison et al. 1999) or to form a rigid glass in which the biologically active material is immobilised (Franks et al. 1991), or a combination of both mechanisms, is still a matter of research .

Certain materials may require specific stabilisers, others may benefit from a combination of stabilisers (Hubbard et al. 2007, Amorij et al. 2007). Proteins are often themselves excellent stabilisers and combinations of polymeric and small molecule stabilisers may be preferable in achieving the long term stability of biopharmaceuticals (Wang 2000). Recent studies have investigated the impact of cycle design on long term stability (Luthra et al. 2008) and the importance not just of the glass transition but of dynamic mobility within the lyophilised material on long term stability (Pikal et al.

2008) Use of reference materials

Potency estimates for lyophilised IL-29 Reference materials. Typical dose-response data from the reporter genes assay are shown in the graphical plots. The geometric mean potency values for each of the 2 ampoules (A & B) of 07/212 (process batch, red and blue lines) and each of the 2 ampoules of PM-037A (intermediate trial batch, green and orange lines) do not differ significantly from one another or from the value assigned to the frozen baseline (black triangular line). The assay background without addition of IL-29 is shown in black squares.

Figure 2

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The rise of interest in biosimilar or biogeneric drugs in the biopharmaceutical industry requires reliable, internationally recognised, stable and well-characterised biological reference materials to act as controls in development and regulation.

These are particularly valuable where the activity of the biological product requires characterisation against both bioassays and biophysical means (Silva et al. 2008). Such

Manufacturing

cell-based assay. The reactivity of the trial and definitive batches closely paralleled each other and the frozen unlyophilised material.

Summary

Lyophilisation is progressively becoming a more rationally controlled process . With the rise of better analytical technologies, to understand the physicochemical processes of freezing and sublimation, together with a range of process analytical controls to optimise the freeze drying cycles and scale them for manufacture, the technology can be applied with confidence to high value biotechnology

Author

reference materials must be more stable than the drugs they are compared with and so lyophilisation to exacting quality control parameters is necessary (WHO 2006). By comparison of therapeutic materials with these standards, often across a range of assay methods, better understanding of dosage and biological equivalence can be achieved and this is complementary to the extensive biophysical and molecular characterisation which is performed. Whereas once such reference materials were usually sera or plasma now a whole range of purified as well as part-purified materials may be used and in addition to proteins, DNA, RNA and even cellular materials are being prepared as standards. To meet their specification these materials like the products they characterise are lyophilised to ensure stability and consistency. A comparison of the potencies of development and definitive batches of interleukin-29 reference material are shown in Figure 2 using a

products. By use of high order lyophilised reference materials the characterisation of new vaccine and biotechnological products, both novel and biosimilars, can be better assured and the process of developing and controlling biopharmaceutical medicines facilitated.

Acknowledgements The author thanks his NIBSC colleagues Dr Tony Meager and Kiran Malik for use of their data and John Gearing (Gearing Scientific Ltd, Ashwell,UK) for the DMA analysis.

Full references are available at www.pharmafocusasia.com/magazine/

Paul Matejtschuk is a Principal Scientist at the National Institute for Biological Standards & Control (NIBSC), a centre of the Health Protection Agency of the United Kingdom, where he leads research on the formulation and lyophilisation of biological references materials.

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55

PharmaEvents

September 2009

July 2009

September 13 - 15, 2009

July 1 - 3, 2009 22nd Interphex Japan Venue : Tokyo Big Sight, Japan Organisers : Reed Exhibition Email : Interphex@reedexpo.co.jp Website : www.interphex.jp July 1 - 3, 2009 Pharma Pack 2009 Venue Organisers Email Website

: Tokyo Big Sight, Japan : Reed Exhibitions : Interphex@reedexpo.co.jp : www.interphex.jp

July 18 - 25, 2009 2nd Annual World Summit of Antivirals Venue : Beijing and Xi’an, China Organisers : BIT Life Sciences Email : yolanda@bitlifescineces.com Website : www.bit-wsa.com

ISPE Australia Conference 2009 Venue : Sydney Convention & Exhibition Centre,

Australia ICMS Pty Ltd Email : ispe2009@icms.com.au Website : www.ispe2009.com September 23 – 25, 2009 World Pharma Trials Asia 2009 Venue Organisers Email Website

: Grand Hyatt Shanghai, China : Terrapinn Ltd. : tingting.wang@terrapinn.com : www.terrapinn.com

September 29 - October 1, 2009 Analytica AnaconIndia Venue : Hyderabad, India Organisers : Messe München GmbH Email : weidner@imag.de Website : www.analyticaindia.com

August 2009

October 2009

August 13 -17, 2009

Oct 22 - 25, 2009

Modernization of Chinese Medicine & Health Products Exhibition Venue : Hong Kong Convention & Exhibition

Centre (HKCEC), Wan Chai, China Organisers : Hong Kong Trade Development Council Email : hktdc@hktdc.org Website : icmcm.hktdc.com

7th Annual Congress of International Drug Discovery Science & Technology Venue

Organisers Email Website

: Shanghai Everbright Convention & Exhibition Center, China : BIT Life Sciences : annie@iddst.com : www.iddst.com www.pharmafocusasia.com

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Committed to quality service and solutions Choksi Laboratories Ltd. (CLL), established in 1982, is a leading analytical, calibration and research group. CLL provides complete solutions for improving quality in: • Processes • Products • Services Better quality products and latest technical procedures result in quality products. CLL currently has facilities for analysis of over 1000 products and materials, with more being added every day. With over 20 regional in Gujarat, MP, Rajasthan, Haryana, Punjab, Karnataka, AP, MP Maharashtra, Goa, Kolkota and New Delhi. CLL has four state-of-the-art laboratories located at Indore (MP), Vadodara (GJ), Vapi (GJ) and Panchkula.

CORE SERVICE AREAS Drugs & Chemical Analysis: With an expert team of over hundred trained analytical chemists, microbiologists and engineers, CLL offers microbiological, wet-lab, instrumentation, and animal-house facilities for allopathic, ayurvedic, as well as herbal drug analysis. Test Methods and facilities as per USP, BP, EP, IP, IHP, BHP, IAP, and several others are available at CLL’s FDA approved labs.

These laboratories are equipped with the most advanced analytical instruments such as LC MS/MS, GC, UV/VIS, AAS, UTM, FTIR, GC-MS, Particle size Analyzer, HPLC, IC. Agro & Agro derivative Analysis: CLL caters to the specific needs of agro producers, dairies farmers as well as secondary market players to meet standards of WHO, AOAC (USA), BIS, PFA, and AGMARK. CLL is an approved laboratory for solvent Extractors Association, SOPA, Food Corporation of India (FCI), and National Dairy Development Board (NDDB).

Water Analysis: Pure & safe drinking water is an important part of life. We ensure the water you use in your family or serve your customers is really ‘pure and safe’, with analysis facilities for potable drinking water, packaged drinking water, DM water and drinking water as per WHO, IS, EPA, FPO specifications.

Building Material Analysis: CLL’s Building Material Division has been serving the construction and infrastructure development community with complete chemical & physical analysis of Bricks, Cement/Lime, Fly ash, Metals, Paints, PVC pipes, Sand / Aggregate and Tiles. CLL has been a partner of choice for several national projects such as indore – Dewas Expressway, GAIL’s Vijaypur-Hazira Natural Gas Pipeline, Bharat Petroleum’s MIPL Pipeline etc.

Environment Management: The Environment Management Division of CLL offers O&M as well as Turnkey services for Wastewater management and Air pollution

monitoring, ISO-14000 EMS, EIA Studies, Environment audit, Hospital & Hazardous water management.

Consultancy: CLL’s currently offers consultancy on HACCP Compliance for Food industry, Lab setup for Packaged Drinking water manufacturer, compliance to GMP / schedule-M for Indian Drugs manufacturers, Environment audits and Analytical Laboratory set up for manufacturers.

ACCREDITATIONS CLL is approved by Bureau of Indian Standard (BIS), Ministry of Health & Welfare (MoHW – GoI), MoEF, Food & Drug Control Administration (FDA), State Pollution Control Boards (PCB), Agricultural Marketing Advisor to the Government of Indian (AGMARK) and National Accreditation borad for Testing and Calibration Laboratory (NABL – ISO Guide 17025) in the field of chemical, biological, Mechanical, Thermal, Elector-technical equipped with the state of art Test & Measurement facilities, managed by qualified and experienced personnels and Export Inspection Council Of India (EIC) NABL has mutual recognition agreement (MRA) with Asia pacific Laboratory Accreditation Co-operation (APLAC) and International Laboratory Accreditation Cooperation (ILAC). This arrangement means analysis or calibration done in India by an NABL accredited laboratory will be accepted by 28 others economies including USA, UK, Australia and Canada. CLL offers on-site, laboratory and plant shutdown calibration for equipment in all major categories i.e. Pressure, Thermal, Electrical, Mass, Force, Volume, and Dimension Metrology. We also offer calibration of analytical instruments. Direct traceability is provided to NPL (India) and NIST (USA) in major areas.

Additional Benefits • NABL Accredited Laboratories • Internationally accepted level of services • Traceability to National/International Standard (i.e.

NPL,NIST, ERTL etc.) for instruments.

• Uncertainty Measurement in all calibration as per international requirement • High accuracy analytical standards from NIST (USA) or USP/EP/BP. • 24 hour turnaround service on request • On site calibration and plant shut down calibration as required by customers • customized annual contracts – affordable and hassle-free quality assurance solutions.

To find out more about how we can help you with your Quality Assurance needs, feel free to contact us at info@choksilab.com

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57

Advertorial

Where do the current partnering opportunities lie for Pharma and biotech?

Because R&D productivity is a problem for pharma the partnering opportunities are basically seen in licensing and acquisitions. There are many opportunities because this year itself you have seen the speed of deal making in the US and in Europe between all kind of companies on one side. You have seen Roche, Merck, GSK, all deals were best which were based on this.

With more multinational companies showing interest, the M&A activity in India is expected to go up in the near future. What does this mean for the Indian pharma sector? Do you think was long overdue?

I donâ&#x20AC;&#x2122;t think it is long overdue. It is just that now after Daiichi Sankyo bought Ranbaxy a lot of Indian promoters began to think about should we sell or should we hold on. Because if we hold on, it would

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require a lot of investment and in far away future generics may become increasingly difficult to make money from. It is a big business, but may be if the big pharma enter, the returns may go down. So it is better to sell now when the value is high than later. So one thinking like that has come. In terms of foreign multi-national companies, they also have started thinking last two to three years that India and China are the most attractive markets.

And they need to do more to increase the size of their companies here which is actually small. So both from MNCs who want to increase the size in India, and from Indian promoters who may want to cash in, that means that there is a likelihood that the deal may be done.

With smaller firms being targeted, where does this leave the big pharma acquisitions that were so rampant not so long ago?

Both small and large firms are being

targeted. If you see in recent days there was lot of talk about Wockhardt, Nicholas Piramal in the press. Talking from an Indian perspective, those are large firms. And in the global level, you have seen some billion dollar mega mergers between Pfizer and Wyeth, Merck and Schering Plough.

On the contrary, big firms are equally in demand India, along with other developing countries in the Asia-Pacific region, holds huge potential for drug makers.

Do you think market is finally getting ready for major players?

I think it is getting ready because lot of developments are taking place which, for example, will enable more investment in infrastructure, better quality of pharmacy retail, there are a lot of regulations and legislations in IP that the government is promoting in order to give more IP protection such as in

M&A and Partnerships in Pharma Rising opportunities

Sujay J Shetty Associate Director Pharma Life Sciences Advisory Corporate Finance PriceWaterhousecoopers, India

data exclusivity, clinical trail establishment which will afford more protection and more transparency to outsource and compete in pharmaceutical sector.

The environment is and enabling environment at the policy level and at the infrastructural level it is getting much better.

gone up in the last few days, they will continue to expect very high valuations.

Indian firms are very richly valued or highly valued. That is one of the reasons why as many deals as should have taken place have not taken place due to promoters wanting excessive valuation / big valuation.

Compared to their European and American counterparts, Indian firms are considered to be undervalued. Do you think this is one of the major factors in bringing multinationals to India?

Not at all. I don’t think Indian firms are undervalued. In fact, we are hearing that the valuations are rich. So that is actually one of the reasons for the deals have not been done as much as they should have been done. So, we feel the opposite of this question is true, that, Indian firms are highly valued. In fact because promoters expect unrealistic valuations and now sensex have been

From and Indian biotech / pharma company’s point-of-view, what is better, a partnership or an acquisition?

It is difficult to answer because it is different for each company. It depends on the strategies and the objectives of the acquirer. If they feel they have specific skills that they can tap into which can be better addressed in partnership, for example drug discovery, if they want to do drug discovery then may be partnership is better. But if they want to gain scale and gain size in India, then may be acquisition is better. So it is directed towards the objective.

Has the global recession had any effect on this trend?

No, because pharmaceutical companies are kind of defensive and anti-cyclical.

So they have been seen in a safe bets in this economy. And we have seen that even big mergers like Pfizer-Wyeth, Merck-Schering Plough, which are tens of billions of dollars, have had no problems in raising money for those acquisitions. So, we haven’t seen that much of an impact.

Any other comments you would like to make?

I think this is very fertile time for M&A environment in India because the market is growing and there is a lot of interest from MNCs both in India and in generic companies. While the pace of deal making may be slow, it can’t be denied that Daiichi and Ranbaxy was a watershed event and we do expect such deals in due course of time.

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59

Where do the current partnering opportunities lie for Pharma and biotech?

Partnering opportunities exist across all segments of the Industry, namely, drug discovery, development, clinical trials, data management (IT), manufacturing and marketing.

With more multinational companies showing interest, the M&A activity in India is expected to go up in the near future. What does this mean for the Indian pharma sector? Do you think was long overdue?

Historically, Indian pharma companies have been founded and managed by owner-entrepeneurs. Consequently, Indian pharma companies are costconscious and responsive organisations.

The growth trajectory of the Indian pharma companies began with establishment of Indian Patents Act 1970.

However, most companies remained

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India's growing respect and legal / regulatory framework for IPR, favourable economic policies resulting into attractive investment destination and availability of huge talent pool for sustaining and growing operations is making India an attractive destination for multinationals now.

essentially domestic players till 1990.

Thereafter, the Indian Economy started opening up, and the industry made efforts to integrate with its global counterpart. Increased M&A activity is the consequence.

Indian pharma companies have acquired companies abroad and Multinationals have made acquisitions in India. To the Indian pharma companies, this brings an opportunity to play on a much bigger turf, and learn to acquire skills to play on a much wider turf.

The acquired organisations will expect to see quantum jump in the volume of activities, since most acquirers would like to leverage the cost advantage to supply to global markets. The acquirers would have to learn to â&#x20AC;&#x2DC;quickly digest the acquisitionsâ&#x20AC;&#x2122; and operate in different, challenging and rapidly changing environments.

M&A and Partnerships in Pharma Indian scenario

Ganesh Nayak Executive Director Zydus Cadila, India

With smaller firms being targeted, where does this leave the big pharma acquisitions that were so rampant not so long ago?

Large or small, companies are valued for their strategic worth. There has been a healthy debate on ‘sense’ of Big Bang Acquisitions in Pharma Industry for a while. Big Bang acquisitions are difficult to digest. Going forward, wisdom shall prevail. However, as of now, many large pharma companies have made their intent public by announcing that they would stay away from Big acquisitions.

India, along with other developing countries in the Asia-Pacific region, holds huge potential for drug makers.

Do you think market is finally getting ready for major players?

Certainly. With signing of the WTO, and larger part of population agreeing to

honour IPR, markets in Asia Pacific are ready to be a pert in global play. Apart from India and China, countries like Indonesia and Bangladesh have large population bases, varied disease profiles and, now, growing potential to pay.

Compared to their European and American counterparts, Indian firms are considered to be undervalued. Do you think this is one of the major factors in bringing multinationals to India?

Valuation is one consideration. Indian pharma companies are undervalued and that makes them interesting targets.

Acquirers are prepared to pay higher multiples for undervalued assets with huge strategic upside. In addition, what makes India an attractive destination for multinationals now, is, her growing respect—and legal / regulatory framework—for IPR, favourable economic policies resulting into attractive

investment destination and availability of huge talent pool for sustaining and growing operations.

From and Indian biotech / pharma company’s point-of-view, what is better, a partnership or an acquisition?

Partnering is always a better option from Indian perspective.

Has the global recession had any effect on this trend?

The ‘Health Care Costs’ feature as the top most concern for most governments in developed world. When their economies are heading southward, healthcare costs have become all the more important. Therefore, recession would only accelerate the need for more efficient players in the healthcare industry, so that, inclusive care can be provided to a wider section of population at lower costs.

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61

Clinical trials

Managing a Major eCTD Filing An Amgen case study

This is a case study of how Amgen manages a major electronic Common Technical Document filing. It focusses on tools and processes developed and refined from 2005 to present. During this time, Amgen has filed three original Marketing Applications with an operational goal of submitting these simultaneously in four major regions (US, Canada, EU and Australia). Since operations groups exist in a fluid environment defined by evolving technology, it is important that these tools and processes adapt to meet the changing landscape of regulatory publishing.

Bryan M Noel Senior Associate Submission Publishing Group, Amgen, USA

T

he electronic Common Technical Document (eCTD) format provides an opportunity for regulatory operations groups to gain significant efficiencies through the standardisation and automation of publishing processes. In order to take advantage of this opportunity, it is important to first identify what kinds of tools are needed. Some of these tools are elementary: a Document Management System (DMS), Portable Document Format (PDF) authoring tools and eCTD construction software. Some of these tools are specialised and will aid in the automation of processes: authoring templates and PDF plug-ins.

A DMS is the foundation of any regulatory submission whether the final format is paper or electronic. Such a system should provide version control for auditing purposes, a centralised location for each submission and should utilise a “lock out” feature that prevents changes

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to final documents without notifying the publisher.

Amgen publishing works with what are termed as “submission-ready” PDF files created from word processing source files provided by the authors. To create these documents, software or print drivers are needed to convert the word processing files into PDFs. There are a number of tools available for this task; one that makes use of various heading styles, caption styles and other template features in the source files to create navigational elements, is highly recommended.

An eCTD submission can be created by manually coding the required Extensible Markup Language (XML), but the complexity of the actual code behind an eCTD submission makes the need for eCTD construction software apparent. Construction software will create the XML code, manage the required metadata, create folder structures and allow for life-cycling management of

documents, but those are just the basic expectations. In addition to these features, the programme should allow multiple users to access the same submission simultaneously and have a feature that enables cloning of a submission in order to take full advantage of the resources available during a global filing. The importance of multiple-user access becomes clear when the structure of Amgen’s global publishing team is examined. Amgen currently uses the US submission structure as the base, portions of which are cloned by regional publishers throughout the global filing timeline. This ability to repurpose submissions eliminates a large amount of rework and aids in creating a consistent submission across regions.

Another key component in creating successful submissions is creating and managing global authoring templates.

When creating these templates, regional differences must be considered. Putting region-specific information such as a

ing, perform basic quality control checks across one or more files and set standard document settings such as open options, inherit zoom magnification, fast web view and PDF version. Although these items may seem small when examined individually, a macro view of the entire publishing process makes the benefits obvious.

Publishing workflow

While the development of software tools available to an operations group is largely determined by product vendors and economic realities, the processes that make use of the tools are almost entirely controllable. There are certainly limitations around any proposed changes in processes: how nimble is the organisation, will other business partners be amenable and are the proposed changes realistic. However, significant benefits can be reaped if processes are efficient, scalable and flexible.

Amgenâ&#x20AC;&#x2122;s publishing group is made up of several regional groups that can be categorised into two major sub-groups: component publishing and submission publishing. How and when these groups interact with authors as well as each other is a large part of the publishing process.

The responsibilities of authors and publishers should be clearly defined and accepted. Use and ownership of templates, formatting duties and quality of source documents are some of the major areas that must be defined. Establishing an agreed upon and mutually beneficial set of standards requires early planning and open communication.

When publishers and authors interact at Amgen, it is with the understanding that publishers are responsible for technical aspects of the submission while authors manage content-related issues. Authors are asked to make use of global templates in the central DMS location, while the

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CaseStudy

license number or a proprietary product name in the header of a document can mean the difference between a regional publisher being able to use a document as-is or having to reprocess the file to remove the offending information. Proper use of templates affords other benefits as well. As authors become familiar with a standard set of formatting tools, such as macros and styles, publishers spend less time dealing with corrupted documents or tailoring the formatting to accomplish a standard appearance. A consistent document style, the â&#x20AC;&#x153;look and feelâ&#x20AC;? of a file, creates a coherent interface for reviewers across files, modules and applications.

There are a number of third-party manufacturers who provide software solutions that aid in the creation and publishing of PDF files. Amgen utilises a number of these products to aid in the publishing process, including software that can create and manage bookmarks, automate intra and inter-document link-

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Clinical trials

publisher formats these source documents.

Publishers and authors open communication channels early to discuss such critical items as hand-off dates, construction of documents from multiple files, standard syntax of hyperlink references and Main responsibilities of submission publishers include: tracking documents, ensuring all required documents are present in the DMS, building documents in the eCTD construction software, applying standard leaf titles and filenames, post-publishing tasks (such as inter-document linking) and managing comments received during final team review of the completed submission.

final approval of published documents.

The publishing also provides support to authors on technical issues.

Component publishers are the first line of contact for an author. Primary component publishing responsibilities include formatting source files, generating PDFs from those files, creating intra-document navigational items and gaining author approval of component published documents. Once these tasks are completed, approved â&#x20AC;&#x153;submissionready componentsâ&#x20AC;? are delivered to submission publishers.

Typically, one submission publisher is assigned to a product per region, but for a major filing, this model is not always effective. During a major filing, a publishing lead is established for each region of interest, and the lead is given the flexibility to assemble a team of submission and component publishers as needed.

Since the US submission is used as the base for all other regions at Amgen, most of the component publishing is handled by the US team. Regional component publishers take responsibility for regionspecific documents.

During the most recent filing at Amgen, for example, the US submission team utilised four module submission publishers: one for Modules 1 and 2 and one for each technical module

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(Modules 3-5). Five component publishers were assigned to the project: one for Module 2, one for Module 3 and three for Module 5, due to the size of this module. For Module 1, the submission publisher also took component responsibilities due to its relatively small size.

Because the studies in Module 4 were finalised before many of the other documents, the submission publisher was able to component publish these files. In this particular submission, many Module 3 documents were completed far enough in advance that the Module 3 submission publisher also served as the Module 2 component publisher. In total, eight publishers (component and submission) filled eleven roles; (the total number of roles and individuals can be adjusted depending upon need, timelines and resources). Once the team structure was established, regularly scheduled meetings between all regional leaders as well as individual regional team meetings were held to track progress towards completion and discussion of any issues encountered.

There are a number of finalisation steps that take place after the submission is published and before it is submitted to the regulatory agency. Although these steps may seem minor, they can take a significant amount of time, and adequate planning is required to ensure a successful submission.

Current Amgen process requires a team review of the final published submission. This review period is an opportunity to take one last look to ensure that all documents are present, correct versions are included and documents reside in their expected locations

within the eCTD. A review panel of appropriate size, one large enough to include major contributors but small enough to avoid unnecessary or repetitive comments, should be determined based on varying needs of a particular submission. The review panel convened in this example included representatives from the global regulatory team responsible for reviewing the overall submission, technical module leaders from functional areas to review the technical modules and related summaries, and submission publishers to review technical aspects.

This review was performed in stages as individual modules were completed.

Staggering the review period provided the module submission publishers time to incorporate comments received and allowed the regional publishing leads to clone completed modules earlier which granted them more time to make regional adjustments, including the production of a paper dossier, if necessary.

Once final team review comments are received and incorporated by submission publishers, final validation procedures are performed. Quality control plug-ins are used to take a high-level look at the entire submission. Checksums are generated using built-in functionality in the eCTD construction software, or a separate application, and the final submission is validated in each region. Virus scans are performed on the final submission, which is then sent to the regulators on an appropriate media format.

Working globally

Thus far, the discussion of Amgenâ&#x20AC;&#x2122;s publishing processes has focussed on the US filing. While regional publishers

Changes in technology and process during the period discussed have allowed for a greater degree of simultaneous work across regions and targeted cloning of the base submission. The eCTD construction software allowed for more than one submission publisher to work on the same application at the same time, reducing the overall timeline for construction. This reduction in time allowed modules to be completed earlier, and as a result, other regions were able to clone the submission in phases rather than waiting to clone the entire application. This early and targeted cloning allowed regional publishers to begin any required modifications at an earlier point in time and freed resources that could be put towards the remaining modules.

Future improvements

Every process has room for improvement, and Amgenâ&#x20AC;&#x2122;s process is no different. As the DMS software improves, better inte-

gration with the eCTD construction software can develop. Global publishers can take better advantage of time differences and standardisation of publishing processes across regions to create a nearly continuous production cycle. As submission formats continues to evolve, we also move closer to the goal of full reuse of technical modules. These are but a few of the areas in which improvements can be made, but an operations group must be able to adapt to the changing submissions landscape in order to take full advantage of new technologies and develop processes that will lead to a successful simultaneous global filing.

CaseStudy

information globally; certain regulatory authorities prefer different locations for some Module 3 information; some regions request additional information that would not be submitted elsewhere.

Examining the overall submission table of contents and identifying where these differences exist, especially eCTD location differences, can allow these issues to be addressed before publishing begins or avoided entirely.

Author

follow a similar process, there are certain challenges to consider; the earlier those challenges are identified and addressed, the greater the chance for efficient and successful submission. Major issues include timing of regional filings, cloning structures and regional differences.

The timeline for each region should be established early on in the process.

It should be realistic and should gather input from all functional areas. This timeline should be based on past efforts and adjusted to compensate for changes in technology and process improvements.

Early completion of modules on a global scale allows more resources to be directed towards regional differences.

Although the idea of the eCTD is to enable the reuse of technical modules across each region, the reality is different. For example, the US makes use of Study Tagging Files in Module 5; regional portions of Module 3 contain different

Bryan M Noel is a Senior Associate in the Submission Publishing Group at Amgen with over eight years of experience in regulatory publishing.

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Information technology

Regulatory Information Management Leveraging standards and efficiencies of eCTDs

In managing Chemistry, Manufacturing and Controls documents, the larger process is involved for electronic regulatory submissions to health authorities.

This is a case of an entire process standard providing significant gains in efficiency. A solution is needed for this area of the biopharmaceutical industry.

Donald Palmer Associate Director Regulatory Systems Group, USA

W

ithin a Regulatory department, there are Information Management needs, particularly related to the electronic Common Technical Document (eCTD) submission process. There are a number of methods for adding efficiencies to the submission process, particularly through automation and standards.

To begin with, what does it mean to add ‘efficiencies’?

From TheFreeDictionary the definition of ‘Efficient’ is ‘Acting or producing effectively with a minimum of waste, expense, or unnecessary effort.’ However, to actually become efficient, we should look at areas that are not efficient and change them.

From the same source, the definition of ‘Inefficient’ is ‘wasteful of time, energy, or materials’ So we should be looking for

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processes that involve lots of time, lots of energy, and / or lots of materials.

For example, consider the overall process of a sponsor producing an eCTD submission and within it the specific process of transferring Chemistry, Manufacturing and Controls (CMC) documents from a manufacturer to the sponsor. Keeping in mind the overall eCTD process, consider the specific CMC process to illustrate where and how inefficiencies can be changed. The high-level process involves: 1. Manufacturer, who is the author, uses a word processor to electronically produce the CMC documents 2. The author prints the CMC documents out 3. The paper CMC documents are sent to the sponsor 4. Sponsor scans in the paper CMC documents 5. Software is used to convert the scanned images to Portable Document Format (PDF).

Using the specific CMC documents, how might a manufacturer and sponsor ‘reduce the cost of operations’, ‘reduce the time of operations’ ‘increase the speed of

operations’, and ‘increase the throughput of operations’? When attempting to add efficiencies, the organisations should also consider the affect of changing one of these items on the others.

A sponsor might reduce the cost of operations by choosing a cheaper transportation method—maybe choosing regular mail over a specialised courier.

This might increase the time of operations, however. Since both the manufacturer and the sponsor use a lot of paper in this process, maybe they could use cheaper paper. This might, however, impact the scanning step as more pages jam and need to be reproduced. A quick conclusion can be made that although reducing cost might be a driver for efficiencies, simply looking at this aspect can have expensive side effects.

Aside from cost, what other places can a sponsor realize efficiencies by addressing specific inefficiencies? There are two important methods of reducing efficiencies to address: Automation and Standards.

These two can be implemented independently. However true efficient systems require both. The following discussion will illustrate this dependency.

Information technology

To look at what is meant by ‘Automation’, consider the specific process of getting the CMC documents to a sponsor. Automation might include: • Placing the paper pages on a conveyer belt • Automatically transporting the pages to a fax machine • Automatically faxing the pages to the Sponsor • Receiving the fax pages by the sponsor • Placing the pages on a conveyer belt • Automatically transporting the fax pages to a scanner • Scanning the fax pages • Transforming the scanned images to PDF. This is automation, although not really very efficient. It could also be quite expensive.

To look at what is meant by ‘Standards’, consider the same process of getting CMC documents to a sponsor. A couple of standards needed would include standard size paper for each page and a standard fax machine that sends a standard message over a telephone line.

Note that if there isn’t a standard size to paper pages, all the automation aspects discussed above could be in trouble. The printer would need many sizes of paper to print on, the conveyer belt would need to adjust for different page sizes, the fax machine would need to read and send pages of different size, and the scanner would need to handle different size pages as well.

So, in this case, automation must use standards to be efficient. What about standards depending upon automation? A quick look at the above example with a manufacturer in Europe and the sponsor in the US should help. There are now two standards for paper size—A4 and US Letter. If each side keeps with their standard, will this process operate efficiently?

Local standard

The conveyer belts, set to the ‘local’ standard, may not work well, since the sponsor

will receive the CMC documents in A4 page size and its conveyer and scanner are set for US Letter. Since the paper sizes are close to being the same, the systems might work ‘okay’, but may not be really efficient.

To conclude this, it is important to understand that standards covering an entire process can lead to more efficiencies than any number of point-solution automation or standard steps within a process. For submissions to health agencies, the single best example of this fact is the Common Technical Document (CTD). This standard took more than a decade to put into place; however the efficiencies that can be gained from this

Typical drivers for increasing efficiencies Reduce the cost of operations (including reducing resources required) Reduce the time of operations Increase the speed of operations Increase the throughput of operations.

one standard are immense in this global world of biopharmaceuticals. Without it every health agency could have different layouts of a submission and be very difficult to automate. Without this standard, submitting globally might not be a practical possibility. Even with regional differences, the CTD is a key step towards efficient submission processing.

Manufacturers’s process standard

Using PDF documents. If this standard did not exist, a sponsor might have to work with MS Word, WordPerfect, HTML, as well as PDF documents.

A sponsor might use TIFF formats for images and Excel spreadsheets for graphs. Data (in the US) might come in comma-delimited files, comma-andquotes-delimited files, Excel files, or even

scanned image files. Those of you who lived through the Computer Aided New Drug Application (CANDA) era should attest to the problems of a lack of such a document standard. Only through the use of a standard format for submission documents can a sponsor add automation to its processes and gain efficiencies.

These efficiencies apply to the production of a submission as well as to the review of a submission.

In addition to the CTD standard, and the efficiencies we are now gaining through use of this standard, is the electronic CTD (eCTD) standard. As the industry moves forward into the electronic submission paradigm, the eCTD standard needs to be understood as a means for providing additional efficiencies.

Within the eCTD, how else might a sponsor increase efficiencies in the CMC documents example process? If a sponsor looks at what tasks take a lot of time, it might find that the scanning step takes a lot of time. It is also very repetitive. If a sponsor uses an inexpensive scanner, a person might have to take each page, place it on the scanner, scan the documents, then remove the page from the scanner. This is both very repetitive and time consuming. The sponsor could spend some money and purchase a multi-document scanner with an automatic loader.

This would both increase the speed of scanning one document and increase the throughput of the process. Note the importance of a standard page size.

To take this example a step further, even with standards and automation for this transfer of a CMC documents, it is still inefficient. Another method of gaining efficiencies is needed. A sponsor needs to increase or, in this case, change the scope of operations. So long as the sponsor is tied to the step of producing paper, it will only be able to speed up the print – transfer – scan process. The sponsor might get a one or two times increase in speed for each task automated and/or standardized. To really increase efficiency in this process a sponsor needs to change the scope of the process.

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Information technology

This might be done by using, instead of paper, the electronic form of the documents.

If the manufacturer takes the original word processor documents and sends it electronically to the sponsor, both can increase efficiency many-fold. They do have to completely change the tasks and equipment in the process. They can forget the printing, paper transfer, and scanning tasks altogether. They can forget the printer, the fax machine, the conveyer belts, and the scanner. They will, however, need other items not used before, like a CD Writer, or email, or an FTP server.

Changing the scope of an operation can have far reaching impacts on the tasks and equipment required to complete the changed operation. This might save time and money on one hand, but incur costs on the other. If the efficiencies gained are significant, the shift in costs can be justified. Organisations should consider this trade off and ‘take the plunge’ when significant efficiencies can be gained.

By changing the scope of the process and removing the paper steps, both manufacturer and sponsor can gain significant efficiencies in speed, throughput and time of operations. They will incur transition costs to make this move, however the costs of paper, people to support the printing and paper delivery, and especially the costs of scanning should be much less than the cost of a secure email system to send the documents electronically.

When sending CMC documents from a manufacturer to a sponsor, there are a number of information items very useful to the process. In Electronic Document Management (EDM) systems, this information is usually held as ‘properties’ or ‘attributes’ of the documents. A more general term for these information items is ‘metadata’. This information, this metadata, provides the means to categorize and organize documents into hierarchic structures, similar to the folder structures on a computer drive. It also provides the means to search and retrieve the documents, and to process the documents through a set of tasks. More to the point

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of this article, this metadata is the means through which we can automate processing of documents for the purposes of electronic submissions.

The metadata in EDM systems is also a place, sometimes unrecognized, where significant inefficiencies exist. To return to the example CMC documents process, when electronic documents are sent from the manufacturer to the sponsor, the metadata about the documents is usually not passed along. This might be because one or both organizations do not use an EDM system. These days it is more likely that both have EDM systems and so another issue is at stake. Consider the earlier problem of the manufacturer printing the CMC documents to paper, sending the paper CMC documents, and then the sponsor scanning in the paper

In addition to the CTD standard, and the efficiencies we are now gaining through use of the electronic CTD (eCTD) standard.

CMC documents. Compare this to the situation with the metadata associated with the CMC documents. The manufacturer creates the CMC documents and enters metadata about the CMC documents into its EDM system. Next the manufacturer exports the CMC documents (without the metadata) and sends it to the sponsor. Finally the sponsor receives the CMC documents, imports the documents into its EDM system and enters metadata about the CMC documents. Here is a case of an inefficient process.

How could these organisations address this inefficiency? By automating the process? If it were simply a matter of automation, this probably would have already been done. The problem with attempting to automate the process is that there are

no standards through which automation can be efficient. In particular, there are no standards for the metadata in the different EDM systems. This is similar to the problem of not having standard page sizes for the printer, conveyer belts, and scanner discussed previously. The problem is brought back to the inter-dependency of automation and standards.

A standard for EDM metadata is needed in order to address this inefficiency and allow for automation to be efficient.

Without such a standard attempts to automate EDM processes, especially between EDM systems as with the manufacturer and sponsor, will not be efficient – not be cost effective, from the standpoint of the trade off mentioned earlier. In the case of the CMC documents example, the larger process involved is for electronic regulatory submissions to health authorities.

This is a case of an entire process standard providing significant gains in efficiency.

A solution is needed for this area of the biopharmaceutical industry.

The topic of the eCTD standard was raised earlier in this article and now enters again. For documents held in an EDM system and used in an electronic submission, the eCTD standard provides a basis for defining standard metadata to be used in the EDM system. Through use of such an EDM metadata standard, automation can be applied to such processes as sending a CMC documents from a manufacturer to a sponsor, transferring documents between EDM and publishing systems, even for submission review systems—especially if the submission is held in an EDM system. Being an entire process standard, there will be many places efficiencies can be gained with an appropriate standard.

A final word about the title of this article: A ‘Standard’ is really information about how to generate some object, be it paper size, character fonts, nuts and bolts, or an eCTD submission. It is this information aspect of a standard, in the Regulatory Submissions arena, that requires Regulatory Information Management.

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The compact LF-BLI machine is ideal for sample testing between the existing Blister Line and Cartoner Packing line. The blister packs are manually inserted on a test base, which may take up a number of blister packs depending on the size. A sensitive membrane is then sealed on the test base and a vacuum is applied, which

(when set under a predetermined vacuum) will analyse the swelling of each blister cavity, thus indicating which blister pack is faulty. The machine will also indicate which cavity is leaking.

The main advantage of this machine is that no extra tooling is required for different size blister packs as the Sensitive membrane will adjust to any size and shape.

The LF-BLI machine is fully computerized utilising a SCADA platform. The software is easy to operate and includes utilities such as a products database, statistical reports, remote assistance via modem etc. A printer may also be installed for printing test results and parameters. The technology is

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The pay back of the investment will depend on the cost of the blister products being tested but will normally be in the range of a few months. This is because when using the LF-BLI the cost of destructive testing and the cost of the waste disposal will be avoided thus the investment pays off by itself and after this payback period the machine will be actually rendering profit.

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