Foreword
Current State of Regulatory Compliance in Pharma Industry Pharmaceutical companies operate in one of the most dynamic environments. Changes in regulations by leading bodies such as US Food and Drug Administration (USFDA) and the European Medicines Agency (EMA) have increased the significance of regulatory compliance management for drug manufacturers. Pharma companies across the globe are compelled to alter their compliance practices to conform to changes in regulations and stringent anti-corruption laws. The US FDA oversees regulatory activity across the globe forcing pharma & life sciences companies to identify quality issues before they impact the production. Historically pharmaceutical industry has been dealing with malpractices across the value chain ranging from improper branding to masking safety information and disregarding quality manufacturing standards. This has led to regulators keeping a strict watch on the pharma companies. Enforcement agencies the world over have become more active. Any violation of regulatory methods or non-compliance of standards could tarnish a company’s reputation, risking its future. According to the 2014 global survey on reputation risk conducted by Deloitte, reputation problems had a severe impact on revenue, loss of brand value and regulatory investigations. In the US and European markets, companies have become increasingly cautious about regulatory compliance. Leading pharma companies in these markets have reportedly implemented effective compliance management systems internally, suggests an article published by The Smart Cube, a firm offering research and analytics services. However, the situation in Asian market and
India in particular is not encouraging. Increased regulation, concerns over data integrity have only contributed to the compliance challenges facing the industry. A survey titled ‘Analyzing the state of Data Integrity Compliance in the Indian pharmaceutical industry’ conducted by E&Y in 2015, noted that the Indian pharma industry has been struggling with regulatory compliance. The reports indicate that companies lack skilled/ well-trained compliance teams/practices and that many companies did not consider investing in compliance a priority. Pharma companies, importantly the ones operating in India, will need to realign their quality and compliance structure to conform to the constantly evolving regulatory guidelines. With the FDA and other regulators broadening the scope of compliance requirements, it helps if companies have a holistic approach and make regulatory compliance a part of their corporate strategy. This includes effective training, proper timely communication, periodic reviews, and support from the top management. Companies ought to be proactive in setting up stringent internal controls as part of their commitment towards quality and compliance. Regulators have to focus on aligning country-specific regulatory frameworks to global standards enabling harmonisation of standards and help companies drive efficiencies.
Prasanthi Potluri Editor
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COVER STORY
Contents
EXPERT TALK
STRATEGY
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06 State of Pharmacovigilance Proposals for streamlining the system
Contract Manufacturing in APAC An innovative solution provider Vetter
Giovanni Furlan, EU QPPV Helsinn Birex Pharmaceuticals, Ireland
11 Decision-making in Vaccines How the fusion of price with access risks a tragedy of the commons
Peter Soelkner Managing Director Vetter Pharma International GmbH USA
Michael Watson, President, Valera, A Moderna Venture, US
18 The Genetically Modified Organisation New research points to how leaders can accelerate their firm’s evolution Brian D Smith, Managing Director, PragMedic, UK
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24 Growing the Regenerative Medicine Industry in Asia-Pacific with Help from Regulatory Science
Christopher Milne, Associate Professor and Director of Research Center for the Study of Drug Development, Tufts University School of Medicine, US
Josephine Awatin, Research Analyst, Tufts Center for the Study of Drug Development, US
30 Analytical Characterisations of Bio-similar Products and Peptide-based Drugs
M V Narendra Kumar Talluri, Asst. Professor & In-Charge LC-MS Dept. Pharmaceutical Analysis, NIPER, India
MANUFACTURING 36
36 Towards the Operationalisation of Production Systems Simultaneously increasing effectiveness and efficiency
Friedli, Thomas, Managing Director TECTEM Director at the Institute of Technology Management University of St.Gallen Switzerland
Ponce, Nicolas, Research Associate, University of St.Gallen Switzerland
Maender, Christian, Research Associate University of St.Gallen, Switzerland
48 Books 50 Industry Reports
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Advisory Board
Editor Prasanthi Potluri Alan S Louie Research Director, Health Industry Insights an IDC Company, USA
Christopher-Paul Milne Director of Research, Tufts Center for the Study of Drug Development, Tufts University, USA
Douglas Meyer Senior Director, Aptuit Informatics Inc., USA
Editorial Team Grace Jones Karishma Kumar Art Director M A Hannan Product Manager Jeff Kenney Product Associate David Nelson Circulation Team Naveen M Sam Smith
Frank Jaeger Regional Sales Manager, Metabolics, AbbVie, USA
Subscriptions In-charge Vijay Kumar Gaddam
Georg C Terstappen Director and Head of Biology, Neuroscience Discovery AbbVie Deutschland GmbH und Co. KG, Germany
IT Team Jareena K Ranganayakulu.V Sitaram Y Uday V
Kenneth I Kaitin Director and Professor of Medicine, Tufts Center for the Study of Drug Development, Tufts University, USA
Head-Operations S V Nageswara Rao
Laurence Flint Head Clinical Research Cough, Cold & Respiratory Disease Novartis Consumer Health, Inc., USA
Neil J Campbell President & CEO, Helomics Corporation HealthCare Royalty Partners University of Liverpool, UK
Pharma Focus Asia is published by
In Association with
A member of
Phil Kaminsky Chair, Department of Industrial Engineering and Operations Research University of California, Berkeley, USA
Rustom Mody Senior Vice President and R&D Head Lupin Ltd., (Biotech Division), India
Sanjoy Ray Director, Strategic Alliances & Health Innovation Merck, US
Confederation of Indian Industry
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State of Pharmacovigilance Proposals for streamlining the system
In recent years there has been a proliferation of pharmacovigilance guidelines and regulations. Regulatory authorities have implemented different requirements, templates and regulations, and some of them have asked pharmaceutical companies to produce many documents with overlapping content. These requirements risk draining resources from the scientific assessment of safety information to bureaucratic tasks. It is proposed that pharmacovigilance regulations are harmonised and simplified. The implementation of the drug safety master file could be a step towards this goal. Giovanni Furlan, EU QPPV, Helsinn Birex Pharmaceuticals, Ireland
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n recent years pharmacovigilance has been recognised as being one of the most important sciences in the health sector and this has led to develop new regulations and guidelines not only in Europe, but also in the developing countries around the world. The only goal of pharmacovigilance is protecting safety and this, of course, is also the aim of new regulations. However, following the proliferation of drug safety regulations and guidelines, it is now time to question if they have really reached the aim of protecting patient safety or if they have become too cumbersome and complex, thus representing an excessive burden for the healthcare sector, thereby, failing to achieve their objectives .
A first issue: Divergent pharmacovigilance regulations
For a drug safety professional working at global level, one of the most striking weaknesses of the drug safety regulations is the lack of harmonisation. An example is Periodic Safety Update Reports (PSURs). In 2012 6
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the International Conference on Harmonisation (ICH) released a guideline describing a new format for PSURs. But this guideline has not been implemented by all countries. For example, in China and Brazil PSURs are required in the old format. In the US, both PSURs (in the new format) and Periodic Adverse Drug Event Experiences (PADERs) are accepted. However, the periodicity with which PADERs need to be prepared (quarterly for the first two years since product launch and then annually) is different from that of PSURs. In Europe they need to be prepared every six months after the drug is placed on the market, then once a year for two years and finally every three years, unless the list of European Union reference dates and frequency of submission of periodic safety update reports, known as the ‘EURD list’, has different requirements. This implies that a company marketing a drug in Europe, the US and China, will need to prepare country-specific documents for the same drug. In addition to this, Brazil requires the PSURs to be submitted with an ad hoc cover letter that summarises the information contained in the PSURs itself and in the Risk Management Plan. Therefore, the same safety information is presented in different formats, thereby increasing the bureaucratic burden. Unluckily, the inconsistencies of document format and submission timelines is far from being limited to PSURs, Individual Case Safety Reports (ICSRs) are another example of these different requirements. The international standard for submitting ICSRs to the authorities is the form developed by Council for International Organizations of Medical Sciences, known as CIOMS I form, if the report is submitted on paper and the ICH E2B format, if the report is submitted electronically to the authority. However, in China, there are three templates for submitting ICSRs: the first one, for cases originated from China, is similar (but not identical) to the CIOMS form, then there is a separate form for cases originating outside of China and finally another form for submitting cases associated with a
they are by far the most detailed and comprehensive.
In pharmacovigilance, it is time to stop thinking that we are protecting patient safety by continuously adding regulations and guidelines.
product complaint. The differences regard not only the ICSRs submitted on paper, but also those submitted electronically. In fact, it is sufficient to compare the number of pages of the document on the regional and technical implementation of electronic reporting requirements in the EU to those in the US (more than 100 pages and 15, respectively), to understand how the same requirements have been differently implemented in these two regions. The list of divergent requirements is too long (and boring) to be detailed within this article, so only another example will be made: the timelines for submitting ICSRs. For non-serious cases, these go from 90 days (in some European Countries) to 10 working days in some Latin American Countries. Who leads harmonisation?
The role of ICH is that of harmonising the pharmaceutical sector guidelines at an international level. The above described lack of harmonisation in pharmacovigilance guidelines shows that there is a need for widening the role and scope of ICH. However, in recent times, some countries seem to look elsewhere rather than to the ICH guidelines. The Arab League, for example, has implemented Good Vigilance Practices and the Pharmacovigilance System Master File, a document that is not mentioned in ICH guidelines. It is not surprising that some countries are looking to the European guideline as a model since
A second issue: redundant and complicated requirements
European guidelines also tend to be redundant and complicated. Volume 9a (the pensioned European pharmacovigilance guideline) was a single 229 page document. It has been replaced by Good Vigilance Practices; at the time of writing this article there were 12 finalised Good Vigilance Practices and three which were still not finalised, an addendum, a sixty page template for Risk Management Plans (RMPs), one for PSURs and nine ‘other pharmacovigilance guidance’. Additionally, there are guidance documents on a number of ‘“other pharmacovigilance related’ topics. Only for data submission on medicines to the European Authority there are nine guidelines; of these ‘chapter 3.1:specifications‘ is 224 pages. This large number of voluminous guidelines not only implies that it is increasingly difficult and complex to be aware of the regulations and comply with them, but, more importantly, they require the pharmaceutical industry to prepare many redundant documents. Signals, risks or the benefit-risk balance of an authorised medicinal product are described by PSURs, RMPs, Signal Detection Reports, Addendum to Clinical Overview (a document, similar to the PSUR, that needs to be submitted upon product renewal) and, if the drug undergoes a referral, by the documents that need to be submitted during this procedure. In addition, if the product is still in clinical development, signals, risks or the benefit-risk balance of the drug need to be described in the Development Safety Update Report and in the Investigator’s Brochure. According to the new EU Clinical Trial Regulation, they also need to be reported in the protocol and in the Investigational Medicinal Product Dossier. When we add the different documents requested by the non-harmonised regulations of other countries (such as the PADER or the PSUR old format as www.pharmafocusasia.com
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previously mentioned) to the documents containing redundant information due to the EU requirements, we understand the extent of the burden on drug safety departments. The risks of having similar documents with contradictory information or of drug safety departments being absorbed by copy and paste exercises instead of focusing on understanding the risks of a drug and how to minimise them are far from theoretical. Interestingly, the European Authority has recognised that some pharmacovigilance documents are redundant: the EU document implementing the Periodic Benefit-Risk Evaluation Reports (PBRERs, the new version of PSURs), states that, out of the 40 sections of a PBRER, 16 share commonalties with PSURs and 4 with RMPs. The guidance, therefore, encourages interchangeable use of the sections of these documents. In practice, however, this is seldom possible because the periodicity with which PBRERs, DSURs and RMPs need to be prepared is different, and the safety profile of a drug evolves over time. To be fair, it has to be noted that the tendency of having ever more demanding requirements is not limited to the EU. For example, the ICH guideline on Periodic Safety Update Reports which now requires this document (PBRER) is made of 19 chapters, while in the old version it consisted of ten. Similarly, the ‘old’ E2B guideline on electronic reporting of individual case safety reports (E2B) was 29 pages. The new guideline has a 166-page implementation guide and 8 appendices. Consequences of non-harmonised, complicated and redundant regulations
With such a tendency to develop more and more demanding and redundant regulations, it is not surprising that not all countries have implemented the new ICH guidelines or the European regulations. Probably in a developing country they would not be sustainable from an economic point of view due to the resources needed to implement them. 8
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However, even in developed countries, the economic aspects cannot be ignored. In a sector such as pharmaceutical, where costs increase but margins don’t, the industry does not tend to develop drugs with low margins such as antibiotics, but focuses on sectors where the margins are higher— such as orphan drugs (where it is easier to get a drug on the market), monoclonal antibodies (biogenerics are more difficult and expensive to register), or on widespread and severe disease, such as cancer and hepatitis, where a novel and more effective drug can be sold at a high price. Pharmaceutical industries stop selling old drugs with very low margins and when there is only one pharmaceutical company left to sell a drug, then it is
For a drug safety professional working at global level, one of the most striking weaknesses of the drug safety regulations is the lack of harmonisation.
likely that, all of a sudden, the price of that drug will skyrocket as the company has gained a market monopoly. In pharmacovigilance, in order to contain the increasing costs, companies tend to outsource or insource work to lowcost countries (where quality is not always the highest), work is sometimes done by under qualified personnel (because it costs less and the increased requirements demand more skilled, experienced and qualified pharmacovigilance professionals than there are on the market) or it exceeds staff capacity. Finally, due to the need to repeat the same information in different documents and formats, there is the risk of doing copy-and-paste exercises rather than focusing on understanding what are
the risks of a drug, their characteristics and how to minimise a risk. The need for a systematic approach to pharmacovigilance
Pharmacovigilance regulations and guidelines have an essential role in requiring collection of high quality and complete safety information, driving a sound scientific assessment of the received information and facilitating the production of high quality documents that drive appropriate risk minimisation actions so as to protect patients’ safety. However, when regulations and guidelines increase the administrative burden and bureaucratic requirements are complex, posing different requirements in different countries, the results will be the opposite of the above-mentioned desired situation. The reason is that, in a resource-constrained world, economic pressure limits the quality and quantity of the human resources available for doing the job. Even if complex and redundant regulations and guidelines require more and more quality personnel to prepare the required documents, due to economic pressure, the necessary increase in human resources will not be available. Therefore, the risk is that regulations and guidelines transform pharmacovigilance in a tick-box exercise, draining resources from detecting the risks of a drug and minimising them to a bureaucratic exercise, which is not in the interest of patient safety. In order to avoid this risk, it is necessary that pharmacovigilance adopts a systematic approach: the pharmacovigilance system should not be the sum of single rules, regulations and guidelines that have each been developed in isolation, without considering the relationships among all the socio-technical components. This means that in order to have an efficient and effective pharmacovigilance system, the interactions between all stakeholders, components and factors need to be taken into account. The aim of protecting patient safety is not achieved by adding one requirement to the other, but by designing a pharmacovigilance system through a wholesome and holistic approach.
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Proposals for streamlining pharmacovigilance As previously mentioned, one of the factors that cause pharmacovigilance to be ineffective is the lack of harmonisation in the requirements of different countries. Thus, there is a need to have a global organisation (be it ICH or a new organisation), where the regulators of every country discuss and agree a minimum set of pharmacovigilance guidelines that should be adopted in as many countries as possible. Of course, complete harmonisation would be very hard to achieve, if not unrealistic. However, in the interest of patient safety, a minimum set of regulations should be agreed upon. Countries should be free to add additional (but not different) requirements, taking, however, into account that having too many requirements are not in the interest of the patients. Another factor that causes pharmacovigilance to be less efficient and effective is the requirement for many aggregate reports containing at least partially overlapping information. To avoid this redundancy, it is necessary to disassemble these documents and identify their single components. In essence, drug safety aggregate reports describe: • What is known about a medicinal product (e.g. its mechanism of action and metabolism, the extent of patient exposure, the actions taken by regulatory authorities or by the marketing authorisation holder for safety reasons, the most important outcomes of the studies that have been conducted, the effect of products of the same class etc.) • What is not known about a product (e.g. safety or efficacy in specific population subgroups)
The pharmaceutical sector should learn from what happened in 1994 when a US army Blackhawk helicopter was shot down by friendly fire in north Iraq. The analysis of the accident showed that there were multiple layers of control to identify which aircraft was a friend and which was foe. Many departments were involved and there were many overlapping responsibilities. The operations had become so complicated that different departments in charge of controlling aircraft traffic were using different communication codes and different wavelengths. Not surprisingly, problems in communications contributed to the accident. 10
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• The drug’s efficacy • New safety information received during the reference period (e.g. new risks, new information on risk characteristics, signals, new information on the drug benefits) • How drug risks are minimised • What has to be done to collect information on what is unknown regarding the product • Benefit-risk evaluation The above list might not include all the topics that characterise aggregate reports, but it helps to set the basis for defining a single modular document that could describe all that is known on the safety profile of a drug. In analogy with the pharmacovigilance system master file (the document describing a company’s pharmacovigilance system), this document, that could be named drug safety master file, could be updated every time there is new information impacting on the drug’s benefit-risk balance and could serve to be the solitary document which needs to be submitted to regulatory authorities. Having only one document for describing the safety profile of a drug would avoid all the inconveniences and costs of having multiple overlapping documents and would finally permit pharmacovigilance departments to focus on understanding risks of drugs and how to minimise them rather than being absorbed by bureaucratic exercises.
This should teach us that complication, redundancy and overlap do not prevent failure: more is not always better, it can be worse. In pharmacovigilance, it is time to stop thinking that we are protecting patient safety by continuously adding regulations and guidelines. We should, instead, change our mind-set
A u t h o r BIO
Conclusions
• The main risks of the drug (including the risk characteristics as well as the paucity of information relevant to them)
and think about how we can do things in a smarter way. Acknowledgements
The Author would like to thank Mr David Power, HelsinnBirex Pharmaceuticals, for reviewing this chapter
Giovanni Furlan has 15 years’ experience in the drug safety arena. He has worked at all levels in pharmacovigilance, from case processing to setting up and merging pharmacovigilance departments, and leading drug safety physicians. Experience includes working on a local, European and global level in Pharma companies and in a CRO. Delivered presentations in major congresses and has published many articles on various pharmacovigilance topics.
strategy
Decision-making in Vaccines
How the fusion of price with access risks a tragedy of the commons If we are to maintain a healthy global market for vaccines, R&D and production as well as optimising its benefit to mankind, those taking public health and financial decisions about vaccinations must have access to the expertise that will prevent them from taking pricing and procurement decisions that will lead vaccinations into the traps awaiting all public and merit goods. Multiple metrics in todays’ vaccination market and ecosystem suggest that many of these traps have been sprung and we risk difficult times ahead. Michael Watson, President, Valera, A Moderna Venture, US
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n 2016 four global vaccine producers—Sanofi Pasteur, Merck, Pfizer and GSK—invested significantly (over US$200 m each) in global vaccines R&D each year. This has shrunk from 14 global R&D vaccine producers in 1998 and 6 in 2014. Today there are only two producers for each of the northern hemisphere’s principle infant, adolescent and adult vaccines. In the past these R&D based producers also supplied many vaccines to the lower income markets. However pressure on prices and loss of commercial viability have left this mantle increasingly to the Indian producers such as Bharat, Panacea, Biological E, Shantha Biologics and most significantly, the Serum Institute of India. This shift of suppliers is the result of an increase in Indian capability and capacity and a decrease in the ability of other producers to sell at increasingly low vaccine prices. The Indian producers have focused their business model on the largely pooled procurement markets of
GAVI/UNICEF and PAHO/Revolving fund in addition to their domestic and regional markets. They have also focused initially on the development and production of existing heritage vaccines rather than the long, expensive and unpredictable challenge of R&D into new vaccines. In many cases, such as MenA conjugate and rotavirus vaccines, leveraged significant financial and technical support has come from PATH, in turn funded by BMGF. This focused business model as well as the lower costs of building and operating production facilities in India has allowed the Indian producers to remain in markets that R&D-based producers have been forced to leave due to insufficient profit margins. As a result The R&D-based producers have ceased to develop and produce whole cell pertussis combinations, measles and rubella vaccines, rotavirus vaccines and yellow-fever vaccines. There are, of course, positive aspects of this transition of vaccine capability and
capacity supply from the North to the South, most importantly, the re-globalisation of vaccines production capability and capacity. On the surface there also seems to be a parallel between the falling prices for heritage vaccines and the transition from branded to generics in the small molecule market. However, the role of price pressure in this transition should be of increasingly concerning for all policy makers, procurers and producers, regardless of their business model. The concerns are three-fold. The first concern is that if the prices that have forced the R&D-based Northern producers to leave the market, continue to fall, then so will the profit margins. As a result, even the commoditised Southern producers may face increasing difficulties in retaining their presence within the market. The second concern is that lower prices may allow the donors, philanthropists and purchasers to buy more vaccines but it is clear that these lower www.pharmafocusasia.com
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prices have not improved access for the 20 per cent of the world’s children that don’t get even the minimum vaccines. So there is a real risk that lowering prices is not solving the true root cause underlying poor vaccine access. Thirdly, if margins are continuously eroded, who will pay for the R&D needed to develop improved versions of existing vaccines and vaccines for the many unmet needs in infectious diseases, especially in the markets that are increasingly served by the low cost business model? This raises the fundamental question of whether the purchaser’s anxiousness to minimise prices may actually be risking a tragedy of the commons for this incredibly valuable global public good without solving the underlying objective of access and impact. This in turn poses the question: who is catalysing this ecosystem and why is vaccinations’ value being underestimated and/or under-rewarded? Few deny the immense contribution of vaccinations to individual, societal, economic and global health. Vaccinations
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make us healthier individuals, families and communities. Healthier societies are better able to invest time, people and resources in social, economic and environmental health. Since it is increasingly acknowledged that wealth follows health at least as much as health follows wealth, it is clear that vaccinations are an essential ingredient in generating a virtuous cycle of health, wealth and happiness. A public good is something that everyone has access to (non-excludable) and by having access, they don’t prevent access by others (non-rivalrous.) Textbook examples of public goods are fireworks displays, lighthouses, clean air and defense. Eighty-five per cent of the world’s vaccines were purchased by governments and donor-funded groups, such as GAVI. These vaccines are provided free of charge to the afflicted (non-excludable) and whilst supply is sufficient, everyone has the right to be vaccinated (non-rivalrous.) Vaccination can, therefore, be thought of as a public
good. Some may refute this because a single vaccine can only be used for one person, thereby rendering it rivalrous and that the only true public good of vaccination is the herd immunity resulting from the total public health benefit being far greater than the sum of the individuals protected. Those who argue that vaccination is not a true public good prefer to label it a merit good. A merit good confers benefits on society in excess of the benefits conferred on individual consumers; in other words, there is a divergence between private and social costs and benefits. The benefits accruing to society, therefore, tend to be greater than the private benefits to the individual. As a result, a private market cannot be relied upon to ensure an efficient allocation of society’s scarce resources to the good. Vaccinations exhibit the positives but also the risks of public goods and merit goods. The immense and widely accepted value of public and merit goods such as vaccinations is also their potential Achilles
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heel. Anything as valuable as vaccinations is quickly embraced as a global human right, like education, sanitation and clean water. It seems unthinkable that the whole world should not have access to such an important public good. However, if everyone accesses a public good for free, how would we fund its continuity and improvements for the future? Historically vaccinations have had to manage the fact that not all governments have the means to fund them. For those with lesser means, the Lower Income Countries (LICs), mechanisms have to be found to try and prevent cost from being a barrier to vaccinations. The most visible and effective of such mechanisms is tiered pricing. This works for globally distributed vaccines and broadly matches vaccine price to ability to pay, so that High Income Countries (HICs) pay more than LICs. This results in a viable average selling price and means adjusted affordability. However, this does not work for products confined to lower income countries, such as cholera or whole cell pertussis vaccine nor does it work for countries for which the lowest viable pricing tiers are out of reach. These vaccination market failures are covered by multi-billion dollar donor funded programs such as the polio eradication program (GPEI) or the GAVI alliance or by financing mechanisms such as PAHO’s revolving fund. The single largest purchaser of vaccines in volume is GAVI, through UNICEF. GAVI purchases 33-38 per cent of global vaccine production by volume for about 5 per cent of the value. Until recently, tiered pricing has allowed this balance to be maintained. However, over the last 5-10 years, price pressure and erosion has appeared at a number of points in the continuum of vaccine pricing. At the lower end of the pricing continuum GAVI, UNICEF, BMGF,
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CHAI and India have been engaged in a concerted campaign of Market-Shaping supported by highly vocal advocacy campaigns from organisations such as Doctors without Borders (MSF.) They have focused on bringing down the price of GAVI vaccines using a combination of volume commitments, support of new producers for some vaccines (esp. pentavalent) and market mechanisms such as the Advanced Market Commitment (AMC) for the Pneumococcal Conjugate Vaccines (PCV.) Others, such as PAHO’s revolving fund, maintain low prices by reference pricing to the GAVI rate through the ‘Lowest Price Clause’ in their contracts. However, these donor-funded programmes are themselves under immense pressure from the donor governments, and philanthropists to demonstrate the maximum impact of every dollar given and spent. They are obliged to minimise to administration costs and demonstrate that they pay the lowest price possible for vaccines. The donor and purchaser demand to minimise cost is understandable. But it is, by definition, almost always shortterm in focus. The combination of the small number of global vaccine volume purchasers and the long cycle times for manufacturing a vaccine (12-36 months) mean that suppliers have little choice over who to sell to and must move their stock if they are to avoid the double impact of lost sales and write-off costs. There is no explicit consideration built into the tender process for the longer term impact of such a short-term focus comprising of very few dominant purchasers on a public good. There is no explicit tracking of the impact of falling vaccine prices
either on the health of the public good or whether low price is actually achieving the public health goals rather than just the donor’s demands for efficiency. The fact that these children don’t receive Oral Polio Vaccine (OPV) at 12 cents a dose or Diphtheria-Tetanus-Pertussis vaccine (DTP) at 19 cents a dose tells us that in reality, the main barriers to access are the challenges of children physically accessing vaccines, and gaps in education, awareness and acceptance, not the price. Short-term focus on low price and low costs rather than sustainable Paretoefficiency may not be solving the true underlying barrier to access to vaccination and it may be creating significant risk for the future. Indeed, the last decade has seen very little reduction in the 20 per cent of the world’s children that don’t receive even the minimum vaccines. Conversely falling margins have forced some producers to exit due to loss of sufficient profitability. Those that remain will be increasingly forced to make important decisions on where to invest dwindling income in terms of competency and capacity. We may only know that these choices have inadvertently had a negative impact on vaccine quality, supply reliability and innovation when it is too late. In economic terms, the impact of concentrated buyer power is known as a race to the bottom. This may be acceptable for commodities but vaccines are not commodities and treating them as such risks a tragedy of the commons.
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Short-term focus on low price and low costs rather than sustainable Pareto-efficiency may not be solving the true underlying barrier to access to vaccination and it may be creating significant risk for the future.
consequences as early as possible and what can be done to avoid them? Sustainable vaccination is predicated on maintaining the integrity of a triangle of affordability, reliable quality supply and innovation. Focusing on affordability risks reducing resources available for quality production and innovation, and focusing on innovation and/or quality supply will necessitate additional resourcing either from the sale of vaccines or from elsewhere. The expectation of a combination of lower prices, increased quality and continuing innovation is therefore paradoxically unrealistic, unless the pressure is able to stimulate a paradigm change in how vaccines are discovered, developed, produced, released, purchased, shipped and used. Today there are six vaccines for which UNICEF has only a single contracted supplier. These include DiphtheriaTetanus-Pertussis vaccine (DTP), Measles-
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A tragedy of the commons is the result of an over-exploitation and under protection of a public good. The result is a degradation or loss of a public good because everyone wants as much of it as possible but no-one takes responsibility to protect it. For example, if localised pollution of the air has its negative impact either elsewhere or for a long-term, there is little incentive for the polluter to focus on the short-term and ignore the broader and longer term consequences. Short-term exploitation of a public good by those that don’t bear the immediate consequences (free-riders) may result in the longer term destruction of the good (a tragedy of the commons). Famous examples include over fishing and destruction of the Grand Banks, the destruction of salmon runs on rivers that have been dammed, the devastation of sturgeon fisheries and the limited water available in arid regions (e.g., the area of the Aral Sea). It is even suggested that antibiotic resistance is an unfolding tragedy of the commons. Once a tragedy of the commons occurs, the positive externalities such as herd immunity are lost. For instance, the far-reaching benefits of a free flowing public roads system is rapidly reversed by its overuse and resulting accidents, traffic pollution and multiple opportunity costs. A world in which low vaccine prices compromised supply reliability, quality and innovation would be equally concerning. The immense contribution of vaccinations to saving and improving lives is frequently cited and claimed by global health leaders. The same leaders invariably swiftly follow this unreserved acknowledgement of the value of vaccination with calls for even lower prices, but with increased supply, high quality standards and continuing innovation in all aspects of vaccines and vaccination. Give the impact and value of vaccination, these calls are entirely understandable and laudable but are they realistic and what are the potential unintended consequences that we should all be aware of? How can we recognise these unintended
Rubella vaccine (MR), Measles-MumpsRubella vaccine (MMR), meningococcal A/C polysaccharide vaccine (Men A/C), Yellow Fever vaccine (YF), rabies vaccine (Rab.V) and Meningococcal C conjugate vaccine (MCCV). This compares with only 2 vaccines with single suppliers in 2001. A look at UNICEF’s supply status reveals that all but two of the vaccines that they procure for GAVI are moderately or severely supply-constrained. The recent Ebola and Zika outbreaks have also highlighted the yawning gaps in vaccines R&D for marginal and neglected diseases. For three of the sole supplier vaccines (MR, MMR and Men A/C) it was the loss of an R&D-based producer that left a solitary supplier within the market. For one (YF) it is only the persistence of an R&D producer and the ability to raise prices that keeps global supply close to minimum demand. For one it was the exit of one R&D and one non-R&D producer (DTP) that left a single supplier and for two (Rab.V and MCCV) it is the presence and investment of SII that has been critical to assuring supply. The vaccination community has always worked to try and find ways to vaccinate as many children as possible. Price reduction is an attractively simple way to show how effective the purchasers are at controlling the suppliers in the short-term but unless we re-establish absolute clarity on our goal, which is to protect more people, and align our actions and metrics with this goal, our over-dependence of price risks will perpetually cause a tragedy of the commons and damage the extraordinarily valuable public good of vaccination.
Michael is a UK trained physician in Internal Medicine and infectious diseases and post-graduate training in Pharmaceutical Medicine. He has worked for the last 20 years in vaccines. His roles have included UK Medical Director of Aventis Pasteur MSD, Head of Clinical and Epidemiology for SPMSD in Lyon, France, Head of R& D for Acambis in Cambridge MA and Global Head of Vaccination Policy and Advocacy at Sanofi Pasteur, and Global Head of Policy for the SANOFI Group. In April he was appointed President of the mRNA vaccine company Valera, a Moderna Venture.
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I
n a market characterised by change, it is a truism that life science companies must adapt to survive. Yet such change is notoriously difficult, as the extinction of our industry’s great names shows. Between 1988 and 2011, for example, the Pharmaceutical Research and Manufacturers of America (PhRMA) lost 75 per cent of its members. This attrition suggests that CEOs lack the tools to manage the evolution of their firms. Change management, for its fads and
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The Genetically Modified Organisation New research points to how leaders can accelerate their firm’s evolution
To paraphrase Darwin, it is not the strongest nor most intelligent life science company that will survive, it is the one most able to change. Yet many companies find it very difficult to change in ways that preserves the best of the corporate DNA whilst adapting to the changes in our technological, political, economic and social environments. New research in this area sheds light on what constitutes a firm’s DNA, what changes are demanded by the market and how firms make these changes. This work allows senior executives to perform the equivalent of gene therapy on their firms: identifying the genes that are necessary for competitiveness and inserting them into their corporate genome.. Brian D Smith, Managing Director, PragMedic, UK
models, is an unscientific discipline. This is a gap that my University of Hertfordshire research group is beginning to fill with original and useful new research. All good science uses strong theory and ours applies Darwinian Evolution to the life sciences sector. Far from being only a biological theory, evolutionary science has been used for decades to explain how industries change. Both biological species and business models evolve by Darwinian natural selection:
variation, selection and amplification of information-carrying entities. In organisms, we call these entities genes; in organisations they are habitual activities called routines. And just as thousands of genes work together to express proteins that lead to physiological traits, thousands of routines combine to create capabilities that lead to organisational traits. The gradual shift in gene distribution that leads to speciation is mirrored by the mimicking of routines that leads
to new business models. How the life science industry changes over time is not like evolution, it is evolution, as shown in figure 1 and 2. Our research uses evolutionary science to explain how the life sciences industry came into being and to predict how the market environment is shaping its newly emerging business models 1. One practical outcome of this work is an understanding of why and how 1 Available from the author on request
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firms try to train a chimpanzee to talk whilst successful companies genetically engineer the ape to express the genes necessary for speech. The routineome is as fundamental to organisations as the genome is to organisms. If the genetic engineering analogy explains successful organisational transformation, it also elucidates the difficulty of the process; the organisational version of gene therapy process is just as complex and challenging as the biological one. Our research reveals that life science companies which that have achieved organisational transformation go through five deliberate steps to engineer their routineome, as shown in figure 3. Step 1: Reify the intended model
Figure 1: The Mechanism of Biological Evolution
Figure 2: The Mechanism of Industry Evolution
some organisations evolve faster and more successfully than others. In short, success lies in a firm’s DNA. In other words, companies that adapt well, do so by modifying their ‘routineome’ to express the necessary capabilities and so develop the organisational traits that are demanded by the market’s new selection
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pressures. By contrast, firms risk extinction when they leave their ‘routineome’ substantially unchanged and try to superimpose traits by training or restructuring. This fails, leaving unchanged business model traits that are selected against by the new environment. To draw a parallel with biology, it is as if unsuccessful
The first step in routineomic modification is to make concrete the intended business model. Our work reveals the emergence of 26 new life science business models that differ along multiple dimensions such as innovation levels, target markets, vertical integration and technology breadth. Each model requires different traits in innovation, operations and customer management and so requires a routineome specific to the model. To succeed, firms must choose which model they want to adapt to and think through what that model looks like in their particular part of the market. Our work sees examples of this in companies such as Roche, Novo Nordisk and Medtronic, all of whom are moving towards differentiated new business models but it also sees negative examples in companies such as Teva and Pfizer, which seem unable to focus. Without a reified view of the intended new business model, it is impossible to transform the current model. Step 2: Identify the distinctive traits
Just as a giraffe’s neck and prehensile tongue characterise the species and makes it successful, a business model’s traits such as its strategies, structures and processes characterise it and enable its competitiveness. And, as with animal
From clinical trials to epidemiology intelligence - Integrated, real-time R&D insight into the pharmaceutical industry
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species, traits vary greatly between business models. Illumina’s new business GRAIL, demands processes for combining technologies but also for integrating with oncology patient pathways and sample management operations. By contrast, AZ seems to be developing a model in respiratory that requires the organisation to collect data and extract value from millions of smart inhalers. Whatever model is reified in step 1, it is characterised by a number of distinctive organisational traits, many of which may be novel and necessary to evolve. So the identification of these essential, new and model-defining traits is the vital second step in driving the firm’s evolution. Step 3: Specify the necessary capabileome
The phenotypic traits of a species are a result of its unique proteome, its complement of proteins that do the work in every cell. The business model analogue is its capabileome, the set of capabilities that allow the organisation to function and enable its traits. Changing the business model therefore means modifying the capabileome, which is more challenging than it sounds. Most firms concentrate on changing 1st order capabilities, which are the most visible and enable competitiveness. Examples of these include generating good clinical data, manufacturing efficiently and selling to key accounts. However, our work suggests that firms tend to neglect 2nd order capabilities, which allow the organisation to reconfigure its assets.
Figure 3: The 5 Steps to Routineome Modification 22
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The gradual shift in gene distribution that leads to speciation is mirrored by the mimicking of routines that leads to new business models.
These include creating market insight, strategy making and cross-functional working. Since capabilities work together, an incomplete capabileome will lead to dysfunctional traits, as we observe, for example, when firms fail to achieve market access or to localise global strategies effectively. Without a clearly specified capabileome, attempts to create a new model will fail. Step 4: Map the corresponding routineome
An organism’s unique proteome is the expression of its unique genome. Analogously, an organisation can only
create the necessary capabileome if it has the necessary routineome. Routines, the small, stable sets of activities that the organisation performs almost unconsciously, are the equivalent of genes. Clusters of routines act together and express capabilities, either 1st order or 2nd order. In the latter case, the enabling role of 2nd order capabilities means they behave rather like genetic switches, turning on or off 1st order capabilities. Routines are much smaller than business processes and examples include activity sets for identifying differentiating motivators, which contributes to the market segmentation capability, and setting strategy aligned goals, which contributes to the cross-functional working capability. Every new business model trait requires a number of new capabilities, each of which requires a number of new routines. So an essential fourth step in organisational evolution is the mapping of the required target routineome. Step 5: Acquire the necessary new routines
The target routineome for an intended new business model will differ from the firm’s existing routineome in proportion to the differences between the old and new business models. The more innova-
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organisations that interact in a mutually beneficial way. We see this in the increasing number of networks combining big life sciences companies, academic institutions, charities and governments. Holobionts fail either when they lack critical component members or when the relationship between members is not symbiotic and becomes exploitative. We see this happen in some transactional supplier-customer networks. In practice, life sciences companies acquire their new routines from a combination of all three sources. In any case, the acquisition of new routines, along with the removal of some old ones, is essential to express new capabilities, create new organisational traits and so transform the business model. The genetically modified organisation
Genetically engineering the organisation may seem like nothing more
A u t h o r BIO
tive the new business model, the more engineering of the routineome is needed. Life science companies can acquire new genes in one of three ways: exaptation, routine capture or via a holobiont. Exaptation is the repurposing of routines currently used in other capabilities. For example, activities that contribute to preparing regulatory dossiers can be adapted to the compilation of market access submissions. Exaptation works when the activity is generalisable but fails when it is not. In market access, it often fails but in financial accounting exaptation seems to be a more viable approach. Routine capture, like its gene namesake, is the incorporation of new routines from outside the organisation. For example, activities that contribute to product invention or discovery can be imported from universities or small biotechs. This works when the imported routines are allowed to function independently, like Sanofi does with Genzyme and Roche do with Genentech, but capture fails when the routines are hampered by host organisation routines or cultures. The third way to acquire new routines is via a holobiont. These are symbiotic networks of organisms or of organisations. Holobionts work well when the gather together complementary
than an extended metaphor, but that would amount to underestimating the importance of evolutionary science. Biologists have shown us that almost everything about an individual, from hair colour to political attitudes, is more or less influenced by the information that is stored in, expressed from and replicated by our genes. The application of Darwin’s powerful idea to the life sciences industry now reveals that everything about an organisation, from innovation rate to patient-centricity, is more or less influenced by the information carried in its routines. Understanding this for primates tells us why we can’t train a chimp to talk. Understanding this for life science companies tells us how we can accelerate our firm’s evolution. This article is based on Professor Smith’s latest book “Darwin’s Medicine: The Evolution of Life Science Business Models."
Brian D Smith is a world-recognised authority on competitive strategy in the pharmaceutical and medical technology sectors. He researches the evolution of the sector at the University of Hertfordshire, UK and SDA Bocconi, comments and questions on brian.smith@pragmedic.com.
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Growing the Regenerative Medicine Industry in AsiaPacific with Help from Regulatory Science Regenerative medicine (RM) is a game-changing area of medicine with the potential to bring products that incorporate a viable cellular component intended to repair, replace or restore diseased, damaged or missing tissues into the marketplace. However, because most RM products represent breakthroughs in medicine, they also represent a real challenge for the major international regulatory and reimbursement authorities making regulatory decisions regarding RM. In response, regulators increasingly rely on Regulatory Science (RS), which refers to the development of tools and standards necessary for predicting, evaluating, and determining, fairly and promptly, the quality, efficacy, and safety of novel therapies. Major regulatory agencies all use the term regulatory science, but have assigned different priorities for its implementation and employ different methods for utilising it, particularly with regard to RM. Without some determined intervention in the next few years to harmonize RS approval pathways and risk assessment parameters for RM products, the resulting scientific, regulatory, and funding uncertainties will continue to delay advances in this promising field. Christopher Milne, Associate Professor and Director of Research, Center for the Study of Drug Development Tufts University School of Medicine, US Josephine Awatin, Research Analyst, Tufts Center for the Study of Drug Development, US
D
espite the scientific advances and progress in medicine, there are only a few effective ways to treat the root causes of many injuries and diseases especially age-related diseases. Regenerative Medicine (RM) has the ability to repair and regenerate tissues and organs damaged by injuries, diseases, or the natural progression of age. These therapies have the potential to treat a wide range of degenerative disorders, offering solutions and hope for people who have conditions that today are beyond repair. There has been a significant progress in both basic and applied research of regenerative medicine,
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including cutting-edge technical innovation and great scientific discovery. The Asia-Pacific (AP) region is active in regenerative medicine research particularly in cell therapy, gene therapy and tissue engineering. The AP region is comprised of a large number of countries, including Indonesia, Malaysia, Philippines, Singapore, Thailand, Vietnam, China, Hong Kong, Taiwan, South Korea, Japan, Australia, and New Zealand, which offer the potential for scientific achievements for new therapies. The main healthcare drivers for this region are the ageing population, transplant needs per organ donation
statistics, and the emergence of personalised medicine. The unmet needs are driving the research for RM technologies, not only for health reasons but also for economic ones. In Japan, there are more than 4.6 million people living with Alzheimer’s disease, and by 2050, the socio-economic cost of Alzheimer’s disease will be greater than the Japanese government’s annual income unless the disease becomes preventable. RM technologies have the potential to alleviate these healthcare burdens. RM research has reached the point where there are now many available and advanced techniques that have shown
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evidence of efficacy hinting at a large potential market for these products. However, countries in the AP region are going through different stages of RM development and vary in regulations for approvals. Advancement of more consistent RM regulation policy and establishment of standards for RM products and their clinical application will facilitate technology development in the future. Regulatory advancements in AsiaPacific
Because most RM products represent breakthroughs in medicine, they also
represent a greater challenge for regulatory and reimbursement decisions. In response, health and pricing authorities increasingly base their decision-making on Regulatory Science (RS), which refers to the development of new tools and standards necessary for evaluating the quality, efficacy, and safety of novel therapies. RS is beginning to influence the approval processing in the AP region to help advance these therapies into the market. Taiwan has been one of the first countries in the AP region to have an experimental model of RS. In 1998, Taiwan set up the Center for Drug Evaluation
(CDE) to protect and promote public health by performing regulatory consultation, clinical trial protocol, new drug application, and health technology assessment conducted by the legal regulatory authority, the Bureau of Pharmaceutical Affairs (BPA). Over the last 10 years, this innovative experimental model of regulatory science in Asia has had many achievements. Recently, in March 2013, Taiwan’s National Cheng Kung University (NCKU) announced that it had set up a new Center for Pharmaceutical Regulatory Science, which is intended to ‘promote the administration and education of pharmaceutical regulation in Taiwan.’
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In order to further overcome these regulatory differences for cellular and gene therapies, international regulatory efforts have been made to “harmonise” and several groups have been formed to create these efforts (See Table I). ‘Harmonisation’ can refer to a convergence of regulatory perspectives that informs the independent development of national guidelines and regulations, while ‘regulatory convergence’ can be used to describe interactions that generate a shared regulatory perspective but do not have the explicit goal of production of a consensus guideline. One of the groups, Regulators Forum Cell Therapy Group (RFCTG), was created for information sharing as well as to work towards convergence or harmonisation of regulatory approaches for cell therapy products. Regulators Forum Gene Therapy Group (RFGTG) has the same purpose as RFCTG but with focus on gene therapy. Another major group is the AsiaPacific Economic Cooperation (APEC), which was established in 1989 to promote and facilitate trade within its members. Members of APEC are also involved in Life Sciences Innovation Forum (LSIF), which consists of people from government, industry and academia. Its purpose is to create a policy environment for life sciences innovation. For example, there was an APEC/LSIF workshop in July 2011 on Stem Cell Quality Assurance (QA) and Quality Control (QC) in Bangkok, Thailand that recorded the participation of 13 countries. The goal was to bring together a group of stem cell leaders from corporate, academic and government sectors to discuss and develop a regulatory framework for QA/ QC aspects with respect to stem cell therapy products. In 2009, the LSIF started the Regulatory Harmonization Steering Committee (RHSC) to further promote harmonisation activities. APEC / LSIF / RHSC continued their efforts with the acceptance of the new priority work area in 2012 to ‘Promote Regulatory Convergence for
Advancement of more consistent RM regulation policy and establishment of standards for RM products and their clinical application will facilitate technology development in the future.
the Regulation of Cell and Tissue-based Therapies.’ The short-term goals are to establish a harmonised understanding of cell and tissue-based therapies in order to design training programs while the long-term goal is to stimulate prospective convergence of technical requirements. Hopefully, with the next steps of international regulatory convergence and the implementation of regulatory science, the regulatory environment will enhance the development of safe and effective RM products. Regenerative medicine approvals in Asia-Pacific
Currently, the AP region is starting to receive and approve cell and gene-based Country
APEC/LSIF
therapies (see Table II). Around the world, companies have faced setbacks while pushing uphill to bring treatments to the marketplace. Even in the US, where the overall innovation environment has usually been the most favourable, Geron Corp., which started the first nation-approved trial of human embryonic stem cells, ended the program in 2011, citing research costs and regulatory complexities. The RM regulatory environment is more complex in the AP regions because of variable levels of scientific achievement, technical development, and regulatory infrastructure as well as differences in market access, polices, and procedures. China
There are currently two cancer gene therapy products that have received market approval in China. In October 2003, the State Food and Drug Administration (SFDA) of China approved Gendicine, the first gene therapy product. It was developed by Shenzhen SiBiono Gene Technology Co Ltd to treat Head and Neck Squamous Cell Carcinoma (HNSC). In November 2005, the second gene therapy to be approved was Oncorine, which was developed by Shanghai Sunway Biotech Co., Ltd for the treatment of head and neck cancer. These approvals put China on the map of RM research. RHSC
Australia
China
Japan
New Zealand
Russia
Singapore
South Korea
Taiwan Thailand
RFCTG
RFGTG
Table 1: Countries in Asia-Pacific that are Members of International Regulatory Engagements for Cell and / or Gene Therapies 26
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Country
Approved Product and Related Devices
Manufacturer
China
Oncorine
Shanghai Sunway Biotech
China
Gendicine
Benda Pharmaceutical
South Korea
HerticellGram-AMI
FCB PharmiCell
South Korea
Cartistem
Medipost
South Korea
Cupistem
Anterogen
New Zealand
Prochymal (Remestemcel-L)
Osiris Therapeutics
Japan
TEMCELL
Mesoblast / JCR Pharmaceuticals Co Ltd
Japan
Heart Sheet
Terumo
Japan
JACE® (Autologous cultured epidermis)
Fujifilm Group company Japan Tissue Engineering Co., Ltd.
Japan
JACC® (Autologous cultured cartilage)
Fujifilm Group company Japan Tissue Engineering Co., Ltd.
Table 2: Examples of Countries in Asia-Pacific with RM Approved Products and Related Devices
China has also made considerable progress in basic research for stem cells and attracted the most patients for stem cell treatment worldwide. Since 2002, the Chinese government has provided research funding, such as that from the National Basic Research Program of China, National High Technology Research and Development Program of China, and National Natural Science Foundation of China, to support research on stem cells. However, the therapeutic market for stem cell applications is not mature enough in China, resulting in a lack of large-scale market-oriented stem cell-based products. China has now been closely monitoring stem cell clinical trials to responsibly manage and drive rapid development of stem cell therapies in China. South Korea
In 2011, the South Korean Food and Drug Administration approved the sale of Hearticellgram-AMI that was developed by FCB-Pharmicell Inc. for myocardial infarction treatment. It is also the first therapeutic stem cell drug
approved for marketing by a government. In January 2012 Caristem was approved to be marketed for the treatment of knee cartilage defects such as traumatic articular cartilage, degenerative arthritis and rheumatoid arthritis. In July 2012, Cupistem was approved for marketing. Cupistem was developed by Anterogen for a mesenchymal stem cell treatment to reduce inflammation and regenerate damage joint tissues, indicated for the treatment of Crohn’s fistula. The approvals of these therapies especially Hearticellgram-AMI, indicates that therapeutic stem cells have been recognised as a drug for regenerative medicine. It also brings into focus South Korea’s regulatory infrastructure based on adaptive licensing and conditional marketing approvals. These approaches allow a stepwise learning of gathering data for regulatory re-evaluation, which allows commercial sale in certain instances while trials are underway. This approach has recently led to the approval of Herticellgram-AMI and the world’s first allogeneic, off-theshelf MSC-based product, Cartistem. The country’s Ministry of Health and Welfare
is continuing to expand the support for clinical research on stem cells in order to see that the basic research reaches clinical studies. In 2012, the South Korean health ministry provided 33 billion won (US$29 million) for research into stem cells and regenerative medicine. The South Korean health ministry is committed to boosting RM research as well as monitoring responsibly to protect the public. New Zealand
In 2012, Osiris Therapeutics received approval for its first-in-class stem cell therapy Prochymal (remestemcel-L) in New Zealand for the treatment of graft-versus-host disease. New Zealand has also shown the regulatory approach to adaptive licensing and conditional marketing similar to other AP regions. Osiris submitted a New Medicine Application (NMA) to Medsafe, New Zealand's medical regulatory agency, in May of 2011. It was granted Priority Review in June 2011 to provide expedited review for new drugs which offer a significant clinical advantage over current treatment options. Japan
In October 2007, the Japan’s Ministry of Health, Labour and Welfare (MHLW) issued approval to Japan Tissue Engineering Co., Ltd a Fujifilm Group company to culture and sell Autologous Cultured Epidermis (JACE) for serious burns treatments in Japan. Then in July 2012, the same company received another government approval for Autologous Cultured Cartilage (JACC) to treat traumatic cartilage defects and osteochondritis dissecans for knee joints. Last year, two cell therapy products were approved, TEMCELL and HeartSheet, in Japan. In recent years, the Japanese government has made great efforts to improve the RM environment to facilitate scientific innovation by heavily implementing Regulatory Science (RS) into the evaluation of RM-based products and therapies. In Japan, regulatory science refers
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minimum study data required for premarket reviews of regenerative medicine products, and forming a basic common viewpoint on product quality assurance, through the efforts of its global unit within MHLW implementing Japan’s International Pharmaceutical Regulatory Harmonization Strategy. Japan is also expecting to expand their RM efforts and to collaborate with their neighboring countries in the AP region to keep pace with the advancing regulatory science and RM technology.
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to the science of predicting, evaluating, and determining the quality, efficacy, and safety of pharmaceuticals, medical devices, and RM-based products, based on scientific knowledge in a fair and prompt manner. Japan has one of the highest proportions of aged individuals in the world, and cell and tissue based products were beginning to show promise for addressing the consequent health problems; however, regulatory oversight in the new field of RM was outdated and inadequate. For these reasons, the new Regenerative Medicine law, which was approved in April of 2013, directs the Ministry of Health, Labour and Welfare (MHLW) to adopt procedures that permit an accelerated clinical development pathway for regenerative medicines and living cell therapies. This is expected to fast-track therapies by focusing on comprehensive promotion of policies on RM from research and development to implementation. Japan continues its efforts to improve RM and RS environment by building a framework intended to establish a common international ground on the
Regenerative medicine holds the promise for effective cures instead of mere control of chronic diseases, with additional positive implication for achieving cost-effective and affordable health care solutions by healing the body from within. However, before the true hurdle in translating regenerative medicine to market in a global sense can be crossed, the exchange of related information and the understanding of differences in regenerative medicine regulation policies among different regions must be the first step. Implementation of regulatory science can help advance the regulatory environment for quick and safe approvals of regenerative medicine, therapies, and technologies. Japan is a leader in using regulatory science for regenerative medicine advancement in the Asia-Pacific region. Regulatory science figures prominently in Japan’s overall strategic plan to advance medical products and device development. The plan includes revamping its medical products strategy in order to promote cooperation with key neighboring countries, and by achieving Europe/ US-level status, become a leader in Asia for regulatory science and become a pioneer for establishing regulatory science framework in the Asia-Pacific region. References are available at www.pharmafocusasia.com
Christopher-Paul Milne joined the Center for the Study of Drug Development, Tufts University School of Medicine (TUSM) in 1998, and is currently a TUSM Associate Professor and Director of Research at the Center. He has published over 75 book chapters and papers on biopharmaceutical regulatory and policy issues worldwide, while serving as an Innogen Center Associate (University of Edinburgh), and recently as Visiting Professor at Kyushu University in Japan. Josephine Awatin is involved in various projects with the Tufts CSDD research faculty to build a detailed understanding of clinical pharmacology, drug development and regulation. Ms. Awatin received a B.S. from Syracuse University in Biotechnology with a minor in Economics. Her prior experience includes neuroscience research that explored the molecular mechanisms that control seizure activity at Syracuse University.
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Analytical Characterisations of Bio-Similar Products and Peptide-based Drugs Biosimilars can exhibit tremendous heterogeneity in terms of structural and posttranslational modifications. Therefore, comprehensive characterisation of biosimilars is necessary to ensure safety and efficacy. The analytical tests to demonstrate similarity of a biosimilar product to a reference drug with respect to protein content, activity, physiochemical integrity, stability, impurities are discussed. M V Narendra Kumar Talluri Asst.Professor & In-Charge LC-MS Dept. Pharmaceutical Analysis, NIPER, India
B
iopharmaceuticals such as monoclonal antibodies and recombinant proteins have emerged as important life-threatening therapeutics for the treatment of diseases including cancer. Recently 250 products are approved for various human diseases in the United States of America and the European Union. Moreover, 2,000+ biopharmaceuticals are currently in various stages of clinical research and development. Generally, protein therapeutics are complex and large molecules, heterogeneous and subject to a variety 30
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of chemical and enzymatic modifications during recombinant expression, purification and even in longterm storage. This makes a vast analytical challenge than commonly used small drugs. The biopharmaceutical product manufacturer requires comprehensive physicochemical structural characterisation of the therapeutic protein. Especially for biosimilars, this task is extravagant and forms the basis for further comparability. As per regulatory guidelines, characterisation should be performed at different stages of product development. Initially, batches of the target originator molecule should be systematically characterised to determine the exact sequence of the target protein, the post-translational modifications and the other variability of quality attributes in different batches over time. Then, once the biosimilar product is manufactured, systematic characterisation needs to be performed to confirm the structure. Finally, manufacturers must provide data for comparison of biosimilar with the originator molecule. Analyses must conclude the proteins have the same bio-physical/ chemical and physiological attributes. Analytical strategies should include a series of physicochemical analytical methods/techniques for primary and higher order structure (ICH Q6B) to detect product related impurities and variants. The present article, describes common analytical strategy for characterisation of biopharmaceuticals. Regulatory guidelines:
• 2005, EMEA issued guidelines on ‘Biosimilars’ • 2009, WHO ‘Guideline on Evaluation of Similar Biotherapeutic Products’ • 2010, Biologics Price Competition and Innovation Act (BPCIA) signed • 2012, FDA issued draft guidance documents to accompany legal acts • 2013, FDA fourth guidance issued.
The International Council for Harmonisation (ICH Q6B) requirements: Structural characterisation and confirmation:
a) Amino acid sequence: N/C-terminal sequence: Amino acid sequence of protein is compared with theoretical sequence/nature and homogeneity of termini is identified to find truncated forms. Test
Methods: Mass Spectrometry and Edman degradation. b) Amino acid composition: Amino acid composition of the protein is determined. c) Terminal amino acid sequence d) Peptide map: Primary structure / Identity of protein is confirmed after digestion. Methods: LC and/or mass spectrometry.
USP Method
Remarks
Amino acid analysis
<1052>
Hydrolysis protocol should be specified
NMR
<761>, <1761>
Difficult for long sequences
MS-MS sequencing
<736>, <1736>
Difficult for long sequences
Peptide mapping
<1055>
Complementary to MS-MS, mainly longer sequences/ conjugates
Enantiomeric purity
Chiral amino acid analysis
Certain sequences are challenging
N-terminal sequence analysis by Edman degradation
<1045>
Complicated analysis, especially for N-terminally blocked sequences
Secondary structure
FTIR, CD, NMR
Mainly for characterization
Bio-identity
ELISA
Useful for molecules where folding is difficult to assess
HPLC
<621>
Comparison with reference Material.
Quantitative amino acid analysis
<1052>
Impact of recovery in hydrolysis and quality of standard
Quantitative NMR
<761>,<1761>
A stable internal standard is Required.
HPLC
<621>
Specific method(s) for drug substance, must be validated for both process-related impurities and degradation products
Residual solvents
<467>
Process solvent impurities
Elemental impurities
<232>, <233>
Required if metal catalysts are used
Residual TFA
<503.1>, <1065>
Only if TFA in manufacturing process. IC used if peptide not soluble in acid
Residual fluoride
<1065> or ion-selective electrode
Only if HF in manufacturing process
Table1: USP Analytical Control Strategies for Synthetic Therapeutic Peptide APIs www.pharmafocusasia.com
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e) Sulfhydryl group(s) and disulfide bridges: Higher order of structure/ location and/or connectivity of S-groups is confirmed. Methods: HPLC and/or mass spectrometry. f ) Carbohydrate structure Physicochemical properties
a) Molecular weight or size: MW of protein is confirmed. 1D SDS PAGE/CE or mass spectrometry, AUC. b) Isoform pattern c) Extinction coefficient (or molar absorptivity): EC of known substance is confirmed. Methods: UV absorption or calculation after determination of amino acid composition d) Electrophoretic patterns: Identity, homogeneity, purity, aggregates and truncates of substance is established Methods: 1D SDS PAGE, CGE, IEF or 2D PAGE or CE. e) Liquid chromatographic patterns: Identity, homogeneity and purity of substance is established. Methods: HPLC / RPHPLC ,IEX, SEC, AC, HILIC, HIC. f ) Spectroscopic profiles: Higher-order structure is determined. Methods: IR, Fluorescence, CD and NMR. Amino acid analysis
Amino acid analysis is extensively used to accurately quantify a protein. In a first step, amino acids are liberated through 6N HCl acid hydrolysis (at 110°C, 24 hr). Liberated amino acids are subsequently subjected to automated pre-column derivatisation. Derivatised amino acids are separated by HPLC and detected by fluorescence (FID) or ELSD detector. In case of FID, commonly the derivatisation is carried out by using o-phtaldialdehyde for primary and 9-fluorenylmethyl chloroformate for secondary amino acids analysis. Finally amino acid composition will be determined.
Key factors in the determination of Biosimilars product composition and degree of similarity to reference products involves a vast array of analytical methods /techniques. Recent developments in analytical techniques allow a more detailed characterisation of both the biosimilar and the innovator’s product.
Peptide mapping
Peptide mapping is the most widely used identification test for therapeutic proteins. It involves four different important steps: 1. Isolation and purification of the protein 2. Selective cleavage of the peptide bonds 3. Chromatographic separation of the peptides and
4. Analysis and identification of the peptides. This process involves generally trypsin enzymatic digestion of a protein to produce peptide fragments, separation and identification of peptide fragments. This helps the monitoring and detection of • Single amino acid changes • Oxidation • Deamidation • Degradation products. It also enables the direct detection of common monoclonal antibody variants like • N-terminal cyclisation • C-terminal lysine processing and • N-glycosylation, as well as unexpected variations such as a translated intron. Generally peptide separations are performed on HPLC-QTOF-MS instrument due to the convenience of HPLC coupling and more structural information, even for larger peptides, due to its mass accuracy and high resolution. Charge isoform
The analysis of charge isoforms in therapeutic protein preparations is very
Critical Quality Attributes (CQA)
Methods
Aggregation
SEC - HPLC
Glycan (Afucosylated, Mannose variants)
NP-HPLC
Sialic Acid, Oxidation
RP-HPLC
Low molecular weight fragments
Non-reduced CE-SDS
Aglycosylated, Thio-ether Bridging
Reduced CE-SDS
Charge Variants , Deamidation
cIEX and cIEF
Secondary Structure
CD Spectroscopy, FTIR
Disulfide Bridging
Non reduced Peptide, Mass Fingerprinting
Peptide Mass Finger Printing, Intact Mass / LC and HC Mass Binding Assay
Mass Spectrometry Biacore or ELISA or flow cytometry
Table 2: Methods for Evaluating CQAs for Monoclonal Antibodies (mAbs)
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Raw Materials
Backbone Assembly
• Insertion sequences, Diastereomers, Substitution sequences
• Deletion sequence, Inner sequence, Truncation sequence, Diasterioemer • Functional group modifications
Acidolsis
• Functional group modifications
Disulfied Bond Formation
• Functional group modifications • Disulfied modifications
Fragment Coupling
Purification
• Trancation sequence, Diastereomers, Functional group modifications
• Purging of impurities
Isolation
• Disulfied modifications
API
• Other Process related
Stability
• Functional group modifications (Deamidation, Acetylation) • Disulfied modifications
Figure1: Formation of Impurities in Synthetic Peptides
important during the manufacturing processes. The production and purification procedure makes the proteins (mAbs) to exhibit changes in charge heterogeneity. These changes may not only impact stability but also finally on activity and they even cause adverse reactions. Therefore cation exchange chromatography is regularly used to determine the acidic (left of the main peak) and basic charge isoforms (right of the main peak). These isoforms are 34
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generally deamidation and glycosylation products. The isoform characterisation involves calculation of the percent area of acidic and the basic forms. Each peak will be analysed on a mass spectrometry for confirmation after desalting and volatile buffer exchange. Identification of intact protein and impurities
Although protein biologics are relatively stable molecules, a number of chemical
modifications and degradation reactions can occur during manufacturing, storage and in formulation. Electrophoresis, chromatography and mass spectrometry techniques are most often used to determine the molecular weight of intact proteins and their degradation products. SDS electrophoresis: Ability to visually identify proteins, aggregates and impurities in the migrating bands. Samples can be collected for further analysis by cutting out gel bands. Size-Exclusion
strategy
Chromatography: advantages: High-resolution separations of aggregates and impurities based on their size. Short analysis time compared to SDS-PAGE. Simple method commonly used for in process monitoring to monitor aggregate purification and removal of impurities. RP-HPLC/QTOF-MS: Provides mass information for intact protein, variants, impurities and non-target proteins derived impurities. Fig. describes formation of Impurities in Synthetic Peptides. Conclusion
A u t h o r BIO
Biosimilars are now recognised throughout the world as safe and effective medicines. Key factors in the determination of Biosimilars product composition and degree of similarity to reference products involves a vast array of analytical methods/techniques. Nearly all characteristics of a biosimilars and its corresponding innovator product has to be as similar as possible. Recent developments in analytical techniques allow a more detailed characterisation of both the biosimilar and the innovator’s product. Liquid chromatography is already well established for intact protein analysis e.g. size-exclusion, ion-exchange chromatography. Gel electrophoretic approaches remain the gold standard for obvious molecular weight, size heterogeneity, purity, consistency manufacturing process determinations. Capillary gel electrophoresis and capillary isoelectric focusing methods permit the combination of the high resolution of gel techniques and the advantages of the microfluidic format of capillaries. Capillary zone electrophoresis appears to be a good candidate, since its easy coupling with time of-flight mass spectrometry could provide important information with simple and efficient analytical method. The top–down approach of Mass spectrometry and spectroscopy are also widely used to collect complementary structural information regarding 2D and 3D protein conformation. However, several analytical approaches are always needed to cover all other properties. Recent instrument technological progress will contribute to a better knowledge of these parameters and help to understand the impact of changes in manufacturing process on the quality and consistency of biopharmaceuticals.
M V Narendra Kumar Talluri is a Asst. Professor and In Charge LC-MS at NIPER, Hyderabad. Previous positions held by him include Associate Scientific Manager at Biocon. He has a broad pharmaceutical experience in analytical activities in drug discovery, development and quality control, such as method development, specification design, regulatory documentation, analytical solutions for patent related issues etc. He received PhD degree from Indian Institute of Chemical Technology, Hyderabad.
Siegfried offers more integrated capability with new facilities spanning the Western and Eastern hemispheres Zofingen Switzerland Drug Substance Drug Product
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Siegfried acquires BASF custom synthesis and part API business 3 new sites Custom Synthesis APIs and IMs
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The acquisition of BASF marks another step in Siegfried’s Transform Strategy to become the leading fully integrated drug substance and drug product partner of the pharmaceutical industry. Earlier phases of the Transform Strategy included Siegfried acquiring California-based AMP and the German company Hameln Pharma, both active in the sterile filling drug delivery business. Siegfried offers solid oral dosage capability at a third site located in Malta. In addition, to backward integrate, Siegfried built a new facility in China’s most modern industrial park in Nantong, offering a brand new State of the Art plant with GMP-capacity of 300 m3, which was inaugurated in August 2015! Siegfried now has worldwide presence with chemical manufacturing multipurpose cGMP sites located in: Zofingen, Switzerland; Pennsville, New Jersey USA; Nantong, China; BASF (3) Minden, Germany; Saint-Vulbas, France; Evionnaz, Switzerland, and drug product manufacturing sites in Zofingen, Switzerland (Pilot); Malta, Irvine USA and Hameln, Germany.
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Towards the Operationalisation of Production Systems Simultaneously increasing effectiveness and efficiency
In recent history, Multinational Corporations (MNCs) from all industries have established their own production systems based on Toyota’s unique success story. Nevertheless, industrial companies are still facing issues when it comes to the quantification of the influence of single system elements on the company’s overall performance. The following article presents an approach which allows decision makers to better determine site priorities, define more impactful improvement measures, and further leverage one’s own production system by using the steadily increasing data available in manufacturing. Friedli, Thomas, Managing Director TECTEM, Director, Institute of Technology Management, University of St.Gallen, Switzerland Ponce, Nicolas, Research Associate, University of St.Gallen, Switzerland Maender, Christian, Research Associate, University of St.Gallen, Switzerland
H
istoric development of contemporary production systems Although the Toyota Production System (TPS) was developed as a specific production model for Toyota’s unique circumstances in the 1960s, such as lack of natural resources, lifetime employment practices, enterprise unions, need for an increased variety of products in smaller quan-
tities (Sugimori et al. 1977, Lee and Jo 2007), TPS and its derivatives have clearly become the dominant production system of the 21st century, evidenced by its superior performance versus global competition (Cusumano 1988, Krafcik 1988, Womack et al. 1990). TPS has enabled Toyota to outperform its competitors in quality, reliability, production, cost, and growth,
thus becoming the most successful car manufacturer worldwide (with annual sales of over 10m vehicles). Over the last decades, the Toyota Production System has been widely studied by practitioners and researchers, and several companies from different industries have tried to adopt TPS within their own environment, resulting in very different success rates of implemenwww.pharmafocusasia.com
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tation (Spear and Bowen 1999, Hino 2006, Morgan and Liker 2006). One of the reasons attributed to this variance in the adoption rate is that most of the companies have focused on the tools and tactics of TPS without focalising on the basic set of operating principles. However, it is in fact the people who bring the system to life by working, communicating, resolving issues, and growing together, that companies should put emphasis on. Only a relatively low number of companies have adapted the basic principles of TPS to their advantages, by focusing on some of the core TPS principles (Liker 2004). In this regard, many scholars coincide in necessary preconditions and constraints related to the transferability of TPS. This academic group stresses that the successful implementation of TPS is dependent upon various organisational factors at recipient sites, such as longterm management strategies, labourmanagement cooperation, employee and union involvement, open communication and flat hierarchies, and investments in training (Haber et al. 1990, White et al. 1999, Lee and Jo 2007). Various case studies have proven that the adoption of lean involves a complex evolutionary process of organisational learning and interpretation and have demonstrated that both external and internal factors combine to form a complex causal chain, influencing the adoption and generating a certain pattern of pathdependence in the evolutionary trajectory of a particular production model (Maritan and Brush 2003, Jensen and Szulankski 2004, Collins and Schmenner 2007, Lee and Jo 2007). Need for a better understanding of one’s own production system
Many production systems are specific to individual manufacturers, having evolved over time—by means of the continuous selection, interpretation, assimilation, and transmutation of the principles and operational elements of TPS. Nevertheless, in order to deal 38
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Big data enabledautomation and manufacturing allows real-time detection and diagnosis of production issues, and thus reduces significantly downtime risks and costs.
with changing business circumstances, nearly all companies fail when it comes to quantifying the influence of single system principles and elements (including manufacturing methods, work organisation, human resource management, and supply chain management) on the company’s overall performance. In our understanding, sustainable performance improvements can only be attained if the company is able to determine what the strongest levers within their own production system are, in order to better determine site priorities and for target setting, define more impactful improvement measures and assign resources accordingly, and in the long run further enhance one’s own production system. For this purpose, the first step is to quantify the impact and influence of single production system principles and elements on the performance of the various sites within the manufacturing network. Once a profound knowledge of the coherences within the system has been achieved, the company can accurately tackle low performing sites and areas by setting a clear focus on principles and defining improvement initiatives that will assuredly lead to a significant performance increase. This need arises, on the one hand, from the fact that a large number of MNCs have strategically used the rapidly increasing globalisation of the past two
decades to grow internationally through acquisitions, mergers, and green-field establishments in foreign markets. Today, as economic conditions tighten and global competition toughens, many MNCs find themselves struggling with a dispersed, heterogeneous and lowperforming manufacturing network. To improve operational capabilities in all sites of the network and, hence, increase the competitiveness of the MNC as a whole, the latest trend sees MNCs going from plant-specific improvement projects to multi-plant improvement programmes (Netland 2012, Netland and Aspelund 2014). In regards to the content of such multi-plant improvement programmes, MNCs generally make use of proven production philosophies including, for example, Total Quality Management, Just-in-Time, Lean Thinking, Continuous Improvement, Six Sigma, Business Process Re-engineering, and World Class Manufacturing (Deming 1986, Schonberger 1986, Hammer and Champy 1995, Womack and Jones 1996, Zangwill and Kantor 1998, Schroeder et al. 2008, Monden 2010). In general, programmes that are based on one or a combination of these philosophies retain the same purpose under different names: They focus on making the most out of the existing resources and capabilities of a plant and share a common goal of improving the productivity of manufacturing operations (Repenning and Sterman 2002, Netland and Aspelund 2014). The question that arises at this point is whether the improvement measures and initiatives included in such multi-plant improvement programmes are based and/or aligned with the principles and elements of the underlying productions systems. Given the fact that these so-called meta-routines (Feldman and Pentland, 2003) and strategic organisational practices (Kostova, 1999) are vehicles for how organisations update what they do, the core challenge is to update and share knowledge within the network of sites – most often standardised in what has been called best
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practices (Voss 1995, Netland and Aspelund 2014) and may have been perpetuated in the MNCs production system. On the other hand, the need for a thorough understanding of oneâ&#x20AC;&#x2122;s own production system is reinforced by the ever increasing significance of (manufacturing) data in terms of its growing volumes, variety, and velocity (the speed with which it is being created and processed) (DBIS 2013). While data analytics has certainly been a part of MNCs agendas over the last decade, it is the scale and scope of change that big data is bringing that has attracted so much attention. As many novel phenomena it is oftentimes over-sold because of hype or misunderstanding. Nevertheless, there are several tangible case studies to-date that give evidence of the power of big data to generate value and competitive advantage. Among others, there are some first-hand examples our Institute is currently performing with various manufacturers in Europe within the scope of an industry project financed by the Swiss Commission for Technology and Innovation (CTI).
Big data analytics is defined as a â&#x20AC;&#x153;collection of data and technology that accesses, integrates, and reports all available data by filtering, correlating, and reporting insights not attainable with past data technologiesâ&#x20AC;? (APICS 2012). Its applications have been strong in financial services, insurance, retailing and healthcare sectors, while in manufacturing such examples remain comparatively small in number to-date. Companies such as Rolls Royce and Ford, which have reported to derive success from big data in predicting engine failures prior to their occurrence and in managing supplier risk (Goodwin 2013) further support the assumption that big data will undoubtedly become a key competitive factor for manufacturing companies of all sizes and sectors.
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Data analytics in manufacturing has the potential to enable more sophisticated data-driven decision making and new ways to organise, learn, and innovate (Yiu 2012, Kiron 2013). Its effect may be evidenced in strengthening customer relationships, managing operations risk, improving operational efficiency, enhancing product quality, increasing service delivery or whatever the key business drivers may be (Kiron 2013). Lately, organisations are experiencing much more voluminous and unstructured data environments. In turn, this real-time information from sensors and RFID tags facilitates better asset and business process monitoring, greater end-to-end supply chain visibility, improved manufacturing and industrial automation, and an overall increased operations efficiency and effectiveness (Zelbst et al. 2011, Davenport et al. 2012, Wilkins 2013). For instance, big data enabled-automation and manufacturing allows real-time detection and diagnosis of production issues, and thus reduces significantly downtime risks and costs. Based on its high operational and strategic potential, big data analytics has recently become the focus of a variety of scholars and practitioners. Some researchers suggest that big data is “the next big thing in innovation” (Gobble 2013), “the fourth paradigm of science” (Strawn 2012), or “the next frontier for innovation, competition, and productivity” (Manyika et al. 2011). As a result of this development, businesses and organizations are confronted with an increasing number and complexity of challenges related to big data, and many managers are still struggling to understand the major concepts and implementation possibilities, consequently failing to capture business value from big data. Developing a data-informed improvement management system
The Institute of Technology Management at the University of St.Gallen, Switzerland, is among the leading research institutions in the field of Operational Excellence (OPEX) in the
pharmaceutical industry and has been conducting research as well as industry projects in this field for more than 11 years. Today, our OPEX benchmarking database consists of 317 manufacturing sites from 124 different pharmaceutical companies, thus representing the largest independent OPEX benchmarking database in the pharmaceutical industry – worldwide. This strong quantitative benchmarking database allows us to support company-specific analyses with external data and therefore enhance the relevance and quality of project outcomes. Last year, a globally leading pharmaceutical company approached our Institute for the conception of a DataInformed Improvement Management system (DIIMS) based on their production system, which should bring the actual performance of the different production sites into the equation. Through a better understanding of the implications of their production system principles on site performance, and moving toward a data-based prioritisation of improvement measures, the pharma company hoped to significantly accelerate the realisation of a high performing manufacturing network. In order to ensure reliable and robust conclusions from the analyses, we quickly recognised that we would need to facilitate a performance comparison of the company’s internal manufacturing network with external sites included in our OPEX benchmarking database. At the same time, we should also allow for a comparison between the implementation level of the company’s production system principles in each manufacturing site and our so-called enabler (defined as methods and tools leading to better performance whose levels indicate the undertaken efforts for implementing OPEX) within the OPEX benchmarking database. By this, we would build the foundation for a semi-automated benchmarking of company-specific performance metrics and enabler with our continuously growing St.Gallen OPEX database. Consequently, we would enable more sophisticated data-driven decision
making and new ways to define site’s priorities and for target setting. In the long term, the goal would be to further enhance the underlying metrics system and continuously improve the production system principles to accelerate performance upgrades of the manufacturing network and strengthen people’s involvement. For this purpose, we jointly defined the following project steps: • Matching of the company’s production system principles to the St.Gallen OPEX enabler • Matching of the company’s performance metrics to the St.Gallen OPEX metrics • Understanding the implications of the company’s production system by quantitatively analysing the impact of single principles on the overall site performance • Participation of various companyowned sites at the St.Gallen OPEX benchmarking in order to check the validity of DIIMS • Start on-going benchmarking as longterm collaboration. The described project is still in progress, and we are currently in the phase of enhancing the company’s metrics system by adding further relevant performance metrics in order to ensure a holistic calculation of the overall site performance. After having successfully matched the company’s production system principles to the OPEX enabler and having understood the impact of single principles on the overall St.Gallen OPEX performance, the next activities will focus on matching the different company-specific performance metrics. Once this step is finalised and the validity of DIIMS has been checked by comparing the project results with benchmarking data from several company-owned sites, our client will henceforth be able to semiautomatically assess the performance of their manufacturing network against a resilient database currently comprising 317 sites and with a confident outlook for stable growth. The main advantage of matching the company’s internal performance metrics www.pharmafocusasia.com
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and enabler to the St.Gallen OPEX database is overcoming the need of a regular participation at external benchmarks by relying on one’s own metrics system, which is semi-automatically updated one way or another. This potential will even tend to increase over the near future with the ongoing technological developments toward big data enabled-automation and manufacturing, finally resulting in real-time comparisons of automatically generated data from machines, products, etc. However, the status quo (in our projects and described in literature) proves that there is still a long journey to go in order to reach that ultimate goal, and that profound knowledge about the implications of single production system principles is key for an impactful implementation of such data-informed improvement management systems. References are available at www.pharmafocusasia.com
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A u t h o r BIO Thomas Friedli is Director at the Institute of Technology Management, where he leads a team of 15 researchers, and is lecturer in Business Administration. His main research focus lies on the management of industrial enterprises with an emphasis on Production Management. He is editor and author of several books, among others his latest book “Leading Pharmaceutical Operational Excellence” within the field of Operational Excellence.
Nicolas Ponce is a research associate at the University of St.Gallen (Switzerland). His research at the Institute of Technology Management focuses on the challenges faced by manufacturing companies on their pathway towards Operational Excellence, with an emphasis on the pharmaceutical industry. Nicolas graduated with honors from RWTH Aachen University (Germany) with a degree in Mechanical Engineering, majoring in Production Engineering.
Christian Maender is a research associate at the University of St.Gallen (Switzerland). His research at the Institute of Technology Management focuses on the challenges faced by the pharmaceutical industry. The focal point of his industry and research projects is the management of Operational Excellence programs. Christian graduated from the Karlsruhe Institute of Technology (Germany) with a degree in Mechanical Engineering, majoring in Production Techniques.
rd 3 rd Annual Middle East Healthcare Informatics Summit
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Health Information Management, Documentation Standards and Benchmarking
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COVER STORY
EXPERT TALK
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Contract Manufacturing in APAC An innovative solution provider - Vetter
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EXPERT TALK
In this executive management interview, Peter Soelkner of Vetter explains the company’s strategy behind its increased APAC presence, offers his insights on the position of the APAC region as compared to other world markets, and discusses the advantages that can result when large pharma and small/emerging biotech companies work together.
Peter Soelkner Managing Director Vetter Pharma International GmbH, USA Peter Soelkner has been a Managing Director of Vetter Pharma-Fertigung GmbH & Co. KG since June 2008. In 2009, he was also appointed Managing Director of Vetter Pharma International GmbH, the company’s marketing and sales organisation. Soelkner graduated from the University of Dortmund, Germany, in 1992 with a degree in chemical engineering and earned an MBA from Columbia University, New York, in 2001.
1.For our readers’ acquaintance with Vetter, can you briefly discuss what the company does and the service portfolio it offers? Vetter is a globally operating independent Contract Development and Manufacturing Organization (CDMO) headquartered in Ravensburg, Germany. We are a solution provider to the pharmaceutical and biotech industries and specialise in the clinical development, the aseptic manufacturing, and the final packaging of syringes, cartridges, and vials. Our facilities, located in the US and Europe provide support for early-stage drug products with seamless transfer to our commercial manufacturing for large-scale production. We have an extensive experience of working with biologics and other complex compounds including monoclonal antibodies, peptides, interferons, and vaccines. As a complete service provider with approximately 3,600 employees, we offer support to our customer’s products throughout their lifecycles from preclinical development through global market supply. Vetter is the originator of dual-chamber technology which enables easier, safer lyophilised drug administration. We are also a leader in the use of RABS technology in clean rooms which mitigates the risk of product contamination throughout the manufacturing process. As a family owned independent company, we do not manufacture our own drugs but focus solely on our customer’s product success. 2. Two years ago your company announced the opening of a sales office in Singapore which represented your first physical presence in Asia. What was the thinking behind choosing Singapore? There were a variety of reasons behind our choice of Singapore as our first Asian-based office. Singapore is considered a global biomedical sciences hub, and Asian healthcare market is one of the fastest growing markets worldwide. This market offers great potential for pharmaceutical and biotechnology companies, and as a result also requires the services that a Contract Development and Manufacturing Organization (CDMO) like ours can offer.
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EXPERT TALK
Also, an important fact was that a lot of the companies doing business in Asia Pacific (APAC) region are already key customers of Vetter and call Singapore their home. Therefore, choosing this geographic location was an easy decision. Additionally, our choice was underlined by the characteristics of Singapore as a politically neutral, vibrant city with an international airport and convenient location in the heart of the APAC region. Our experience to date demonstrates that this prime location has only increased awareness of our service portfolio and has improved our access to this promising market. We have every reason to believe that this positive situation will continue into the future. 3. How do you plan on using your presence to take advantage of the Japanese market in the coming years? Vetter has been working towards a presence in the Japanese market since 2007. In that year, the company was accredited as a foreign manufacturer by Japanâ&#x20AC;&#x2122;s Ministry for Health, Labor & Welfare, and was given official certification as a unit belonging to the pharmaceutical services segment. The certificate states that the companyâ&#x20AC;&#x2122;s facilities meet the quality and safety standards issued by the Japanese Ministry of Health. Thus, Vetter had been in the position to fill and package drugs for Japanese pharmaceutical and biotech companies for nearly ten years already. As for the opening of the Tokyo sales subsidiary, our reasoning for this was simple; it means a further expansion into this specific region, and an investment in our future. It was also driven by the demand from our Japanese customers for manufacturing their quality products, and is also in response to a rapidly growing market. Following the successful implementation of our Singapore hub office, we have continued to target and strengthen our position and highlight our presence in relevant and interesting selected Asia Pacific markets. Japan plays an important role in this approach as the second largest pharmaceutical market for high-value drugs. 4. How would you compare the standing of the APAC region to other world markets today? Do you expect major changes in future years? The APAC region has had a good deal of pharmaceutical contract manufacturing over the past several years. In this time, we have seen a distinct shift taking place both in the nature and manner of contract manufacturing and how the drug products are distributed. To give you a better idea of this shift, consider that traditionally, medicines that were manufactured in the region were also primarily intended for use within the APAC countries. Over the past several years we have begun to see strong efforts to enlarge the customer base for medicines manufactured within APAC, through distribution to countries outside of the APAC region. We think that this trend will continue
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and even increase in the near future. As a result of the opening of this market, we have also seen greater competition among pharmaceutical manufacturers within the region who now face competition from outside the region as well. This change means that manufacturing companies must be able to adapt to differing criteria of the recipient countries. For example, manufacturers must make certain that distinct quality requirements are met for countries located inside, as well as outside, the APAC region. 5. In your opinion, what are the drivers and restraints of pharmaceutical contract manufacturing in APAC region? Today we are seeing a growing market demand in the APAC region primarily due to a large and growing population which, fortunately, is supported by increased access to medicines. Within the fast growing pharmerging markets, which include China, demand will be driven predominantly by economic gains and rising incomes, particularly for the low income earners. This increased income, coupled with government commitments to support expanded access to basic healthcare services, will make medicines more broadly available and affordable to millions of people. As a result, multinational pharmaceutical companies will have a strong interest in gaining access to the region and engage in building infrastructure. As for the restraints affecting the market, it must be stated that especially in the injectable market where our company is operating, a significant level of knowledge and longtime experience is required in order to successfully manufacture parenteral drugs. This is due to the complex nature of the compounds themselves as well as their complex handling requirements. Thus the typical cost saving aspect seen in other production services, often an important benefit of goods produced in APAC region, does not have that great effect on injectables. 6. Let us turn now to the challenges the market presents. According to your long-term sales experience, and your recent in-country experience, what are some of the specific challenges in pharmaceutical manufacturing
EXPERT TALK
within APAC region? Also, what solutions did Vetter offer to address and solve these challenges? In general we are speaking about a very broad and fragmented market and as such, experiences a good deal of cultural and technological differences. Thus, it is difficult to answer this question in general terms. The specific nature of the challenge will always depend on the geographical sector where a company is operating. If we are talking about a global market player, for example, the challenges they face along with their partnering companies are more general in nature, for instance, the evolving regulatory requirements, or the increase in costs of drug development. When we examine the services that Vetter offers to enable a successful navigation through the challenges present in this market, I would like to highlight the following: • We offer our customers a long-term experience with international regulatory authorities since we have been audited and certified by a variety of agencies including the US Food and Drug Administration (FDA), European Medicines Agency (EMA), Pharmaceutical and Medical Devices Agency (PMDA) in Japan, China Food and Drug Administration (CFDA), and many others. Currently we manufacture more than 50 customer products with FDA approval; many of them are marketed throughout the world by our customers. • Our production facilities are designed to meet or exceed stringent cGMP requirements. We are a leader in the use of Restricted Access Barrier Systems (RABS) in cleanrooms which mitigates the risk of contamination by minimising human contact with products during manufacture. • Because we do not have drug products of our own, we avoid any conflict of interest with our customers. • Our portfolio spans resources from preclinical development through to global market supply. As a strategic partner this means we can offer services from a single source to support our customers from the early development phases of their drugs, on through to market supply and long-term product lifecycle management for their medicines. • In summation, as a solution provider we always try our best to be the partner of choice at every stage of a customer`s injectable product lifecycle. It is our goal to grow organically on a long-term basis with our customer base. 7. One often reads about cooperation between established big pharma companies and small or emerging biotech firms. From your CDMO’s point-of-view, can you share your opinion about possible advantages of these cooperations, as well as how service providers like yourself might be able to contribute to such cooperations? In our experience we find that cooperation between these two types of companies most often results in win-win situations. What we have seen from our role as a CDMO is that a small biotech firm may offer a pipeline with promising drug
substances, but lacks the necessary capital to successfully develop the medicines and bring them to the market. Conversely, big pharma companies often have access to the necessary capital, but lack the required pipelines. Thus, the two companies can be very helpful to one another. CDMOs often act as the ‘builder of bridges’ in such situations. In our daily work with both large pharma companies and small or emerging biotech firms, we have gained good insight into how these companies work and what their specific needs are. We know, for example, what the small company must be thinking about today, because it will be important at a later development process stage if they want to attract a large pharma company interested in acquiring a promising small company. Based on this knowledge and insight, efficient development processes can take place resulting in a greater chance of success for both parties. Just as important, it can mean a quicker availability of important medications.
Company profile Vetter is a global leader in the fill and finish of aseptically prefilled syringe systems, cartridges and vials. Headquartered in Ravensburg, Germany, with production facilities in Germany and the United States, the Contract Development and Manufacturing Organization (CDMO) is an innovative solution provider serving the top 10 (bio-) pharmaceutical companies, as well as small and midsize companies. Its portfolio spans state-of-the-art manufacturing from early clinical development through commercial filling and final packaging of parenteral drugs. The company’s extensive experience covers a broad range of complex compounds including monoclonal antibodies, peptides and interferons. Vetter supports its customers every step of the way, guiding their products through development, regulatory approval, launch and lifecycle management. Known for quality, the company of approximately 3,600 employees offers a foundation of experience spanning more than 35 years, including dozens of customer product approvals for novel (bio-) pharmaceutical compounds. The CDMO is also committed to patient safety and compliance with user friendly solutions such as Vetter-Ject®, as well as its dual-chamber syringe Vetter Lyo-Ject® and cartridge system V-LK®. Vetter’s branch office in Singapore and its subsidiary in Tokyo, Japan, increased the presence of the company and the awareness of its service portfolio in the Asian healthcare market. Visit www.vetter-pharma.com. Advertorial www.pharmafocusasia.com
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Books
Value Creation in the Pharmaceutical Industry: The Critical Path to Innovation
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Outsourcing Clinical Development: Strategies for Working with CROs and Other Partners
Author: Alexander Schuhmacher, Markus Hinder, Oliver Gassmann
Author: Jane Baguley, Jane E Winter
Year of Publishing: 2016
Year of Publishing: 2016
No. of Pages: 508
No. of Pages: 200
Description: This practical guide for advanced students and decision-makers in the pharma and biotech industry presents key success factors in R&D along with value creators in pharmaceutical innovation. A team of editors and authors with extensive experience in academia and industry and at some of the most prestigious business schools in Europe discusses in detail the innovation process in pharma as well as common and new research and innovation strategies. In doing so, they cover collaboration and partnerships, open innovation, biopharmaceuticals, translational medicine, good manufacturing practice, regulatory affairs, and portfolio management. Each chapter covers controversial aspects of recent developments in the pharmaceutical industry, with the aim of stimulating productive debates on the most effective and efficient innovation processes.
Description: Outsourcing Clinical Development offers a guide to these new models and to future clinical outsourcing strategy. There is advice on the basis for an outsourcing strategy and guidance on how to work most productively with CROs (contract research organisations); geographical issues, including working in low-cost environments, are also covered. There is a detailed guide to selecting candidates, and managing the proposal, negotiation and contract process successfully; as well as reviewing outsourcing performance and developing fruitful long-term strategic relationships. The pharmaceutical outsourcing process is as complex and as influential as the clinical trials it supports. Outsourcing Clinical Development, with a powerful mix of perceptive insight from leading lights in the industry, advice on long-term strategic direction and tools for immediate help is a must-have read for pharmaceutical companies and their CRO partners.
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Successful Drug Discovery, Volume 1 Author: Janos Fischer, David P Rotella Year of Publishing: 2016 No. of Pages: 256 Description: The first volume of the book series "Successful Drug Discovery" is focusing on new drug discoveries during the last decade, from established drugs to recently introduced drugs of all kinds: small-molecule-, peptide-, and proteinbased drugs. The role of serendipity is analyzed in some very successful drugs where the research targets of the lead molecule and the drug are different. Phenotypic and target-based drug discovery approaches are discussed from the viewpoint of pioneer drugs and analogues. This volume gives an excellent overview of insulin analogues including a discussion of the properties of rapidacting and long-acting formulations of this important hormone. The major part of the book is devoted to case histories of new drug discoveries described by their key inventors. Eight case histories range across many therapeutic fields. The goal of this book series is to help the participants of the drug research community with a reference book series and to support teaching in medicinal chemistry with case histories and review articles of new drugs.
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Industry Reports 1. Biotechnology in Brazil
• Brazil is becoming an increasingly attractive prospect for Biotechnology firms. China has announced plans to invest $250bn in Brazil and trade agreements with the US have been in progress.
Introduction Biotechnology in Brazil industry profile provides top-line qualitative and quantitative summary information including: market size (value 2011-15, and forecast to 2020). The profile also contains descriptions of the leading players including key financial metrics and analysis of competitive pressures within the market. Essential resource for top-line data and analysis covering the Brazil biotechnology market. Includes market size and segmentation data, textual and graphical analysis of market growth trends, leading companies and macroeconomic information.
Executive Summary Market value The Brazilian biotechnology industry grew by 4.3% in 2015 to reach a value of $16.2 billion.
Market value forecast In 2020, the Brazilian biotechnology industry is forecast to have a value of $21.3 billion, an increase of 31.5% since 2015.
Category segmentation Highlights • The biotechnology market consists of the development, manufacturing, and marketing of products based on advanced biotechnology research.
Medical/healthcare is the largest segment of the biotechnology industry in Brazil, accounting for 33% of the industry's total value.
Geography segmentation • The Brazilian biotechnology market is expected to generate total revenues of $16.2bn in 2015, representing a compound annual growth rate (CAGR) of 5.3% between 2011 and 2015. • The medical/healthcare segment is expected to be the market's most lucrative in 2015, with total revenues of $5.3bn, equivalent to 33% of the market's overall value.
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Brazil accounts for 8.7% of the Americas biotechnology industry value. Market rivalry Rapid market growth should encourage new players into the market, and also ease rivalry, which is assessed as moderate overall.
2.Generics in Australia Introduction Generics in Australia industry profile provides top-line qualitative and quantitative summary information including: market size (value and volume 2011-15, and forecast to 2020). The profile also contains descriptions of the leading players including key financial metrics and analysis of competitive pressures within the market. Essential resource for top-line data and analysis covering the Australia generics market. Includes market size data, textual and graphical analysis of market growth trends, leading companies and macroeconomic information.
Geography segmentation Australia accounts for 1.5% of the Asia-Pacific generics market value.
Market rivalry The level of rivalry in the generics market is increased somewhat by the presence of large, multinational companies with high fixed and exit costs.
Highlights • For the purposes of this profile, a generic is defined as a copy of an ethical (prescription) drug formerly protected by patents that have now expired. Both unbranded generics and all branded generics are included. However, off-patent drugs that continue to be offered by the original manufacturer under the original name, and which form part of the 'generic-eligible' market, are not included. • The Australian generics market is forecast to generate total revenues of $1.4bn in 2015, representing a compound annual rate of change (CARC) of -0.7% between 2011 and 2015. • Market consumption volume is forecast to reach a total of 49.8 % of total pharma volume in 2015. • Current pricing policy means that many companies are operating below cost in this market, leading to zero growth in 2012 and negative growth in the following years.
Executive Summary Market value The Australian generics market shrank by 0.1% in 2015 to reach a value of $1,393.9 million.
3.Generics in Brazil Introduction Generics in Brazil industry profile provides top-line qualitative and quantitative summary information including: market size (value and volume 2011-15, and forecast to 2020). The profile also contains descriptions of the leading players including key financial metrics and analysis of competitive pressures within the market. Essential resource for top-line data and analysis covering the Brazil generics market. Includes market size data, textual and graphical analysis of market growth trends, leading companies and macroeconomic information.
Highlights Market value forecast In 2020, the Australian generics market is forecast to have a value of $1,334.6 million, a decrease of 4.3% since 2015. Market volume The Australian generics market grew by 3.2% in 2015 to reach a volume of 49.8 % of total pharma volume.
• For the purposes of this profile, a generic is defined as a copy of an ethical (prescription) drug formerly protected by patents that have now expired. Both unbranded generics and all branded generics are included. However, off-patent drugs that continue to be offered by the original manufacturer under the original name, and which form part of the 'generic-eligible' market, are not included.
Market volume forecast In 2020, the Australian generics market is forecast to have a volume of 57.5 % of total pharma volume, an increase of 15.5% since 2015.
• The Brazilian generics market is expected to generate total revenues of $6.9bn in 2015, representing a compound annual growth rate (CAGR) of 16.6% between 2011 and 2015.
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Industry Reports • Market consumption volume is forecast to reach a total of 28.2 % of total pharma volume in 2015. • The sale of generic drugs is expected to outstrip the larger market, so much so that generics are expected to have a market share of nearly half by 2020.
Executive Summary Market value The Brazilian generics market grew by 4.4% in 2015 to reach a value of $6.9 billion. Market value forecast In 2020, the Brazilian generics market is forecast to have a value of $8.8 billion, an increase of 27.5% since 2015. Market volume The Brazilian generics market grew by 2.2% in 2015 to reach a volume of 28.2 % of total pharma volume. Market volume forecast In 2020, the Brazilian generics market is forecast to have a volume of 45.3 % of total pharma volume, an increase of 60.6% since 2015.
Geography segmentation Brazil accounts for 6.1% of the Americas generics market value. Market rivalry The level of rivalry in the generics market is increased somewhat by the presence of large, multinational companies with high fixed and exit costs.
manufacturer under the original name, and which form part of the 'generic-eligible' market, are not included. • The Indian generics market is expected to generate total revenues of $13.1bn in 2015, representing a compound annual growth rate (CAGR) of 14% between 2011 and 2015. • Market consumption volume is forecast to reach a total of 95.1% of total pharma volume in 2015. • The Indian generics market is one of the largest in the world and the market is set to grow due to an ageing population, increased consumer spending, raising healthcare insurance, and rapid urbanization.
Executive Summary
4.Generics in India
Market value The Indian generics market grew by 15% in 2015 to reach a value of $13.1 billion.
Introduction Generics in India industry profile provides top-line qualitative and quantitative summary information including: market size (value and volume 2011-15, and forecast to 2020). The profile also contains descriptions of the leading players including key financial metrics and analysis of competitive pressures within the market. Essential resource for top-line data and analysis covering the India generics market. Includes market size data, textual and graphical analysis of market growth trends, leading companies and macroeconomic information.
Highlights • For the purposes of this profile, a generic is defined as a copy of an ethical (prescription) drug formerly protected by patents that have now expired. Both unbranded generics and all branded generics are included. However, off-patent drugs that continue to be offered by the original
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Market value forecast In 2020, the Indian generics market is forecast to have a value of $32.3 billion, an increase of 146.6% since 2015. Market volume The Indian generics market grew by 0.4% in 2015 to reach a volume of 95.1% of total pharma volume. Market volume forecast In 2020, the Indian generics market is forecast to have a volume of 96.9% of total pharma volume, an increase of 1.9% since 2015. Geography segmentation India accounts for 13.9% of the Asia-Pacific generics market value.
Market rivalry The level of rivalry in the generics market is increased somewhat by the presence of large, multinational companies with high fixed and exit costs.
Generics in Indonesia
Market volume The Indonesian generics market grew by 4.1% in 2015 to reach a volume of 49.5 % of total pharma volume. Market volume forecast In 2020, the Indonesian generics market is forecast to have a volume of 73.1 % of total pharma volume, an increase of 47.8% since 2015.
Introduction Generics in Indonesia industry profile provides top-line qualitative and quantitative summary information including: market size (value and volume 2011-15, and forecast to 2020). The profile also contains descriptions of the leading players including key financial metrics and analysis of competitive pressures within the market. Essential resource for top-line data and analysis covering the Indonesia generics market. Includes market size data, textual and graphical analysis of market growth trends, leading companies and macroeconomic information.
Highlights • For the purposes of this profile, a generic is defined as a copy of an ethical (prescription) drug formerly protected by patents that have now expired. Both unbranded generics and all branded generics are included. However, off-patent drugs that continue to be offered by the original manufacturer under the original name, and which form part of the 'generic-eligible' market, are not included. • The Indonesian generics market is expected to generate total revenues of $0.9bn in 2015, representing a compound annual growth rate (CAGR) of 17.9% between 2011 and 2015.
Geography segmentation Indonesia accounts for 1% of the Asia-Pacific generics market value. Market rivalry The level of rivalry in the generics market is increased somewhat by the presence of large, multinational companies with high fixed and exit costs.
6. Generics in Mexico Introduction
Generics in Mexico industry profile provides top-line qualitative and quantitative summary information including: market size (value and volume 2011-15, and forecast to 2020). The profile also contains descriptions of the leading players including key financial metrics and analysis of competitive pressures within the market. Essential resource for top-line data and analysis covering the Mexico generics market. Includes market size data, textual and graphical analysis of market growth trends, leading companies and macroeconomic information.
• Market consumption volume is forecast to reach a total of 49.5 % of total pharma volume in 2015. • The Indonesian market should continue to see strong growth as the country’s first compulsory national health insurance system, which aims to make basic care available to every citizen by 2019, was launched in January 2014.
Executive Summary Market value The Indonesian generics market grew by 16.3% in 2015 to reach a value of $0.9 billion. Market value forecast In 2020, the Indonesian generics market is forecast to have a value of $1.4 billion, an increase of 55.6% since 2015.
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Industry Reports Highlights • For the purposes of this profile, a generic is defined as a copy of an ethical (prescription) drug formerly protected by patents that have now expired. Both unbranded generics and all branded generics are included. However, off-patent drugs that continue to be offered by the original manufacturer under the original name, and which form part of the 'generic-eligible' market, are not included. • The Mexican generics market is expected to generate total revenues of $6.6bn in 2015, representing a compound annual growth rate (CAGR) of 14.2% between 2011 and 2015. • Market consumption volume is forecast to reach a total of 86.9 % of total pharma volume in 2015. • The performance of the market is forecast to decelerate, with an anticipated CAGR of 11.1% for the five-year period 2015 - 2020, which is expected to drive the market to a value of $11.1bn by the end of 2020.
Geography segmentation Mexico accounts for 5.8% of the Americas generics market value. Market rivalry The level of rivalry in the generics market is increased somewhat by the presence of large, multinational companies with high fixed and exit costs.
7. Generics in North America Introduction
Market value forecast In 2020, the Mexican generics market is forecast to have a value of $11.1 billion, an increase of 68.2% since 2015.
Generics in North America industry profile provides top-line qualitative and quantitative summary information including: market size (value and volume 2011-15, and forecast to 2020). The profile also contains descriptions of the leading players including key financial metrics and analysis of competitive pressures within the market. Essential resource for top-line data and analysis covering the North America generics market. Includes market size data, textual and graphical analysis of market growth trends, leading companies and macroeconomic information.
Market volume The Mexican generics market grew by 3.5% in 2015 to reach a volume of 86.9 % of total pharma volume.
• For the purposes of this profile, a generic is defined as a copy of an ethical (prescription) drug formerly protected
Executive Summary Market value The Mexican generics market grew by 14.9% in 2015 to reach a value of $6.6 billion.
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Market volume forecast In 2020, the Mexican generics market is forecast to have a volume of 93 % of total pharma volume, an increase of 7% since 2015.
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Highlights
by patents that have now expired. Both unbranded generics and all branded generics are included. However, off-patent drugs that continue to be offered by the original manufacturer under the original name, and which form part of the 'generic-eligible' market, are not included. • The North American generics market is expected to generate total revenues of $105.4bn in 2015, representing a compound annual growth rate (CAGR) of 6.4% between 2011 and 2015. • Market consumption volume is forecast to reach a total of 88.7 % of total pharma volume in 2015. • The North American marketed is dominated by the US, which accounts for nearly 90% of the market’s revenues.
Executive Summary Market value The North American generics market grew by 10.3% in 2015 to reach a value of $105.4 billion. Market value forecast In 2020, the North American generics market is forecast to have a value of $144.4 billion, an increase of 37% since 2015. Market volume The North American generics market grew by 2.3% in 2015 to reach a volume of 88.7 % of total pharma volume. Market volume forecast In 2020, the North American generics market is forecast to have a volume of 94.7 % of total pharma volume, an increase of 6.7% since 2015. Geography segmentation The United States accounts for 89.1% of the North American generics market value. Market rivalry The level of rivalry in the generics market is increased somewhat by the presence of large, multinational companies with high fixed and exit costs.
8. Generics in Russia Introduction Generics in Russia industry profile provides top-line qualitative and quantitative summary information including: market size
(value and volume 2011-15, and forecast to 2020). The profile also contains descriptions of the leading players including key financial metrics and analysis of competitive pressures within the market. Essential resource for top-line data and analysis covering the Russia generics market. Includes market size data, textual and graphical analysis of market growth trends, leading companies and macroeconomic information.
Highlights • For the purposes of this profile, a generic is defined as a copy of an ethical (prescription) drug formerly protected by patents that have now expired. Both unbranded generics and all branded generics are included. However, off-patent drugs that continue to be offered by the original manufacturer under the original name, and which form part of the 'generic-eligible' market, are not included. • The Russian generics market is expected to generate total revenues of $10.0bn in 2015, representing a compound annual growth rate (CAGR) of 15.4% between 2011 and 2015. • Market consumption volume is forecast to reach a total of 79.9% of total pharma volume in 2015. • The Russian pharmaceuticals market is large and dominated by “branded” generic products and imports. The system is largely undeveloped, as the majority of drugs are bought by patients themselves, who are greatly influenced by advertising. The country has around 500 pharmaceutical companies but many are small. The companies’ size and the investment in marketing and sales rather than creation means that mainly older drugs are produced.
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Industry Reports Executive Summary Market value The Russian generics market grew by 14.2% in 2015 to reach a value of $10 billion. Market value forecast In 2020, the Russian generics market is forecast to have a value of $15.9 billion, an increase of 59% since 2015. Market volume The Russian generics market shrank by 1.1% in 2015 to reach a volume of 79.9 % of total pharma volume. Market volume forecast In 2020, the Russian generics market is forecast to have a volume of 75.6 % of total pharma volume, a decrease of 5.4% since 2015. Geography segmentation Russia accounts for 17.5% of the European generics market value. Market rivalry The level of rivalry in the generics market is increased somewhat by the presence of large, multinational companies with high fixed and exit costs.
• The Scandinavian generics market is expected to generate total revenues of $2.8bn in 2015, representing a compound annual growth rate (CAGR) of 6.8% between 2011 and 2015. • Market consumption volume is forecast to reach a total of 49.9% of total pharma volume in 2015. • Denmark has some of the lowest prices on generics in Europe; they are around 86% lower than Norwegian prices and 12% lower than Swedish prices. Generic drugs represent a saving of DKK1bn compared to Norway and DKK750m compared to Sweden.
Executive Summary
9. Generics in Scandinavia Introduction Generics in Scandinavia industry profile provides top-line qualitative and quantitative summary information including: market size (value and volume 2011-15, and forecast to 2020). The profile also contains descriptions of the leading players including key financial metrics and analysis of competitive pressures within the market. Essential resource for top-line data and analysis covering the Scandinavia generics market. Includes market size data, textual and graphical analysis of market growth trends, leading companies and macroeconomic information.
Highlights • For the purposes of this profile, a generic is defined as a copy of an ethical (prescription) drug formerly protected by patents that have now expired. Both unbranded generics and all branded generics are included. However, off-patent drugs that continue to be offered by the original manufacturer under the original name, and which form part of the 'generic-eligible' market, are not included.
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Market value The Scandinavian generics market grew by 7.1% in 2015 to reach a value of $2.8 billion. Market value forecast In 2020, the Scandinavian generics market is forecast to have a value of $3.5 billion, an increase of 28% since 2015. Market volume The Scandinavian generics market shrank by 0.3% in 2015 to reach a volume of 49.9 % of total pharma volume. Market volume forecast In 2020, the Scandinavian generics market is forecast to have a volume of 52.9 % of total pharma volume, an increase of 6.1% since 2015. Geography segmentation Denmark accounts for 42.2% of the Scandinavian generics market value. Market rivalry The level of rivalry in the generics market is increased somewhat by the presence of large, multinational companies with high fixed and exit costs.
10. Generics in Singapore Introduction Generics in Singapore industry profile provides top-line qualitative and quantitative summary information including: market size (value and volume 2011-15, and forecast to 2020). The profile also contains descriptions of the leading players including key financial metrics and analysis of competitive pressures within the market. Essential resource for top-line data and analysis covering the Singapore generics market. Includes market size data, textual and graphical analysis of market growth trends, leading companies and macroeconomic information.
number six healthcare system worldwide by the World Health Organization.
Executive Summary Market value The Singaporean generics market grew by 13.8% in 2015 to reach a value of $327.1 million. Market value forecast In 2020, the Singaporean generics market is forecast to have a value of $577.5 million, an increase of 76.6% since 2015. Market volume The Singaporean generics market grew by 4% in 2015 to reach a volume of 89.2 % of total pharma volume.
Highlights • For the purposes of this profile, a generic is defined as a copy of an ethical (prescription) drug formerly protected by patents that have now expired. Both unbranded generics and all branded generics are included. However, off-patent drugs that continue to be offered by the original manufacturer under the original name, and which form part of the 'generic-eligible' market, are not included. • The Singaporean generics market is expected to generate total revenues of $327m in 2015, representing a compound annual growth rate (CAGR) of 10.7% between 2011 and 2015. • Market consumption volume is forecast to reach a total of 89.2% of total pharma volume in 2015. • Singapore has a well-developed pharmaceutical market. The company’s average purchasing power parity (PPP) per capita of GDP was over $61,000 in 2013, $10,000 more than in the US. The country has also been ranked
Market volume forecast In 2020, the Singaporean generics market is forecast to have a volume of 95 % of total pharma volume, an increase of 6.5% since 2015. Geography segmentation Singapore accounts for 0.3% of the Asia-Pacific generics market value. Market rivalry The level of rivalry in the generics market is increased somewhat by the presence of large, multinational companies with high fixed and exit costs.
11. Generics in South Africa Introduction Generics in South Africa industry profile provides top-line qualitative and quantitative summary information including: market size (value and volume 2011-15, and forecast to 2020). The profile also contains descriptions of the leading players including key financial metrics and analysis of competitive pressures within the market. Essential resource for top-line data and analysis covering the South Africa generics market. Includes market size data, textual and graphical analysis of market growth trends, leading companies and macroeconomic information.
Highlights • For the purposes of this profile, a generic is defined as a copy of an ethical (prescription) drug formerly protected by patents that have now expired. Both unbranded generics and all branded generics are included. However,
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Industry Reports Market volume forecast In 2020, the South African generics market is forecast to have a volume of 82.3 % of total pharma volume, an increase of 8% since 2015. Geography segmentation South Africa accounts for 0.3% of the MEA generics market value. Market rivalry The level of rivalry in the generics market is increased somewhat by the presence of large, multinational companies with high fixed and exit costs.
12. Generics in South Korea Introduction
off-patent drugs that continue to be offered by the original manufacturer under the original name, and which form part of the 'generic-eligible' market, are not included. • The South African generics market is expected to generate total revenues of $729m in 2015, representing a compound annual growth rate (CAGR) of 9% between 2011 and 2015.
Generics in South Korea industry profile provides top-line qualitative and quantitative summary information including: market size (value and volume 2011-15, and forecast to 2020). The profile also contains descriptions of the leading players including key financial metrics and analysis of competitive pressures within the market. Essential resource for top-line data and analysis covering the South Korea generics market. Includes market size data, textual and graphical analysis of market growth trends, leading companies and macroeconomic information.
Highlights • Market consumption volume is forecast to reach a total of 76.3% of total pharma volume in 2015. • The government is showing strong support for generic drugs in Africa, which should see good growth in the future. For example, pharmacists are required by law to inform private patients about generic alternatives.
Executive Summary Market value The South African generics market grew by 9.8% in 2015 to reach a value of $728.8 million. Market value forecast In 2020, the South African generics market is forecast to have a value of $925.6 million, an increase of 27% since 2015. Market volume The South African generics market grew by 1.6% in 2015 to reach a volume of 76.3 % of total pharma volume.
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• For the purposes of this profile, a generic is defined as a copy of an ethical (prescription) drug formerly protected by patents that have now expired. Both unbranded generics and all branded generics are included. However, off-patent drugs that continue to be offered by the original manufacturer under the original name, and which form part of the 'generic-eligible' market, are not included. • The South Korean generics market is expected to generate total revenues of $4.2bn in 2015, representing a compound annual growth rate (CAGR) of 8.8% between 2011 and 2015. • Market consumption volume is forecast to reach a total of 66.8 % of total pharma volume in 2015. • South Korea has a high quality and universal health care system, and medical tourism is booming, particularly in Seoul. Generics are subject to stricter patent protection, price cuts, and competition from countries like China
and India. This has caused South Korean growth to be slightly muted in comparison to many other countries in the Asia-Pacific region.
Executive Summary Market value The Korean generics market grew by 6.5% in 2015 to reach a value of $4.2 billion. Market value forecast In 2020, the Korean generics market is forecast to have a value of $5.9 billion, an increase of 40.5% since 2015. Market volume The Korean generics market grew by 3.1% in 2015 to reach a volume of 66.8 % of total pharma volume. Market volume forecast In 2020, the Korean generics market is forecast to have a volume of 79.3 % of total pharma volume, an increase of 18.6% since 2015. Geography segmentation South Korea accounts for 4.5% of the Asia-Pacific generics market value. Market rivalry The level of rivalry in the generics market is increased somewhat by the presence of large, multinational companies with high fixed and exit costs.
13. Generics in Turkey Introduction Generics in Turkey industry profile provides top-line qualitative and quantitative summary information including: market size (value and volume 2011-15, and forecast to 2020). The profile also contains descriptions of the leading players including key financial metrics and analysis of competitive pressures within the market. Essential resource for top-line data and
analysis covering the Turkey generics market. Includes market size data, textual and graphical analysis of market growth trends, leading companies and macroeconomic information.
Highlights • For the purposes of this profile, a generic is defined as a copy of an ethical (prescription) drug formerly protected by patents that have now expired. Both unbranded generics and all branded generics are included. However, off-patent drugs that continue to be offered by the original manufacturer under the original name, and which form part of the 'generic-eligible' market, are not included. • The Turkish generics market is forecast to generate total revenues of $2.0bn in 2015, representing a compound annual rate of change (CARC) of -2.8% between 2011 and 2015. • Market consumption volume is forecast to reach a total of 50.5% of total pharma volume in 2015. • Despite overall decline, Turkey’s domestic generic market is healthy. Domestically produced generic products grew by 7.3% between 2013 and 2014. 65% of the drugs manufactured in Turkey in 2014 were generics.
Executive Summary Market value The Turkish generics market shrank by 0.1% in 2015 to reach a value of $2 billion. Market value forecast In 2020, the Turkish generics market is forecast to have a value of $1.8 billion, a decrease of 10% since 2015. Market volume The Turkish generics market shrank by 0.1% in 2015 to reach a volume of 50.5 % of total pharma volume. Market volume forecast In 2020, the Turkish generics market is forecast to have a volume of 49.9 % of total pharma volume, a decrease of 1.3% since 2015. Geography segmentation Turkey accounts for 3.5% of the European generics market value. Market rivalry The level of rivalry in the generics market is increased somewhat by the presence of large, multinational companies with high fixed and exit costs.
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Products & Services Company.........................................................Page No.
Company.........................................................Page No.
STRATEGY CPhl & P-MEC China …........................................16 & 17
CLINICAL TRIALS Bioclean……………….................................. ………….13
DigiPharmaX……...................................................... …05
Vetter Pharma…....... …………………………...09 & 44-47
Emirates Diabetes & Endocrine Conference................ 33 Emirates Society of Emergency Medicine Conference.......... 29 Medical Fair Asia……...............................……………IBC Middle East Healthcare Informatics Summit................ 43 UAE Cancer Congress......................................... .........39 RESEARCH & DEVELOPMENT Bioclean…………........................ ……………………….13 CPhl & P-MEC China.............................................16 & 17 DigiPharmaX……..…………………..........……………..05 Emirates Diabetes & Endocrine Conference................ 33 Emirates Society of Emergency Medicine Conference.......... 29 GlobalData……......... …………………………………….21
MANUFACTURING Bioclean………….......................................…………….13 CPhl & P-MEC China …................………………..16 & 17 DigiPharmaX……..…………………….............. ………..05 Emirates Diabetes & Endocrine Conference................ 33 Emirates SkyCargo................................................... OBC Emirates Society of Emergency Medicine Conference.......... 29 Etihad Cargo………………………........……………….IFC ITALVACUUM Srl………………..........…………………..03 Siegfried AG………………….........……………………..35 Vetter Pharma................................................. 09 & 44-47
Medical Fair Asia………........…………………………..IBC
INFORMATION TECHNOLOGY CPhl & P-MEC Chin..................................... ……..16 & 17
Middle East Healthcare Informatics Summit................ 43
DigiPharmaX.............................................. ……..……..05
UAE Cancer Congress.................................................. 39
Medical Fair Asia......................................................... IBC
Vetter Pharma………………….......…………...09 & 44-47
Middle East Healthcare Informatics Summit....... .........43
Suppliers Guide Company.........................................................Page No.
Company.........................................................Page No.
Bioclean………........................………………………….13 www.bioclean.com
GlobalData.........………………………………………….21 www.globaldata.com
CPhl & P-MEC China.............................................16 & 17 www.cphi.com/china
ITALVACUUM Srl..........…………………………………..03 www.italvacuum.com
DigiPharmaX……..….......... ……………………………..05 www.digipharmax.com
Medical Fair Asia........…………………………………..IBC www.medicalfair-asia.com
Emirates Diabetes & Endocrine Conference............... .33 www.edec-uae.com
Middle East Healthcare Informatics Summit................ 43 www.mehisummit.com
Emirates SkyCargo................................................... OBC www.skycargo.com
Siegfried AG......... ………………………………………..35 www.siegfried.ch
Emirates Society of Emergency Medicine Conference.......... 29 www.esemconference.ae
UAE Cancer Congress.................................................. 39 www.uaecancercongress.ae
Etihad Cargo........……………………………………….IFC www.etihadcargo.com
Vetter Pharma................................................. 09 & 44-47 www.vetter-pharma.com
To receive more information on products & services advertised in this issue, please fill up the "Info Request Form" provided with the magazine and fax it, or fill it online at www.pharmafocusasia.com by clicking "Request Client Info" link. 1.IFC: Inside Front Cover 2.IBC: Inside Back Cove 3.OBC: Outside Back Cover