Pharma Focus Asia - Issue 16

Issue 16 2012

www.pharmafocusasia.com

Key Elements of the FDA’s Draft Biosimilars Guidance First Compulsory License Likely to impact the pharmaceutical industry in India Good Clinical PracticeCompliant Clinical Studies in China

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Foreword Clinical Trials in Asia Overcoming regulatory concerns Housing more than half the world’s popula-

The regulatory landscape is dotted by different

tion, Asia is attracting more clinical trials with

regulators, making it important for companies to

rapid patient recruitments. The three key clinical

have different strategies for each country. Local

development regions in Asia—India, China and

regulatory authorities like China State Food and

South East Asia—play a major role in global

Drug Administration (SFDA), Ministry of Health and

clinical trials. Cost savings with convenient and

Family Welfare’s Drugs Controller General of India,

high performing sites available in these regions

the Food Safety and Standards Authority of India,

are attracting sponsors, thus increasing clinical

Pan American Health Organization (PAHO) and

trials activity.

many other bodies enforce rules and regulations

Asia’s clout in global clinical trials, with these

pertaining to clinical trials approval process.

growth regions, is expected to continue grow-

In this issue of Pharma Focus Asia, Alistair

ing in the coming decade. Global CROs are

Davidson an industry expert from PPD, UK shares

expanding their presence in Asia in line with

his ideas about how Asia is becoming attractive

market growth.

for inclusion in global development programs

Given this potential, the number of studies

and how to overcome regulatory barriers in

in the region has increased significantly and

Asia by harmonization of clinical trial regula-

approvals have followed suit. According to the

tory strategies.

US government’s global trials registry, clinical

The issue includes other industry lead-

trials held in India in 2009 were 9.6 per cent

ers’ thoughts on interesting topics like Recent

lesser than the number of trials a year before,

advances in analytical methodologies for the

but the number increased by 15.3 per cent in

determination of impurities in drugs, overview of

China and by 20.7 per cent in Korea as against

the recent FDA draft guidelines on Biosimilars,

the previous year. In 2008, the number of new

Compulsory Licensing, GCP and clinical research

global studies approved rose to 200 in India

standards in China, etc.

and to more than 300 in China.

Concerns about protection of intellectual property (IP) in Asian countries are getting resolved

Enjoy reading the magazine. Write me your feedback on articles to editorial@ochre-media. com

due to international pressure and domestic economic development. Improving clinical trial approval timelines and streamlining regulatory processes in India and China augur well for Asian pharmaceutical industry.

Prasanthi Potluri Editor

Contents

Strategy

CoverStory

CLINICAL TRIALS

40

06 Key Elements of the FDA’s Draft Biosimilars Guidance Peter Gaskin, Principal, Aptuit Consulting, USA

12 Molecular Medicines and Diagnosis A Snapshot Rajneesh K Gaur, Scientist ‘C’, Department of Biotechnology,New Delhi, India

16 Achieving Greater Efficiency in the Production of Biosimilar Antibodies Jonathan Royce, BioProcess Marketing Program Leader, GE Healthcare Life Sciences, USA

20 First compulsory license Likely to impact the pharmaceutical industry in India Aditi Jha, Associate Milind Antani, Head, the Pharma and Life Sciences Practice Gowree Gokhale, Head, Technology, Media and Entertainment law practice Nishith Desai and Associates (NDA), India

Research & Development 24 Application of Biopharmaceutics Classification System in Drug Development Ashley Malins, Research Analyst Christopher-Paul Milne, Associate Director Tufts Center for the Study of Drug Development, Tufts University, Boston, USA

34 Good Clinical Practice-Compliant Clinical Studies in China

Daniel Liu, Director, China Development, Medidata Solutions Worldwide, Beijing, China

MANUFACTURING 48 Recent Advances in Analytical Methodologies for the Determination of Impurities in Drugs M V Narendra Kumar Talluri, Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research, India

INFORMATION TECHNOLOGY ical clin

-track or, irect fast ior D o T , Sen

son fairs, avid f air D lator y A t s i l A Regu PD, UK l a b P Glo cific, Pa Asia

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trials

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Advisory Board

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

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

Douglas Meyer Senior Director, Aptuit Informatics Inc., USA

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

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

Editor Prasanthi Potluri Copy Editors V Rashmi Divakar Rao Jenny Jones Art Director M A Hannan Project Managers Prabha Nandikanti Breiti Roger Khaja Ameeruddin Jeff Kenney Compliance Team P Bhavani Prasad P Shashikanth Sam Smith Steven Banks CRM Yahiya Sultan Naveen M Subscriptions incharge Vijay Kumar Gaddam

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

IT Team Ifthakhar Mohammed Azeemuddin Mohammed T Krishna Deepak Yadav D Upender

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

Head - Operations S V Nageswara Rao

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

Pharma Focus Asia is published by

In Association with

A member of

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

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

Confederation of Indian Industry

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Sasikant Mishra Business, Policy and Network Strategist Pharmaceutical Industry, India 4

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Key Elements of the FDA’s Draft Biosimilars Guidance

On 9th February the FDA announced publication of it's eagerly awaited draft guidance documents for biosimilars.

For the Asian biosimilar industry this represents the first step towards access to a potentially lucrative new market.

We review the key elements of the guidelines and compare and contrast with European biosimilar guidelines.

Peter Gaskin, Principal, Aptuit Consulting, USA

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O

n 9 February, 2012 The US FDA announced the first three of the eagerly-awaited draft guidance documents for biosimilars (follow-on biologics): • Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 • Scientific Considerations in Demonstrating Biosimilarity to a Reference Product

Strategy

• Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product.

FDA defines a biosimilar as “a biological product that is highly similar to an already approved biological product, notwithstanding minor differences in clinically inactive components, and for which there are no clinically meaningful differences between the biosimilar and the approved biological product in terms of the safety, purity, and potency.”

Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009

This guideline has been prepared based on Sponsor questions received during the development of the draft guidelines and covers a number of aspects addressed in the other two guidance documents in more detail.

Below are the key aspects of the two main draft ‘Scientific’ and ‘Quality’ guidance documents and have incorporated aspects also addressed in the ‘Questions and Answers’ document.

Scientific Considerations in Demonstrating Biosimilarity to a Reference Product

The key phrase in the draft guidance is ‘totality-of-the-evidence’ which describes a risk-based approach that the FDA will use to evaluate the data package supporting a biosimilar application. In common with the long-standing European guidance and in line with expectations set by previous communications the FDA draft guidance states the importance of comparison against a reference product.

However, unlike the European guidance the FDA, in the ‘Questions and Answers’ draft guidance indicates that the reference product used in animal and clinical studies does not always need to be licensed in the USA, and Rachel Sherman, Associate Director for medical policy at CDER has stated, “We want very badly to share clinical data that exist with non-licensed reference products”. In order to use data with a reference product not licensed in

the USA bridging studies are required comprising comparative analytical studies and at least one clinical pharmacokinetic study (and if appropriate at least one pharmacodynamic study) conducted with the US licensed reference product. In such cases the reference product would need to be manufactured in, and would also need to be licensed in, an ICH country.

Such an approach would not support a claim of ‘interchangeability’, but does seek to try to address the industry’s concerns about duplication of studies to support US and European claims of biosimilarity, although the hurdles required for using such an approach are set quite high.

FDA suggests a step-wise approach to compare the biosimilar with the reference product starting with structure and function and then moving on to pre-clinical toxicology. They recommend holding a pre-IND meeting when a proposed plan for the biosimilar development program is available and when information on the manufacturing process and preliminary analytical data are available. We recommend requesting a pre-IND meeting as it provides an opportunity to verify that the product is likely to be considered a biosimilar by FDA and to determine whether animal toxicity studies are likely to be considered useful.

As with European Medicines Agency guidelines nonclinical safety pharmacology, reproductive and developmental toxicity, and carcinogenicity studies are not likely to be required by FDA for biosimilars, and in some cases no animal toxicity studies may be required (for example if there is no animal species in which the biologic activity mirrors the response in man). Unlike the European guidelines however, FDA also suggests that non-comparative toxicology studies may be acceptable in some cases where animal toxicology studies are needed.

Having a pre-IND meeting relatively early allows such issues to be discussed with FDA before pre-clinical toxicology studies are initiated, although Sponsors looking to also market their product in Europe will be aware that differences in toxicology requirements may occur between FDA and EMA. It may be possible to combine animal PK and PD endpoints into toxicology studies where they are conducted, thereby reducing animal usage. Finally, the pre-IND meeting also provides a forum to discuss plans for human pharmacokinetic and pharmacodynamic (if there is a clinically relevant pharmacodynamic marker) studies and the requirements for assessment of clinical immunogenicity, safety and efficacy. www.pharmafocusasia.com

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Strategy

Unlike generic small molecules, biosimilars must show clinical “equivalence”. A clinical pharmacokinetic study should demonstrate similar exposure with the proposed biosimilar product and the reference product, with a pharmacodynamic study showing a similar effect on clinically relevant pharmacodynamic endpoints adding weight to the claim for biosimilarity. Comparative clinical pharmacokinetic and, where relevant endpoints exist, clinical pharmacodynamic studies are therefore key parts of a biosimilar submission package. The clinical studies should use dose levels and dosing regimes expected to be used clinically, be conducted in appropriate patient populations, have clinically relevant PK and PD endpoints, and be designed to be sufficiently sensitive to identify potential differences between the reference and biosimilar products.

It is likely that the clinical assessment of immunogenicity for any biosimilar product will include some pre-marketing assessment, but the extent

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The key phrase in the draft guidance—‘totalityof-the-evidence’ describes a risk-based approach that the FDA will use to evaluate the data package supporting a biosimilar application. of pre- and post-marketing assessment required is likely to vary from product to product, based on the extent of similarity between the reference and biosimilar products and the extent of immunogenicity seen with the reference product in clinical use. Importantly, similar biological products with a better immunogenicity profile than the reference product may still be considered as biosimilars.

The draft guidance refers to the ICHQ5E guidance on “Comparability of Biotechnological / Biological Products Subject to Changes in Their Manufacturing Process” suggesting that the principles also apply to the develop-

ment of biosimilars, but indicates that more information will be required for a biosimilar product as it will likely have a different manufacturing process to the reference product. The FDA has also published a draft guidance document which deals in more detail with issues of quality for biosimilars and which is discussed below.

Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product

Whilst the legal and regulatory framework for biosimilar guidance in the USA has only been recently put in place, regulators within FDA have been considering how one can ensure similarity of biological products for some time.

Indeed, some of the central tenets of the guidance on the ‘Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product’ have been developed from those in the 1996 FDA ‘Guidance Concerning Demonstration of Comparability of Human Biological

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studies. Like the European quality guidance the FDA draft guidance document allows for minor differences in clinically inactive components of the biosimilar, with the emphasis for characterization being primarily on the components of the biological product responsible for efficacy and safety.

The importance of the quality package for a biosimilar product cannot be over-emphasised as the assessment of quality of the biosimilar defines the extent of similarity to the reference product and is, therefore, pivotal to the design of the whole development A u t h o r BIO

Products, Including Therapeutic Biotechnology Products.’ The guidance also specifically refers to the “Guidance for Industry for the Submission of Chemistry, Manufacturing, and Controls Information for a Therapeutic Recombinant DNA-Derived Product or a Monoclonal Antibody Product for In Vivo Use” also issued by FDA in 1996.

As with previous FDA guidance for biologicals the draft biosimilar quality guidance emphasises the importance of extensive analytical, physicochemical and biological characterization. In the case of the biosimilar guidance this is a comparative exercise examining the similarities and differences between the biosimilar and a suitable reference product. As mentioned earlier, FDA does indicate that in some cases it may be possible to use a reference product which is not licensed in the USA for certain

programme. Hence, the outcome of the quality assessment will determine the non-clinical and clinical study requirements. We strongly recommend that sponsors conduct a comprehensive, comparative physicochemical and functional assessment of their biosimilar in comparison to a suitable reference molecule. A good package will enable the Sponsor to propose a targeted and selective approach to non-clinical and clinical development with FDA with more likelihood of an agreement on a quicker and less expensive development program.

Peter Gaskin provides strategic technical and regulatory expertise to the biopharmaceutical industry. He has over 20 years experience of successful drug, advanced therapy, biopharmaceutical and biosimilar development in a variety of senior roles in the biopharmaceutical and contract research industry.

Serious reading for decision makers in Pharma Industry In-depth articles on innovations and discoveries. Information and insights on the future of the industry. Discussions and debates between names who matter.

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Molecular Medicines and Diagnosis A Snapshot

Molecular medicines have revolutionized the treatment and diagnosis of diseases. The advent of new genomic and proteomics based tools and techniques offer the opportunity to customise them at individual level. The application of omics science pose multiple challenges especially in developing countries. None the less, the molecular medicine based diagnosis and treatment has tremendous potential to reshape the Indian market.

Rajneesh K Gaur, Scientist ‘C’, Department of Biotechnology, New Delhi, India

T

he patient and physician relationship involves a number of steps such as the advice on hygiene maintenance, chronic or non-chronic/ infectious disease diagnosis, measures to limit the spread of disease, continuous requirement of diagnostic tools, techniques and diagnostic centres, pharmacy, disease monitoring, process and data management, obedience of statutory regulation and raising their concerns at the appropriate forums. From the patient’s point of view, the most important step of this relationship is diagnosis and treatment of the disease. On the other hand, primary healthcare physicians are always under pressure to provide the best diagnosis and treatment to patients in the absence of easily available, affordable and technically less complicated diagnostic methodologies and treatment options. Within last century, physicians and clinicians rely on their monographic education and symptomatic patient treatment. The transition of the century infused more molecular mechanism based medicines in the market 12

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and unfortunately in developing countries, these “Angles on Earth” are lagging behind in terms of their scientific knowledge and updates of the technological advancement.

Transition Justified

Maintaining the patient’s health and enhancing longevity is the ultimate goal of all systematic and non-systematic efforts made by humans. Being at the apex level of evolutionary tree, they can easily modify the most affecting environmental and other factors. Survival pressure forced the human beings to switch their random approach to more disciplined and scientific studies of the surrounding flora and fauna for exploitation of the possible intervention tools. The systematic study of basic human biology is now evolved to decipher the concepts and phenomenon at molecular level as aptly summarised

by Linus Pauling in 1956 that “Man is a collection of molecules”. The technological advancement in biological sciences leads to the unfolding of Human Genome and

opens up the Pandora box against medical scientists to utilise the plethora of information for augmenting the level of human health and care through molecular diagnosis and sophisticated treatment with reduced cost. The application of Genomic and Proteomic information has huge R&D and market development potential along with the flourishing of a demanding, structured and more articulated service sector. The translation of these developments will revolutionise and redefine the patient-physician relationship.

The diagnosis and treatment approaches are continuously adjusted over the time in response to the endemics, epidemics and pandemics. The response to these adjustments against infections is well documented but non-infectious cases are perfected through symptomatic approach and partly supported via molecular approach. If the symptoms are overlapping for a disease, then it is still difficult for a physician to prescribe judiciously. Therefore, it is highly desirable that the modern medical science must be

Strategy

Molecular medicine is the outcome of conglomeration of physical, chemical, biological and medical techniques.

This approach emphasises on cellular and molecular phenomena and their interventions. More scientifically, molecular medicines are application of genomic knowledge and stem cell sciences to human health with an ultimate promise of catching and eliminating diseases before the onset of symptoms.

The current molecular medicine market includes the following segments: disease prevention, diagnostics, treatment, and patient care.

Diagnostics

equipped with tools, which can pin-point the origin, type, nature, identification, possible remedies for a disease. The general requirement is the specificity of the tools and techniques desirable at the molecular level. The question is how to induct tailor made molecular medicines in the system and what are the problems and respective approaches required in doing so?

Emergence of Molecular Medicine

Traditional medicines have been used in several countries for thousands of years.

In some Asian and African countries, 80 per cent of the population still depends on traditional medicine for primary healthcare [WHO (2008): Fact Sheet, No. 134]. In different cultures and regions, the traditional medicine system is in use without the parallel development of international standards and methods for evaluation.

The era of molecular medicine started in 1956 when ‘Linus Pauling’ published a paper on hemoglobin and showed that hemoglobin [HN3] of patients suffering from Sickle Cell Anemia had a different

electrical charge than that from healthy individuals. Since then the molecular insight of various diseases has been explored resulting in the development of sophisticated and advanced physical and biochemical tools for the diagnosis and treatment of both infectious and non-infectious diseases. The continuous growth of the field establishes it as an independent discipline.

The current traditional system has several drawbacks especially considering the rationality of the diagnosis and treatment in comparison to the modern approach based on molecular profile.

The lack of scientific justification of the practices, observation based and judgmental form of diagnosis renders the traditional medicine system susceptible to criticism. The popularity of the modern molecular medicines system is facilitated by multiple factors such as shortcomings of the traditional medicine system, scientific, technical and methodological advancements and quick healing (Table 1).

The current diagnostic business consists of three pillars: in-vitro diagnostics, in-vivo diagnostics and medical imaging. Presently, diagnosis is facilitated by service laboratories either in a public funded dispensary/hospital or private setup [Figure 1]. The basic molecular and histo-pathological tests constitute the bulk of the current diagnostic market segment in India. Medical imaging is not easily available as well as also not cost effective.

In-vitro diagnostics (IVD) involves the removal of tissue samples such as blood, saliva, biopsy samples from a living organism for examination in the laboratory, whereas in-vivo diagnostics involves observing and testing tissue and function in a living organism with the help of techniques such as medical imaging (x-rays, magnetic resonance, computed tomography etc.) and monitoring like electrocardiography, electroencephalography etc. With a compounded annual growth rate (CAGR) of 18.1 per cent from 2009 to 2016, in-vitro diagnostics has emerged as one of the most profitable markets for the Indian healthcare industry. The improving corporate hospital infrastructure and installation of automated and semi-automated biochemistry, immunology, and hematology equipment have enabled the market to achieve this healthy double-digit growth. The major reasons for the Indian in-vitro diagnostics market fragmentation are the low entry www.pharmafocusasia.com

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Strategy

Medicine System Traditional

Molecular

Disease diagnosis is symptomatic rather mechanism based

Pre-symptomatic and symptomatic diagnosis is possible and more reliable

More often the treatment involves hit & trials

Quantitation is aided by modern scientific tools such as Genomics, Proteomics etc.

Diagnostic tools & techniques are qualitative

Primary healthcare physician / professionals have added responsibility

Require specialists intervention

Needs an extensive and continuous skill development of all the concerned personnel.

Also emphasize the role of trained and skilled technicians.

Physician education and training for skill upgradation is infrequent

Patient centered and custom made. Patient will be benefitted as a result of cost reduction due to more in-hand options

Not customized for the individuals

Initial investment is high but may be reduced through public-private partnership

Pharma and Diagnostic companies enjoys greater margin benefits

Pharma and Diagnostic companies needs exclusive business model

Suffer from drug resistance and diagnosis failure problems

Reduction of diagnostic and treatment related problems

Data documentation and data analysis is very limited

Data documentation and data analysis is an essential component. Requires skilled and trained staff for analytical work.

Table 1: The conceptual and fundamental differences between traditional and molecular system of medicine

barriers, which led to the mushrooming of laboratories, and the absence of legislation leading to the complete lack of standardisation. Currently, only 150-200 laboratories in India have accreditation.

In-vivo diagnosis and medical imaging are slowly merging with each other.

Asia-Pacific is likely to emerge as the fastest growing market with a CAGR of 17.5 Per cen. Medical imaging market consists of X-ray, Ultrasound, Computed Tomography, Positron Emission Tomography, Magnetic Resonance Imaging, Nuclear Medicine, Mammography and Fluoroscopy. Among all the imaging techniques, MRI & CT scan represents the largest segment (Source: PR web, San Jose, California, Nov.21, 2011). The global market for 3D Medical Imaging (software and workstations used in MRI and CT; and Ultrasound machines) is forecasted to reach US$5.9 billion by the year 2017, primarily driven by the technological advancements, resulting in improved imaging equipment. The medical imaging sector is a technology-intensive area, which has tremendous market potential as a result of advancements and integration of technologies. The advent of molecular biomarkers in future will greatly enhance the growth rate of medical imaging as well as the molecular medicine sector.

Impact and Outcomes

Diagnostic Business In-Vitro

Service Lab

In-Vivo

Molecular

Histo-Pathological

Imaging

Serology Immunological Toxicological Nucleic acid tests Protein based tests Microarray Metabolomics

Microscopy Cytognetics Cell based assays

Endoscopy Ultrasound MRI TOmography

Figure 1: Currently available types and tools for diagnosis 14

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The medical biotechnology field is constantly flourishing world-wide and now acceptable to common man as a result of the value, safety and choice of products as well as availability of quality services with biotechnology advancements.

Molecular medicine will contribute in improved risk assessment even in remote areas due to the availability of pre-packed kits and probably minimal of mechanical support. The rapid scientific progress in Genomic and Proteomics area will eventually lead to the high cost to return market benefits globally in molecular medicines sector.

India is a developing country and unfortunately 80 per cent of its population still has a daily income of

Strategy

Roadmap The benefits of molecular medicines ought to be captured for health and wealth creation after thorough assessment of multiple factors as mentioned above. Education of the public and community at large forms another vital component of this process. Any change in the public attitude about the scientific progress comes slowly with increasing public familiarity, increased perception of benefits, withering of fear and associated dangers to the scientific innovations. New education programmes in interdisciplinary areas are required to generate skilled human resource and to create new intellectual property. Health professionals must be educated to ensure the rapid transfer of new knowledge and new information.

There is an urgent need to make requisite public and private investment in genomics and related areas. Investment is required to create infrastructure, while private investment is needed for translating the existing and new knowledge into new opportunities. Open discussion of ethical concerns and strong regulatory framework will provide a major impetus to the development of this area. organization that will spend money and will take initiative upfront.

Governmental support for the molecular medicine sector will not only help the R&D and manufacturing, but will also have a huge impact on clinics as a result of easy availability of human genetic maps, bio-marker assisted genetic analysis -- especially for chronic diseases like cancer and diabetes etc--, chip based detection and probably the availability of gene therapy. This kind of treatment approach needs mature understanding between a patient and physician and also patient’s willingness to embrace adventurous and miraculous therapy without hesitation.

Bottleneck

The immediate challenge for medical scientists is to introduce patient-friendly methodologies and course of treatment driven by cutting-edge science, so that A u t h o r BIO

Rs. 20/- only as per Tendulkar Committee report (The Times of India-'Reforms failed to bridge urban-rural divide', July 29, 2011). Furthermore, a newer technology is always expensive. Therefore, any discussion related to molecular medicines seems like making the hill out of a mole.

Under such circumstances, the government funding agencies like Department of Biotechnology (DBT) and Indian Council of Medical Research (ICMR) has to play a greater role in making molecular medicines affordable through extending their support especially for ‘Omics’ based diagnostic tools and techniques.

Several Indian companies including Span Diagnostic Ltd. (Surat), Bhat Biotech (India) Ltd (Bangaluru) and Reamatrix India Pvt. Ltd. (Bangaluru) realised the true potential of this sector and are now driving the Indian market towards prepacked diagnostic products. The market of laboratory diagnostics is growing and is said to achieve a growth rate of around 30-35 per cent in India. The initial investment will create market competition, which will boost easy availability, cost reduction and quality assurance down the line at the consumer level. Profits, Patent protected royalties and commercialization opportunities will benefit the

diseases can be diagnosed and treated accurately with minimum adverse drug reactions, drug over-dosage, drug resistance and accommodation of geographic variations. These challenges can be met only when the disease diagnosis will be based on accurate knowledge of molecular mechanism of diseases and tools to identify the peculiar mechanisms without overlapping. This is certainly a new approach for treatment and requires slow but definite transition from traditional to modern molecule based medicine system.

A futuristic and defined road map is required to achieve the ambitious goals associated with molecular medicine and diagnostics. There are a number of challenges, which need immediate and planned initiatives. These challenges are staggering at each level of development, to be carried out for establishing and capitalising on the potential offered by this area for the benefit patients. Financial support seems to be a foremost concern but there are other challenges including the availability of trained and skilled manpower such as technicians, physicians and even scientists for high-tech data interpretation, encouragement of entrepreneurship, assessment of associated risks, courage to invest, business models, basic infrastructure, technical education, establishment of technology transfer bridge between academia and industry, expertise in legal matters such as Patents, IPR etc., skilled manufacturing labour availability and above all the product designing capability. Marketing and making these products acceptable to general public at affordable cost, without compromising the quality is another major challenge, especially in a developing country like India.

Rajneesh Kumar Gaur is Doctorate in Structural biology from RWTH, Germany and having almost 8 years of experience in active science research. He is currently engaged in Planning, Co-ordination and International Cooperation in Department of Biotechnology, Ministry of Science and Technology, New Delhi, India.

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Strategy

The biosimilars market is set to reach more than US$20 billion in 2020 and both established biopharma and younger therapeutic manufacturers will play their part in meeting demand. Despite growing regulatory acceptance for biosimilars, challenges remain.

How to maximise facility utilisation?

How to minimise investment for scale up? The answers lie with the implementation of modern technologies to minimize early capital investment, and the application of LEAN approaches to maximise process economy.

Jonathan Royce, BioProcess Marketing Program Leader, GE Healthcare Life Sciences, USA

Achieving Greater Efficiency in the Production of Biosimilar Antibodies

B

iosimilars and biobetters represent a new and exciting market for therapeutic manufacturers.

Recent reports indicate that the market for biosimilar monoclonal antibodies (MAb) will reach more than US$20 billion in 2020, with the majority of revenues coming from established markets for MAbs窶馬amely, the USA, 16

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France, Germany, Italy, Spain, the UK and Japan. Additional revenues from new and emerging markets are also expected as much of the manufacturing of biosimilar drugs is currently occurring in South Korea, China, India, the Middle East and Latin America, where large populations with unmet healthcare needs exist. In addition to

pure market forces, there is a strong interest from central governments to encourage local companies to develop biosimilar capabilities, including MAb production, and a pressing need to bring the therapeutic benefits of MAb therapies to greater patient populations, while simultaneously reducing costs.

An extensive pharmaceutical market

Strategy

investigation by the European Commission indicates that avoiding delays to the introduction of generics of any kind, including biosimilars, could have led to approximately 20 per cent additional savings in healthcare costs compared with the â‚Ź14 billion saved over the study period.

In the past 12-18 months, many established biopharma players have announced initiatives or alliances for their own biosimilar counter-strategy.

The entry of originator companies into the biosimilar space will likely result in a significant biosimilar market, but it will also temper the level of price reductions which can be expected.

The traditional hypothesis regarding biosimilars is that they will be less expensive than originator drugs due to lower research and development costs,

reduced financial risk from failed clinical trials, and production facilities based in markets with lower infrastructure and labor costs. However, in order for biosimilar manufacturers to fully realize the potential of this market, they will also have to meet some of the fundamental challenges that originator companies also face: How does one maximise facility utilisation? How can one minimise the investment needed when scaling up a manufacturing process? What modern tools can reduce COGs, even for legacy therapies?

Facility Design

When planning for new production facilities, it is important to consider that most modern plants will be required to produce multiple products in order to reach their maximum payback potential.

Although early antibody-based drugs benefited by targeting indications with relatively large patient populations and limited competition, new biotherapeutics and biosimilar antibodies will enter a very different market, with populations that are smaller (due to increased competition) and possibly less global (due to yet-unresolved regulatory restrictions).

This shift in annual demand per product means that future facilities will have to operate at smaller production scales per batch, which typically introduces new costs related to lost economy-ofscale. Thus, new production facilities for biosimilars can only provide maximum economic benefit if they are designed with multiple products in mind— otherwise under-utilized capacity may paradoxically result in higher rather than lower COGs for biosimilars.

Figure 1: A visual representation of one strategy which can lead to better process economies during scale-up

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Strategy

Scale-up challenges In order to produce clinical product for trials, and eventually commercial product upon approval, process scale-up is typically performed at risk, meaning prior to regulatory approval of an antibody therapy. As financial pressures on the industry increase, the appetite for risk is reduced, and therefore it is important to minimise financial exposure prior to securing a revenue source. Capital investment represents the largest share of financial risk when scaling up prior to approval. Thus, it follows that strategies which reduce or delay capital investment in turn reduce financial risk.

Implementation of single-use and disposable technologies is one of the most effective ways to minimise the need for early capital investment. Figure 1 provides a visual representation of one strategy which can lead to better process economies during scale-up. In the early phases of a company’s life cycle, manufacturing is performed using as much single-use technology as possible. This may increase per batch costs, but ultimately results in better company performance as costs are only incurred when product (and therefore value) is produced. Depreciation costs for under-utilised fixed equipment are minimised, and the smaller capital investment which is required can be leveraged over multiple projects since fluid contact paths can be dedicated or replaced for each campaign. As a company’s production capacity matures (i.e. after revenue sources are secured), more focus can be placed on strategic capital investments which can be leveraged over multiple projects. This is a frequently overlooked point among the numerous discussions regarding single-use implementation—fully disposable manufacturing frequently does not lead to optimal process economy.

Rather, blended implementation of single-use and traditional manufacturing technology may be preferable to maximise results. Identifying the correct blend of these process technologies will be case-specific and requires detailed analysis.

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Multi-product facilities based on traditional manufacturing technology can and have been designed and built in various parts of the world. However, changeover time for such facilities is significant, frequently between 10-14 working days when switching from one antibody to the next. This time is required to ensure proper cleaning and replacement of equipment, as well as to receive analytical results which confirm that proper cleaning and sanitization has been achieved. In dedicated facilities, changeover time is limited to time spent on routine annual maintenance, but in multiproduct facilities, the effect can be dramatic. Consider, for example, a facility designed to produce 31 batches of product per year: if such a facility is used to produce two antibodies rather than one, the facility output is reduced by nearly 30 per cent to 24 batches per year. Similarly, pushing the facility to accommodate four antibodies will reduce the output to only 10 batches per year. Over time, highly skilled manufacturers have improved their change-over routines and achieved significantly shorter times. However, in traditional facility layouts, these gains come only with substantial investments after years of experience.

Smart facility design, proper production planning and implementation of technology which minimises changeover time are all tactics which can be employed to optimise the design of multiproduct facilities.

For example, designing plants with dedicated seed train suites allows for changeover to begin in parallel with antibody production. Planning production so that annual demand is satisfied in a single campaign minimizes the number of changes required per annum; and implementation of single-use and disposable technologies which eliminate cleaning validation and/or can be dedicated to specific campaigns can reduce changeover time by as much as 50 per cent.

Strategy

Modern Processing Tools

Since early entrants in the biosimilar antibody market will focus on originator therapies developed 10+ years ago, there exists much opportunity to introduce modern tools into their production which can reduce the cost of manufacturing.

Consider, for example, four improvements in process technology which have occurred in the past decade.

Although early antibody-based drugs benefited by targeting indications with relatively large patient populations and limited competition, new biotherapeutics and biosimilar antibodies will enter a very different market.

High throughput process design (HTPD)

Downstream purification

MabSelect™ was introduced in 2000 as the first protein A chromatography resin based on high flow agarose. Before that time, the dynamic binding capacity (DBC) of modern protein A resins was approximately 20 g/L, or even lower.

Today, MabSelect SuRe™ LX reaches binding capacities of 60 g/L, while also providing caustic resistance to simplify cleaning-in-place operations and enhancing the lifetime of the resin.

The additional capacity of this modern resin offers good facility fit in classic large-scale plants with production outputs as high as 70 kg per batch.

Seed train

One year after the introduction of MabSelect, Vijay Singh was granted a patent for the WAVE Bioreactor™. Prior to Dr. Singh’s invention, seed trains were

composed primarily of glass and smallscale steel bioreactors which required cleaning, assembly and sterilisation between every batch. The introduction of the WAVE Bioreactor technology to seed train operations has reduced this downtime from approximately 20 hours to 30 minutes, for an efficiency increase of 4000 per cent.

Buffer storage

Finally, in traditional facilities it is common to dedicate huge tanks or single-use bags for specific buffers.

These storage vessels occupy enormous space in classified production areas and thereby introduce fixed costs which are difficult to utilize fully. Today, inline buffer conditioning systems, which work by combining stock solutions to produce numerous buffers on-demand, can dramatically reduce the size and number of buffer storage tanks or bags required to support antibody production. In one case study performed in 2010, introduction of an inline condi-

A u t h o r BIO

While originator molecules were likely developed using traditional process development tools, today rapid development of optimal process conditions can be achieved by working with modern High-Throughput Process Development (HTPD) approaches, such as PreDictor™ miniaturised formats for screening of chromatography resins. Method development using PreDictor formats combined with Design-Of-Experiments (DoE) allows for optimisation of MAb capture and polishing steps in a less time and with fewer experiments. In a recent case study, 192 conditions were screened in approximately 4 hours and analysed in 48 hours.

tioning solution resulted in the replacement of two 25,000 L storage tanks with two 5,000 L concentrate vessels, resulting in a capital savings of more than 300,000 USD and a floor space savings of over 200 square feet.

Conclusions

Biosimilar antibody producers stand to benefit from more than a decade of process enhancements and facility knowledge gain. However, new challenges will be present regarding the scale of demand and the requirements on facility design. Fortunately, these challenges are addressable by implementing modern processing tools and strategies. Flexible facility design, singleuse technology and introduction of high throughput purification products are a few of the strategies available to developers which can maximise the potential of the biosimilar antibody market, while still delivering overall cost reductions and improving access to these breakthrough therapeutics.

One final note of caution for new biosimilar producers. If they are to achieve the expected savings in costof-manufacturing, they will need to apply LEAN approaches rigorously to all of their manufacturing operations.

This will be a major challenge, since originator companies have considerably more experience in maximising process economy and have applied manufacturing excellence programs for years. Nonetheless, regardless of a company’s experience level, the application of modern processing tools to biosimilar antibody manufacturing should be part of the overall go-tomarket strategy.

Jonathan Royce oversees external marketing for the BioProcess division as well as five applications development teams focused on vaccines, antibodies, recombinant proteins, single-use and process development solutions. Jonathan has a Masters’ degree in chemical engineering from Northeastern University and he resides with his wife and two children in Uppsala, Sweden.

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Strategy

First compulsory license Likely to impact the pharmaceutical industry in India

On 9th March, 2012, the Controller General of Patents Design and Trademarks of India, Mr. P.H. Kurian, marked his last day in office with a landmark judgment granting the first ever compulsory license to an Indian generic pharmaceutical company Natco Pharma to manufacture and sell a generic version of Bayer Corporation’s patent protected anti-cancer drug ‘Sorafenib Tosyalte’ (NEXAVAR). This watershed development is likely to alter the complexion of the pharmaceutical industry in India. This judgment brings to the fore many contentious issues such as whether “local manufacturing” of a patented invention is mandatory in India, what drug price is “reasonable” under the current patent regime.

Aditi Jha, Associate Milind Antani, Head, Pharma and Life Sciences Practice Gowree Gokhale, Head, Technology, Media and Entertainment law practice Nishith Desai and Associates (NDA), India

T

he grant of compulsory license (CL) to Natco Pharma in relation to Bayer Corporation (“Bayer”)’s patented anti-cancer drug Sorafenib Tosyalte’ sold under trademark NEXAVAR (‘‘Drug’) is expected to have a major impact on the strategies devised by 20

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both generic and innovative companies.

Since this is the first time that the CL has been granted in India, several issues arise in relation to the interpretation adopted by the Controller of Patents (Controller).

Grant of CL is contemplated under the international conventions as well, viz.

Paris Convention of 1883 and agreement for the Trade Related aspects of Intellectual Property Rights (TRIPS) (Article 31).

What is CL

CL is an involuntary contract between a willing licensee and an unwilling patentee imposed and enforced by law. Up on grant of the CL, the licensee can manufacture the patented product for the remaining term of the patent, unless the CL is revoked earlier. The CL may be granted by the government suo moto in situations of national emergency, extreme urgency or may be granted on an application of any person interested.

The Controller determines the royalty payable by the grantee of the CL to the patentee.

The Controller may grant a CL at any time after three years of the grant of a patent on any one or all of the following grounds on application of the person interested:1) The reasonable requirements of the public with respect to the patented inventions have not been satisfied, or

Strategy

2) The patented invention is not available to the public at reasonably affordable prices, or 3) The invention is not exploited commercially to the fullest extent within the territory of India.

In the Order, Natco raised all the above grounds against Bayer and the Controller upheld Natco’s contention on all the three grounds.

Ground 1: Reasonable requirements of public not satisfied

Natco urged that (i) As per GLOBOCAN 2008 there were approximately 23,000 patients of kidney and liver cancer (for which Drug is used) requiring treatment in India, (ii) Form 27 filed by Bayer, denotes that 200 bottles were imported during 2008-2010 (iii) The Drug was exorbitantly priced, out of stock and had limited availability in India (iv) Bayer launched the product worldwide in 2006 and made sales of approximately US$ 2,454 million internationally (v) The insignificant number of bottles imported in India showed Bayer’s neglectful conduct.

Bayer responded by demonstrating that actual number of patients requiring treatment is 8,842 and that exorbitant price has no link with reasonable requirement of the public. Bayer argued that the availability of the Drug has been considerably increased due to the infringing sales by another Indian generic company Cipla Ltd (“Cipla”) who was projected to sell about 4,686 boxes of the Drug in 2012.

The Controller in deciding against Bayer held that: • The number of patients needing the Drug will be much higher than 8,842.

• As per Bayer’s own numbers they have been able to supply the Drug to not more than 200 patients which is just 2 per cent of the 8,842 patients.

• Sales of Cipla cannot be added to the Patentee’s sales figures as Cipla can be injuncted anytime and thus “an

uncertain supply by an alleged infringer cannot be considered.”

The Controller did not deal with the issue whether expensive price of the Drug has any connection with it being reasonably unavailable to the public.

Bayer did not challenge the reliance

by Natco on the GLOBOCAN 2008 data. Bayer urged that the Drug is only required by patients having Stage IV (as opposed to Stages I to III). Hence the number of patients requiring the Drug was 8,842. Even if the Controller had proceeded on the number provided

by Bayer, the admitted supply was not sufficient to meet the demand. By its own showing, more than 8,000 patients needed the Drug, whereas it had imported 200 bottles in 2009 and 593 bottles in 2011. Cipla’s sales started only in 2010. Bayer had no explanation as to why it did not manufacture/import the Drug between 2008 and 2010. In any event, the Controller was right in holding that Bayer cannot take advantage of sales by Cipla.

Ground 2: The patented invention is not available to public at “reasonable affordable price’’ (RAP)

Natco argued that the price of the patented product is too high and that at INR 2,80,428 per month supply , the exorbitant pricing is an abuse of its monopolistic rights.

Bayer’s arguments were as follows: (i) Innovative drugs cost more than generics since the innovator’s costs include R & D expenses which generics do not incur.

Under the Essential Commodities Act, 1955, the government of India has promulgated The Drug Price Control Order (“DPCO”) which fixes the ceiling price of certain active pharmaceutical ingredients and formulations.

(ii) The higher price includes the costs of failed projects which accounts for nearly 75 per cent of total R&D cost and underwrites additional costs for future innovations. (iii) Replacing innovative drugs with generics will damage patients as originators also provide for the education of doctors and pharmacovigilance which generics do not. (iv) The term ‘reasonable’ should be construed as to mean reasonable for both the patients and the patentee. Bayer argued that “public” denotes different sections of public. A blanket CL which gives the patented product at the same price to all sections of the public is not reasonable.

The Controller in his decision agreed with Bayer that “public” includes different sections of the public, but also observed, that Bayer was free to have offered differential pricing to different classes, but chose not to. The Controller partially disagreed with Bayer that in determining reasonableness, both the Patentee and the public need to be factored in, but observed that “RAP has to be construed predominantly with reference to public”, but has not delved into this aspect.

In the Act, RAP has not been defined nor are there any guidelines as to how it ought to be determined. In his analysis, the Controller has not discussed: 1) what would have been a reasonably affordable price, 2) how to arrive at the conclusion of whether a price is reasonable or not, or 3) what costs of the Patentee ought to be considered while arriving at what is a RAP. Often pharmaceutical companies decide not to introduce patented products in India as they believe that the price which they seek will not be afforded by the market. Innovator companies have no intention of making the patented product available in India. Therefore, the expenditure incurred by the patentee, may not as a rule be taken into account while determining RAP. The interest of the patentee may be taken into account only if the Controller determines that www.pharmafocusasia.com

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Strategy

patentee indeed intends to make the drug available in India.

Interestingly, under the CL Chapter of the Act, prior to 2002 amendment, the expression used was “reasonable price” and in the current CL Chapter the expression used is “reasonably affordable price”. Thus, the element of “affordability” has been specifically brought in.

The English Oxford Dictionary defines “affordable” as “inexpensive; reasonably priced”. Hence, one would wonder whether the intention of the legislature indeed was to take only public interest into account.

Ground 3: Patented invention not worked in the territory of India

This is the most contentious section of the order. Natco urged that since the Drug is being imported, it is not being ‘commercially worked’ in India.

Bayer argued that the ‘working requirement’ does not mean that the patented product has to be locally manufactured.

According to Bayer, “working” of a patent meant that there should be a supply of the patented product in the territory of India. Bayer argued that it had centralized its manufacturing in Germany due to economies of scale and to maintain high quality.

The Controller came to the conclusion that mere importation cannot amount to ‘working’ of a patented product for the purposes of the Act. The CL Chapter of the Act does not define “working of the patent”. But interestingly, Form 27 that all patentees are required to file to inform the patent office about the ‘extent to which the patented invention is worked on commercial scale in India’ requires the patentee to provide information about manufacturing in India and importation into India. Section 48 which relates to the rights of the patentee, specifically recognizes the exclusive right of the patentee to import patented product into India.

Even at the WTO level this issue has not been settled. Article 27(1) of TRIPS requires nations not to discriminate between locally manufactured and 22

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imported products. On the other hand, Art 7 of TRIPs states that intellectual property rights should lead to transfer of technology and dissemination of information. It is not clear, how the two provisions will be read together. In fact, the existence of both these provisions highlights the difficult negotiations that marked the signing of the TRIPs agreement with the developing bloc getting Art.7 and the developed countries getting Art.27. Brazil’s IP law had a similar provision requiring local manufacture of a patented product.

USA had filed a complaint in the WTO Dispute Settlement Body. This case was later settled. Similarly, Art 5(1) of Paris Convention lays down that importation of patented articles shall not entail forfeiture of the patent.

From a reading of the Paris Convention, TRIPS and the Act, there still appears to be an ambiguity as to how to interpret the “working” requirement.

The Controller relied on Section 83 of the Act which states that “regard must be had that patents are not granted merely to enable patentees to enjoy a monopoly for the importation of the patented article.” Sec 83 is merely of a guiding nature and is not a substantive provision. The controller relied on Section 90 (2) of the Act which states that a grantee of a CL cannot import the patented product into India. The Controller stated that “if the licensee cannot import the product into India, for working the invention… Then it implies that importing cannot amount to working for a license”. Section 90(2) is a fetter on the grantee of a compulsory license. It ensures that the ambit of the compulsory license remains the territory of India, and does not adversely affect other markets of the patentee. The Controller’s view seems to be an incorrect interpretation of the law.

Prior to the 2002 amendment of the Act, there existed only two grounds for the grant of CL (i) RRP not being satisfied; (ii) the patented invention not being available at a reasonable price. The “nonworking” aspect has been brought in only by 2002 amendment. While bringing in this amendment, the legislature seems to

have to have interlinked RRP and “working” provisions, which has created confusion in its interpretation.

After perusing the above deliberations, one wonders, does the Act require “local working” or not! The answer at this stage is not clear. We need to await the decision in appeal. The matter may be litigated up to the Supreme Court, which may eventually provide guidance.

On a practical note, most companies, including Indian companies have outsourced their manufacturing to ensure economies of scale. The Controller’s order means that every patent holder will now have to sufficiently manufacture in India, else it will be facing the prospect of having a CL issued against it. If we look at the economics of international trade, by requiring local manufactures against availing the advantages of economies of scale will no doubt adversely impact the Indian consumer.

The Controller granted a non-exclusive, non-assignable CL to Natco to make the Drug available at INR 8,880 for a packet of 120 tablets. Natco has to pay a 6 per cent royalty to Bayer. Since the royalty earned by patentee would be a Per cenage of net sales, in absolute terms, the amount of royalty received by Bayer may not be commensurate with the expenditure incurred by it.

Conclusion

This order marks a watershed in the development of jurisprudence of CL. There has not been significant interpretation of Articles 7, 30, 31 of the TRIPs agreement, nor how it interplays with Article 27(1) of TRIPs and Article 5 of the Paris Convention.

For the pharmaceutical industry, patents occupy a significant place. Drugs, due to high R&D costs, a significantly high level of failed research and ease of successful copying, depend highly on patent protection. Hence, measures that reduce this protection, such as CL, are viewed as harmful for the innovator companies.

A more pragmatic approach to CL is the approach taken by Brazil. Instead of

Strategy

private generic companies obtaining CLs, the government studies which diseases need intervention from the State and uses the CL as a bargaining tool to get the innovator companies to come to the negotiating table. Brazil has been successful in getting various innovator companies to reduce drug prices by up to 40 per cent. The advantage of this approach is that a calculated decision is arrived at as to which diseases and medicines are really required to be made available to the public while at the same time, the innovator retains its exclusivity and the public gets access to medicine at a reasonable price.

A significant issue to be considered is whether price control of drugs can only be achieved through CL. Under the Essential Commodities Act, 1955, the government of India has promulgated The Drug Price Control Order (“DPCO”) which fixes the ceiling price of certain active pharmaceutical ingredients and formulations. The DPCO provides the government an effective mechanism to regulate drug prices thereby increasing access to medicines without interfering with patent rights of innovators.

This case offers takeaways for innovator companies, especially pharmaceutical companies. First is the importance of Form 27. Due care and diligence needs to be undertaken while filing the Form

and not treat it as a mere mechanical exercise.

The second takeaway relates to the working requirement. If Bayer had been able to show a readiness and willingness to manufacture the Drug, they may have been able to get some concessions.

Pharmaceutical companies should be able to demonstrate intention and willingness to make the patented product available in India. Of course, if the patentee does not view India as a market for its product on the assumption that the market will not be able to ‘afford’ its drug and then grant of a CL may not have any economic impact on the patentee.

What remains to be seen is whether oncologists and other treating doctors will consider only the reduced prices of generic versions of the Drug while prescribing it to advanced stage liver / renal cancer patients. While Natco will sell the Drug at INR 8,800, it still has the task of convincing doctors about the quality and efficacy of its product.

The IPAB or the Supreme Court will need to determine what RAP and RRP means. This battle is far from over. The interpretation of "working" of a patent to mean ‘local manufacture’ within India is highly contentious. It is likely that this issue will be agitated right up to the Supreme Court in India as well as at the WTO.

A u t h o r BIO

Aditi Jha has presented her research findings on legal issues in life-form patenting, assisted reproductive technologies to national symposia and her research forms part of a book on IP law in India.

She won national legal writing contest on the subject of freedom of speech & expression on the internet and she has regularly written on legal and non-legal issues.

Milind Antani’s practice areas include Pharmaceutical, Life Sciences, Healthcare, Intellectual Property and Medical Devices. Antani is also the member of FICCI, National Pharmaceutical Committee, FICCIGujarat Healthcare committee and the Committee of Telemedicine Society of India.

Gowree Gokhale’s specialisation includes Litigation and Dispute Resolution, Franchising, Pharma and Life Sciences laws, Commercial laws, HR laws and Intellectual Property. Gokhale is a Solicitor and a registered Patent & Trade Mark attorney. She is also a visiting faculty at Institute of Intellectual Property Law Studies at Mumbai.

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Research & Development

Application of Biopharmaceutics Classification System in Drug Development Along with Regulatory authorities, pharmaceutical manufacturers are also making use of BCS throughout drug discovery and development processes. The article talks about the status of BCS and BCS-analogues in Asia-Pacific countries; the role of the BCS for generic companies vs. the role for biopharmaceutical companies; the relative strengths and weaknesses of the BCS vs. other similar classification systems; as well as regulatory issues that impact the BCS such as global harmonization, public release of data (i.e., transparency), and quality by design.

Ashley Malins, Research Analyst Christopher-Paul Milne, Associate Director Tufts Center for the Study of Drug Development , Tufts University, Boston, USA

S

ince it was introduced in 1995, the Biopharmaceutics Classification System (BCS) has had a major impact on the regulation of oral drug products worldwide.

Fundamentally, the BCS is a scientific framework for classifying drug substances (i.e. active ingredients) based on the factors that determine the rate and extent of absorption from immediate release (IR) solid oral dosage forms for the purpose of establishing equivalence in quality between test and reference drug products. By providing a basis for avoiding unnecessary in vivo studies, BCS helps significantly reduce the cost and time of developing drug products.

BCS has gained importance worldwide as a drug product regulation tool; the system has been formally adopted by the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the World Health Organization (WHO) (with some modifications) as a means to establish technical standards for waiving bioavailability (BA) and bioequivalence (BE) testing requirements for oral drugs. What role BCS should play in the consideration of biowaivers has garnered the attention of regulatory authorities in recent years. International differences in BA/BE-related guidelines should be reconciled in order to realize the potential cost benefits and time savings of the Biopharmaceutics Classification System.

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Research & Development

United States

Class I

Class II

High Solubility High Permeability

Low Solubility High Permeability

Class III

Class IV

High Solubility Low Permeability

Low Solubility Low Permeability

Figure 1: Biopharmaceutics Classification System How does the Biopharmaceutics Classification System work?

BCS is used to establish equivalence in applications for brand and generic medicinal products, variations, fixed combinations, extensions, and hybrids. Developed by Amidon and colleagues, the system classifies IR solid oral dosage forms on the basis of solubility and permeability parameters (when combined with dissolution testing). According to this schema, drug substances are categorised as having either rapid or slow in vitro dissolution and then classified based on aqueous solubility and intestinal permeability of the active pharmaceutical ingredient (API): Amidon posited that human outcomes can be accurately determined based on the evaluation of two intrinsic properties of the API (permeability and solubility) and one property of the drug product (dissolution). The evaluation

of these properties can be performed in vitro, therefore avoiding expensive and time-consuming testing in humans.

How is the Biopharmaceutics Classification System used?

BCS is being implemented by regulatory agencies around the world to predict the in vivo pharmacokinetic performance of drugs based on dissolution, solubility, and permeability measurements rather than on traditional BA and BE testing (see Table 1). The system is used to justify biowaivers – or formal exemptions from clinical BE and/or BA studies for a given drug product – for drug substances that demonstrate certain aqueous solubility and intestinal permeability characteristics. BCS was originally used to grant biowaivers for scale-up and postapproval changes for drug products, but was later extended to the approval of new generic products.

The United States pioneered efforts to establish BCS as a regulatory tool in the drug approval process. In 2000, the US Food and Drug Administration (FDA) set forth a guide for sponsors to justify requests to waive in vivo BA and/or BE study requirements for IR solid oral dosage forms based on BCS criteria. The guidance provides recommended approaches for classifying an IR oral drug product and determining its dissolution characteristics. According to FDA, demonstration of BA or BE may not be necessary for substances that are highly soluble and highly permeable (i.e., fall into Class I) and exhibit rapid dissolution. More recently, the BCS has been used as an exemplar of FDA’s Critical Path Initiative efforts to employ more science-driven approaches to streamlining clinical trials.

However, some scientists have expressed concern that FDA has been too conservative in establishing dissolution, solubility, and permeability limits. Experts have proposed extending biowaiver eligibility to Class II drugs that are poorly soluble weak acids and to Class III drugs that exhibit rapid dissolution. Others have suggested that dissolution requirements be made less restrictive.

Europe

Introduced in 2001, the EMA guidance on the technical standards for biowaiver submission is slightly less stringent than that of the FDA. Under the latest version of EMA guidance (issued in 2010), IR oral dosage forms that demonstrate rapid dissolution and are highly soluble (i.e. fall into Class I or III) may be eligible to waive the in vivo BE requirement. In considering biowaiver applications, EMA places more importance on solubility than permeability; in vitro permeability data is accepted only in support of clinical data. To qualify for biowaiver application under the EMA guideline, drugs must be considered noncritical in terms

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Research & Development

BCS in Industry Regulatory authorities are not the only ones implementing BCS; pharmaceutical manufacturers also make use of BCS throughout drug discovery and development processes. BCS helps sponsors determine what actions are needed to demonstrate the bioequivalence of a new formulation.

Companies can potentially save hundreds of thousands of dollars in costs, and several months of time in development, if bioequivalence studies are avoided. It has been estimated that the application of BCS can result in annual savings of $35 million for the pharmaceutical industry [4].

The practice of submitting BCS-based biowaivers has become more routine as industry has realized the benefits of the system. However, industry is not yet taking full advantage of BCS for a wide variety of reasons. Sponsors are sometimes reluctant to apply for biowaivers due to the perceived lack of certainty of acceptance by the regulatory agencies. Moreover, industry implementation of BCS may also be limited due to unnecessary barriers in existing guidelines, compartmentalization of company resources, or a general lack of knowledge about BCS or the biowaiver process.

of therapeutic range. Additionally, Class I drugs must not include excipients that are suspected of having any relevant impact on BA and Class III drugs must use excipients that are qualitatively the same and quantitatively very similar to those of reference products.

World Health Organization

Based on the FDA and EMA guidelines, the WHO set forth a guidance document for regulatory agencies around the world on the use of BCS-based biowaiver applications in 2006. The guide provides criteria for waiving in vivo studies for drugs featured in the WHO’s Model List of Essential Medicines. Subsequent analyses have shown that 63% of the WHO listed drugs fall into either BCS Class I or III (thus requiring only in vitro dissolution testing to establish BE). Since many top-selling drugs are not on the WHO Model List, a BCS-based provisional classification was applied to the top-selling 200 drugs of United States, Great Britain, Spain, and Japan and approximately 30% could be considered Class I. Under WHO’s guidance docu26

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ment, BCS-based biowaivers apply to Class I and Class III drugs products; more specifically, highly soluble active pharmaceutical ingredients with known human absorption/permeability characteristics are eligible for the BCS-based biowaiver approach for establishing the safety and efficacy of generic products.

In addition, the WHO document also recognizes the potential for biowaivers of Class II drugs that are weak acids.

The WHO is less conservative than the FDA documents in terms of definition of high permeability of a drug, but a bit more stringent regarding solubility requirements.

What is the status of Biopharmaceutics Classification System (and BCS analogues) in Asia-Pacific?

To keep pace with global trends, AsiaPacific countries have begun to introduce standards for waiving requirements for costly bioequivalence studies.

While some of these countries currently maintain their own distinct systems for determining which drugs qualify for BE exemption, others have developed

biowaiver guidelines based on BCS criteria or have proposed to incorporate BCS into their policies. In one way or another, each of the Asian regulatory agencies discussed below takes criteria derived from the concepts underlying BCS into consideration for biowaiver applications.

India

In 2005, India’s Central Drugs Standard Control Organization (CDSCO) issued Guidelines for Bioavailability and Bioequivalence Studies. Although these guidelines do not explicitly utilize BCS, CDSCO’s consideration of biowaiver eligibility is largely based on dissolution, solubility, and permeability criteria and closely resembles the technical standards set by the US FDA (see figure 1).

According to CDSCO, in vitro testing may replace in vivo testing when dissolution is very rapid and permeability and solubility are high; under BCS, this would refer to Class I IR solid oral dosage forms. Indeed, CDSCO has recently considered adopting BCS standards for determining biowaiver eligibility; they have proposed providing biowaivers to rapidly dissolving, highly soluble, highly permeable Class I drugs. The proposal to adopt BCS criteria would not appear to significantly alter the biowaiver system already in place in India.

Japan

Like India, Japan maintains its own set of guidelines to justify BA/BE biowaivers. Japan’s National Institute of Health Sciences (NIHS) has established BA and BE biowaiver requirements for generic products, post-approval formulation, and dosing changes of existing drug products. NIHS establishes BE with the use of multimedia dissolution tests.

Under this system, NIHS recommends that solubility must not be low, but does not consider permeability and does not set strict dissolution requirements for biowaiver eligibility. Biowaivers are not accepted under Japanese regulations for the first approval of generic drug

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27

2000

2001

2006

2004

2005

2006

2010

Waiver of In Vivo BA & BE Studies for IR Solid Oral Dosage Forms Based on a BCS

Guideline on the Investigation of BE

Multisource (generic Pharmaceutical Products: Guidelines on Registration Requirements to Establish Interchangeability

ASEAN Guidelines for the Conduct of BA and BE Studies

Guidelines for BA & BE Studies

Guideline for BE Studies: for Different Strengths of Oral Solid Dosage Forms; for Formulation Changes of Oral Solid Dosage Forms; of Generic Products

Methodological Recommendations for Drug Manufacturers on in Vitro Equivalence Test for Generic Drug Products According to Biowaiver Procedure

Bioequivalence

Guidance Document for BE Study

United States

Europe

WHO

ASEAN

India

Japan

Russia

China

South Korea

BCS / Comparative Dissolution Test

Other

Other

Multimedia Test (dissolution)

Other

BCS / Other

BCS

BCS

BCS

System in Use

Class I

Class I & III

Class I

Class I, II, & III

Not specified

Class I

Class I

Class I & III; Class II weak acids

Class I & III

Class I

Class

Very Rapid (≥85% in 15 or 30 minutes)

Very Rapid (≥85% in 15 or 30 minutes)

Very Rapid (≥85% in 15 minutes)

High (≥90%)

High (85%)

High (85%)

Not relevant

High (90%)

Very Rapid (80% in 15 minutes)

No set requirements (>85% in 30 minutes)

High

Rapid

High (85%)

High

Very Rapid (>85% in 15 minutes) Rapid or Very Rapid (85% in 30 or 15 minutes)

High (90%)

Permeability

Rapid (85% in 30 minutes)

Dissolution

High (pH of 1-7.5)

High (pH of 1.26.8)

High (pH of 1.26.8)

Not low

High (pH of 1-7.5)

High (pH of 1-6.8)

High (pH of 1.26.8)

High (pH of 1-6.8)

High (pH of 1-7.5)

Solubility*

Excipients should not affect the absorption of the active ingredients

Generic oral drugs without excipients that may have impact on drug absorption Excipients should be qualitatively the same and quantitatively very similar between the test and reference products

In vivo studies are typically carried out for to establish BE of generic and reference products

Multimedia test is needed when effects of excipients on dissolution and BE assurance in normal and achlorhydric subjects are considered

Ratio of APIs and excipients is essentially the same; the ratio is the same for drugs of different strengths Drug does not contain an excipient known or suspected to affect GI transit or absorption Method of manufacture is essentially the same An appropriate BE study has been performed on at least one of the strengths of the formulation

BE studies are needed when there is a risk that differences in BA may result in therapeutic inequivalence Excipients are well established and no interaction with the PK of the active substance is expected Method of manufacture should be adequately addressed and documented

Excipients are well established and do not effect GI motility or other processes affecting absorption

The drug must be considered noncritical in terms of therapeutic range Class I: excipients are not suspected of having any relevant impact on BA; Class III: excipients are qualitatively the same and quantitatively very similar between the test and reference products

Excipients have no significant effect on the rate and extent of oral drug absorption Drugs are stable in the GI tract, are designed not to be absorbed in the oral cavity, and do not have a narrow therapeutic index

Other Criteria

* Highest dose strength is soluble in 250 ml of aqueous media at 37°C in given pH range Italicized content is proposed BCS-based criteria, and is not yet formal

2008

2005

Year Issued

Guidance Document

Table 1: Worldwide systems for establishing bioequivalence

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29

Research & Development

Expert Interviews on BCS The utility of the BCS is being recognized throughout the entire cycle of drug development according to a recent survey of 20 experts from generic and brand-name companies, government and academia conducted by the Tufts Center for the Study of Drug Development (Tufts CSDD), sponsored in part by a grant from Absorption Systems, LP. The Tufts CSDD interviews suggest the need for global harmonization.

Interviews with key experts in industry, government, and academia suggest that in order to maximize its utility it will be necessary for the regulatory authorities of major drug-producing countries to harmonize in vitro bioequivalence requirements and provide a central repository of BCS determinations for global access (article in press).

products; for this, NIHS always requires in vivo bioequivalence testing. Overall, NIHS’s biowaiver requirements are less conservative than those of FDA, EMA, and WHO; the requirements allow for all BCS-based classes of drugs products to be considered for biowaiver and for in vitro qualification and allow for a larger range of formulation changes.

It is unlikely the BCS will ever be completely adopted to justify biowaivers in Japan; BCS has been viewed skeptically for regulatory purposes by Japan’s NIHS. NIHS maintains that formulation and manufacturing, rather than solubility and permeability, are indicative of bioequivalence. NIHS also states that while BCS serves to increase the use of dissolution tests in the US, BCS will actually decrease the use of these tests in Japan because they are already extensively applied. NIHS argues that permeability is still not known for many drugs, making it difficult to use BCS to establish regulatory bioequivalence for such drugs.

Russia

In order to establish the safety and efficacy of generic drug products in Russia, in vivo bioequivalence studies are typically carried out. In 2010, the Russian Federal Service on Surveillance in Healthcare and Social Development 30

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proposed that BE for generic products may be evaluated using in vitro testing in a draft guidance on BCS-based biowaivers. The Russian biowaiver procedure was developed according to the EMA, FDA, WHO, and the Health Department of Ukraine guidance documents. It sets forth specific biowaiver criteria for generic drugs by class, taking into consideration solubility, permeability, and dissolution characteristics along with the excipients used in the formulation and the possible risks associated with therapeutic index and adverse events.

China

With a large consumer base for drug products, and an estimated $8 million per year already being spent on bioequivalence studies by its pharmaceutical industry, China stands to benefit a great deal from use of biowaivers, especially as its drug industry expands in size and geographic scope. It was not until 2011, however, that a BCS-based biowaiver policy was put forth to evaluate IR solid oral dosage forms in China. Authors Ning and Qu-neng proposed that China adopt WHO’s in vitro dissolution criteria and suggest that Class I and Class III drug substances be eligible for biowaivers. The authors further suggest that excipients should be qualitatively the same and quantitatively very similar

between the test and reference products. Offering an added caution, Ning and Qu-neng advise that the biowaiver approach should only be used when the potential benefits outweigh the risk of an incorrect biowaiver decision in terms of public health and individual patient risks. As of 2011, China’s State Food and Drug Administration regulations allow for bioequivalence exemption when the IR solid oral dosages forms under question are either generic drugs without excipients that may impact on drug absorption or Class I drugs that are undergoing post-approval changes.

South Korea

South Korea maintains a thorough system of determining biowaiver eligibility. Under the Guidance Document for BE Study, published in 2008, the Korean Food and Drug Administration (KFDA) allows comparative dissolution tests to replace BE studies for solid oral dosage forms. For example, a dissolution test can replace a traditional BE study when a solid oral preparation of a new strength has the same dosage form and API as an approved drug product.

Dissolution tests may also replace BE studies when changes are made in the level of an excipient. The KFDA guidance document also establishes criteria for BE biowaivers based on solubility, permeability, and dissolution characteristics outlined by BCS. Association of Southeast Asian Nations

In an attempt to establish a standardized basis for when BA and BE studies are necessary in drug registration among member states, the Association of Southeast Asian Nations (ASEAN) Consultative Committee for Standards and Quality (ACCSQ) issued guidelines on the Conduct of Bioavailability and Bioequivalence Studies in 2004.

ACCSQ primarily considers the BCS criteria, along with non-critical therapeutic range, when evaluating applications for IR solid oral dosage forms. The guidelines also provide

Research & Development

requirements for the design, conduct, and evaluation of BA and BE studies.

ACCSQ suggests that member states – which include the IMS Tier 3 emerging markets of Thailand, Vietnam, and Indonesia – follow the ACCSQ document in conjunction with EU and ICH guidelines and regulations on good clinical practice.

biowaivers cannot be fully realized until differences among the regulatory bodies of the world’s major drug producing nations are reconciled. Lack

Ms Ashley Malins is a Research Analyst at Tufts CSDD; her current work focuses on biopharmaceutical innovation strategies, regulatory and reimbursement issues, and market access trends.

Ms. Malins is pursuing a Master’s in Public Health, with a focus in Health Services Management and Policy, at Tufts University School of Medicine.

®

F I L T E R S

A u t h o r BIO

Global Harmonisation

BCS is a simple, inexpensive, and reliable tool routinely used to establish regulatory guidelines on which to base BA and BE waiver applications. However, this system is not currently implemented by all regulatory authorities worldwide, nor is it uniformly applied among those nations that have chosen to base biowaiver guidelines on BCS criteria. It is believed that the importance of BCS as a regulatory tool will continue to increase over time. However, the cost and time-saving benefits of BCS-based

of central databases, language barriers, and trademark certificates have also been identified as challenges to global harmonisation.

Christopher-Paul Milne joined the Tufts Center for the Study of Drug Development (Tufts CSDD) in 1998 as a Senior Research Fellow in order to address legal and regulatory issues. His current research interests include: challenges to the R&D of new drugs; innovation capacity in the developing world; incentive programs for pediatric studies, orphan products, and neglected diseases; assessing the impact of regulatory policy; and, tracking progress of new initiatives to improve safety and efficacy and exploratory development such as Regulatory Science, Translational Medicine and Personalized Medicine. He is currently Associate Director of the Tufts CSDD, Research Assistant Professor at Tufts Medical School, a member of the Editorial Board of the Food & Drug Law Journal, and an Honorary Fellow at the University of Edinburgh.

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31

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Article on Charcoal Separation in API & Pharma Industry across the Globe For Active pharmaceutical ingredients purification addition of charcoal has become a necessity and its removal is a must prior to following steps. The removal of charcoal is being done mainly by Sparkler or Zero Hold Up Sparkler Filter in the industry where in lot of inconveniences are caused : 1. The removal of waste carbon is affected manually 2. Exposure of hazardous fumes to the operatives and surrounding areas causes danger to the health of the people in the vicinity.

3. Dusting may occur while removing waste carbon from the Filters 4. When Sparkler or Zero Hold Up Sparkler Filters are used the separate valuable noble metal catalysts it produces oxidative products and reduces the activity of the catalyst Taking into consideration the shortfalls of above method to separate waste carbon or to separate valuable catalyst from the mother product, has introduced ‘‘Subodh ‘ Multi Tube Filtration system with Zero Hold Up concept.

Such Filters are producing wonderful results which are beneficial to the end user also. The Filter has following advantages : i. It has a closed system hence it operates under pressure always. No oxygen contact so oxidative products are not produced.

ii. CIP Nozzles are provided hence there is no need to open the Filter for cleaning of the Filter media. iii. Discharge of waste carbon is done by back blowing Nitrogen to the element after drying and washing is completed so discharge is done in closed loop hence hazardous fumes does not spread in the working area.

Here is the installation data for the filter in use at one place continuously : i. Liquid under Filtration - API intermediate stage in methanol. ii. Quantity of liquid - 5000 Liters [ 5 kl ] iii. Quantity of carbon added - 7 Kgs iv. Filter in use - ‘ Subodh ‘ Multi tube Filter with heel Filter in place v. Area of the Filter - 1.5 SQM cGMP model vi. The Filtration data is as follows : Steps Time duration a. Fill the Filter - 4 minutes b. Circulate till clarity - 2 minutes c. Filtration - 35 minutes d. Scavenging with Nitrogen - 6 minutes e. Washing with fresh solvent - 35 minutes f. Scavenging with Nitrogen - 6 minutes g. Heel Filtration and drying - 15 minutes h. Discharging solids in bin - 5 minutes Total cycle completed in 108 minutes ; say 2 hours to put back the same Filter in service for subsequent batch.

Similarly catalyst in hydrogenation is filtered and back flushed to the reactor.

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33

Research & Development

Good Clinical PracticeCompliant Clinical Studies in China Since the State Food and Drug Administration (SFDA) in China regulated the clinical trial industry with an amendment of the Chinese Good Clinical Practice (GCP) guidance, both the quality and integrity of clinical research have improved significantly, resulting in the recognition of more and more Chinese trial results by the international pharmaceutical community.

This paper outlines the major regulatory practices related to conducting clinical trials in China.

34

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Daniel Liu Director, China Development, Medidata Solutions Worldwide, Beijing, China

Research & Development

S

ince the 1990s, Good Clinical Practice (GCP) has made its way to China through international academic communications and exchanges as well as through investments of many multinational pharmaceutical companies in China, resulting in the increase of clinical trials. With the growing globalisation of the economy in the 1990s, more and more pharmaceutical joint ventures, wholly-owned enterprises and global contract research organisations (CROs) drove the adoption of international standards for clinical trial conduct in China, resulting in a favourable atmosphere for the success of GCP in China. However, many sponsors and CROs looking to establish themselves in this key region need to understand the complexities of GCP-compliant practices of clinical studies in China.

Legal and Regulatory Basis for Drug Researchers

Major laws, regulations and guidelines related to drug studies in China should be as followed: • Drug Administration Law of People’s Republic of China • Regulations for Implementation of the Drug Administration Law of the People’s Republic of China • Drug Registration Regulation • Regulation for Drug GCP • Provisions for Handling Malpractices in Drug Research and Registration (interim) • Rules for Drug Clinical Study • Provisional Rules for Drug Research Record • Measures for Clinical Research Supervision • Guideline of Drug Clinical Trial • Rules for Statistics in Clinical Study • Guidance of Ethic Review for Drug Clinical Trials • Measure for Drug Clinical Trial Institutions Qualification (interim) • Management Guide of Laboratories Serving to Biosample Analyses in Clinical Trials (interim) • Management Measures of Reporting

and Monitoring Adverse Events of Drugs Characteristics of Clinical Trials Conductions in China

Although China’s GCP standards are essentially the same as those in the ICH E6 guideline, there are some differences.

Some examples of such differences between China GCP standards and the ICF E6 guideline include: • ICH E6 GCP calls for investigators to report only unexpected and serious AEs to IRB/ECs, but the GCP standards in China (Chapter 3, Article 10) state that, “any serious events that occur during the trials shall be reported to the Ethics Committee.”

• The Chinese GCP standard states that the investigator must sign the informed consent form, while the ICH E6 GCP states that the subject and “the person who conducted the informed consent discussion” need to sign the informed consent.

• SFDA requires the clinical institution to set up a special administrative office with full-time staff to provide oversight on clinical trial activities and outcomes. The office must strictly implement relevant laws and regulations and establish a quality assurance system for the clinical trials according to GCP. Quality Assurance is responsible for auditing the authenticity and standardization of the clinical research, ensuring that SOPs, science and compliance in the clinical trials, ensuring that the safety and rights of the subjects are protected and ensuring the accuracy and completeness of the clinical data obtained. Some elements of these responsibilities are directly assigned to the investigators in ICH E6.

• All clinical trials in China should be conducted within clinical institutions (hospitals) that obtained, from SFDA, a certificate of qualification to serve as an authorized clinical trial site in relevant medical specialities.

• Without a certificate of qualification to conduct a clinical trial (issued by SFDA), a clinical institution cannot undertake a clinical trial in China.

Such a certificate is granted after an application and then the pass after an on-site regulatory inspection.

• The drug products used in the clinical trials must be submitted to the National Institute of the Control of Pharmaceutical and Biological Products (NICPBP) for an assay. Without the certificate of analysis issued by NICPBP, the institutional ethics committee (IEC) will not approve the clinical study.

• Clinical studies cannot be initiated at clinical institutions until the sponsor and investigator receive the approval letter issued by SFDA. • Clinical studies must be initiated only after the IEC issues an approval letter.

The IEC should be registered to SFDA. The submission package provided by the investigators and sponsors to the IEC generally includes, but is not limited to: • The SFDA approval letter • Certificate of Analysis for the drug issued by NICPBP or corresponding institutes • Investigator Brochure • Clinical Protocol (attached with the list of principal investigator and clinical staff members and their resumes) • Sample of Informed Consent Form • Case Report Form • Relevant subject recruitment materials • Resumes of principal investigators • Other approval, comments or disapproval evidences by other IEC on the protocol, if appropriate.

In addition, imported drugs, biological products and blood products should be tested by NICPBP; other chemical products or TCM products may be tested by corresponding provincial drug control institutions or by sponsors themselves. www.pharmafocusasia.com

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Research & Development

36

Major Provisions to Run a Clinical Trial in China Clinical Study Procedures Before clinical trials

• CRF completion • Trial milestone expectation

While the clinical trial permission is applied to SFDA, the sponsor may prepare the initiation of clinical studies. First of all, the sponsor should look up the certified clinical institutions that meet the medical speciality and other logistic requirements of the clinical trial. A prestudy site visit is necessary for sponsor to verify the qualification of the clinical institutions that will undertake the clinical trial. The sponsor shall sign a Clinical Trial Agreement with the leading and the participating institutes selected for the clinical study, and then provide the SFDA approval document, the draft Informed Consent Form, Investigator’s Brochure and jointly improve the clinical trial protocol with reference to technical guidelines. When a clinical trial agreement is negotiated with a clinical institution, a number of documents must be collected from the clinical institutions. Most of these are required by the SFDA regulations and the IEC submission, although some sponsors may require their own additional documents. Both the sponsor and the investigator must have copies of each of these documents. The conclusion after IEC reviews the clinical studies could be: • Agreed • Agreed after necessary revision • Disagreed • Terminated or suspended previous approved clinical trial Once the agreed conclusion is obtained, the sponsor may initiate the trials at the selected clinical institutions.

Trainings on the investigator and relevant staffs who participate in clinical trials are mandatory and should be completed before the trial is initiated. These trainings include but are not limited to: • GCP • Clinical protocol • Trial flow procedure • Relevant SOPs • ICF requirements and procedure • Establishment and maintenance of source documents and study files

If a sponsor discovers that an institution conducting clinical study is in violation of relevant regulations, or is not following the clinical study protocol, the sponsor shall try to correct the situation. For serious violation, the sponsor may request to suspend or stop the clinical study and shall submit a written report to SFDA and the relevant IEC. SFDA may request the sponsor to amend the clinical study protocol, suspend or stop the clinical study in any of the following circumstances: • The Ethics Committee has failed to perform its duty or • The safety of the subjects cannot be effectively ensured • Serious adverse event was not timely reported • The clinical study progress report was not submitted in a timely fashion • The completion of the clinical study is more than 3 years behind the original completion date and there are still no results which can be evaluated • Evidence that the investigational drug is not any effective • Quality problems in the drug used for clinical trials • Fraud in the clinical study • Other circumstances violating GCP. Study monitoring on the conduction of clinical trials is one of regulatory requirements sponsor should take. The frequency of the study monitoring should be dependent on the actual length and needs of clinical trials, and the focus of the study monitoring should be placed on: • Protection of rights, safety and wellbeing of human subjects • Subjects status, including enrolment rate, eligible rate and compliant rate to the approved protocol/amendments • Principal investigator behaviours, including compliance with the approved protocol/amendments, SOPs, GCP and other regulatory requirements

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During clinical trials

• Reporting data integrity, including accuracy, complete and reliability, adequate informed consent process, consistence of medical records and lab results relative to CRF. During the clinical study, in case a large range or unexpected adverse reaction or serious adverse event occurs, or there is evidence to prove that the investigational drug has significant quality problems, SFDA may adopt emergency mandatory administrative measures to suspend or stop the clinical study, and the sponsor and institutions must immediately stop the study. Any SAE should be reported promptly to SFDA through a national safety web report system.

At the end of clinical trials

It is important that the reported data completely and accurately reflects the findings and events of the clinical trials.

It is well recognised that the good data management practice is the foundation of good clinical practice. The key areas of the good data management practice have been regulated by SFDA as followed below: • Procedures for the entry, verification and validation management of reported data • Management for data queries of any errors, omissions or items requiring clarification or changes to collected data detected during the trial, by computer edits or during the data analysis • Expected requirements for database lock • Measures for statistical analysis of the reported data • Generation of a clinical study report.

Outcomes of any clinical trials are required to be reported to SFDA in the clinical study report setting. When the CDE is technologically reviewing the NDA application, the sponsor or relevant investigators may be invited to have defenses on the questions and give information about the project and/or the outcomes.

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Research & Development

Safety Monitoring in Clinical Settings A monitoring and reporting process of drug safety profiles has been recently regulated. The key procedures and requirements of drug safety profiles are as follows: It is mandatory for pharmaceutical companies and investigator sites to appropriately complete and submit “Reporting Form of Drug Adverse reaction/event” for any adverse events they are aware of.

Domestic drugs developed and manufactured by local pharmaceutical companies should be reported with all AEs related to the drugs in the monitoring period of new drugs; other domestic drugs should be reported with new and serious adverse events.

Foreign drugs developed and manufactured by foreign pharmaceutical facilities should be reported with all AEs related to the drugs since they are granted to an import permission into China from the first day of approval up to five years; after five years, the foreign drugs was then required to report new and serious adverse events.

Any new and serious adverse event (NSAE) of drugs should be reported in 15 days after they are firstly aware, of which death report should be submitted immediately. Other adverse events of drugs should be reported within 30 days after they are firstly aware. Any follow-up information are expected a submission without delay.

When serious adverse events of imported drugs or domestic drugs that are used and occurred oversea (including collections or found from spontaneous reports, post-marketing clinical researches and literature reports) are received, drug enterprises should complete the “Reporting Form of Drug Adverse Events Occurred Oversea” and submitted to the state monitoring center of drug adverse events in 30 days after they are received. Once the source reports or relevant information are requested by the state monitoring center of drug adverse events, the drug enterprises should complete the submission in five days.

Except individual drug AEs, the drug group AEs are required to be reported via a submission of“Basic Information Form of Drug Group Adverse Event.” A drug group AE is defined as any harmful or threaten event to body health or life of certain herbs in relative density of period and geographic area by the same batch of drug, which needs to have urgent interventions.

Expectations for laboratories performing biosample analyses in clinical studies Any laboratories that perform the biosample analyses in clinical studies have to be qualified and operated based on the special regulations targeted to the management of laboratories serv38

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A u t h o r BIO

An annual reporting system of drug safety updates in the monitoring period of drugs is essential except the regular AEs/SAEs monitoring and reporting practices.

ing in clinical studies. A management system of quality control in allocation to independent QA staff is essential. Any software and hardware used in the collection, analysis, report and archive of lab data as well as data receiving and transferring are expected to be validated, deployed and implemented according to the GCP-compliant SOPs. The lab facilities and environments, including waste disposal, material handling, reagents administration etc., are expected to meet specifications. The process management of contract administration, standard operation practice and lab data management are regulated in details.

Looking Ahead

As global sponsors and researchers are aware, both the breadth and level of clinical research activities is on the rise in China. The SFDA has taken great strides to regulate the process of clinical trials on the basis of GCP standards by strengthening international communications and applying learnings from a number of trials, ensuring consistency of compulsory regulations with the global pharmaceutical community. Overall, the SFDA has made it a priority to become more transparent in its regulated activities, offering an improved regulatory environment that enables more sponsors to derive value from data obtained in studies in China.

As the spirit of “One World, One GCP Standard,” the SFDA should look to further improve its measures of drug administration, inspection and supervision as it continues to evolve and help drive innovation in drug development.

Daniel Liu is the Director of China Development at Medidata Solutions. Since receiving his PhD in pharmacology, Daniel has dedicated his career to management and operations of global clinical studies, working with such companies as Novartis, Pfizer, Schering-Plough and Johnson&Johnson. He is a member of the DIA China advisory council, a board member of the DIA global training committee and author of the book “Clinical Trial Methodology of Medicinal Products”.

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CoverStory

-track fast o T 40

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ical n i cl

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CLINICAL TRIALS

Asia currently represents some of the fastest growing markets for pharmaceuticals. Accessible patient populations, coupled with a strong and growing infrastructure for quality conduct of clinical research, make Asia very attractive for inclusion in global development programs.

However, an absence of meaningful harmonization in the regulatory environment, especially with regard to the requirements, processes and timelines for approval of clinical trials, continues to present a challenge.

In this article, the reasons for and potential strategies to overcome these challenges are discussed.

Alistair Davidson Senior Director, Global Regulatory Affairs, Asia Pacific, PPD, UK

T

he last decade has seen a significant increase in the number of global clinical trials being conducted in Asia. In China and India, the number of new global studies approved rose from less than 20 in each country in 2004 to more than 200 in India and to more than 300 in China in 2008 . This growth is due to a number of factors which have aligned to make Asia an attractive region for global clinical development.

Perhaps the most significant factor is population size. The populations of the countries in Asia represent a huge patient pool, much of which is located in urban areas and close to sites and investigators involved in global studies. The combined population of China and India alone is equivalent to over one-third of the total global population. Asian patient populations are generally quite motivated to participate in clinical studies, and levels of patient compliance are usually high.

Healthcare delivery systems in Asia, and particularly in China, are characterised by very large hospitals, where a single site or investigator may have access to a large patient population, making patient recruitment more efficient once the right sites have been selected. Many patients are treatment-naĂŻve, enhancing the likelihood of meeting inclusion criteria.

In terms of therapeutic indications, while Asia will continue to be an important region for the development of products for infectious diseases and endemic tropical conditions, its contribution to more ‘Western’ conditions has steadily increased. The proportion of study sites in Asia in 2008 for oncology (19.6 per cent), cardiology (14.9 per cent) and psychiatry (12.7 per cent) were higher than the overall global proportions, demonstrating that Asia has now firmly cemented its place in the global clinical development landscape for such indications. www.pharmafocusasia.com

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CoverStory

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With respect to investigators, many Asia-based physicians have been trained in Europe or the United States. English is widely used at the professional level, and investigator participation is usually driven by interest in research in the disease area, with investigator fees often being ploughed back into local research activities. Additionally, many investigators in Asia are also considered global opinion leaders in their fields, making their regular involvement in clinical development essential.

Asia also offers some cost efficiencies; a higher patient recruitment rate per site can translate into lower study management overhead. Shorter recruitment time frames can keep operating costs under control.

Finally, with economies booming in many countries in Asia, getting drugs to Asian markets is another key factor in the appeal of Asia for clinical development.

Regional Regulatory Evolution

Along with this rapid growth in clinical studies in the past decade came a need for local regulatory authorities to quickly bring their processes and guidelines up to date and in alignment with the changing clinical trial environment, to ensure medical needs are met, healthy growth of the local pharmaceutical industry and, above all, patient safety. While some countries, such as Japan and Australia, already had mature regulations in place, the majority of countries in the region have had to play catch up.

The evolving regulatory environment in Asia plays an important role in the decision to include countries from the region in clinical development programs.

Although there is no formal regulatory harmonisation between the requirements of the different countries in terms of process, requirements and timelines for clinical trial approvals, there is a certain element of convergence as the various regulatory authorities have, over the last decade, absorbed information and intelligence and ideas from other regulatory authorities in the region and the more 42

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well-established agencies such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). This has led to a certain degree of convergence as regulatory authorities try to find a common approach to regulatory pathways and principles while implementing local regulatory changes in a way that is compatible with local resources and environments.

Inclusion of Local Populations

The most challenging aspect of Asia’s regulatory environment is the development and execution of strategies that will most effectively address new drug registration regulations that require inclusion of a local or regional population in a clinical study if the desired outcome is local market approval. This is a key requirement in China, Korea, India, Japan and Taiwan. A development plan that can cover the unique needs of these countries in a timely and efficient manner is an important consideration in planning Phase III studies in Asia.

Strategies are often a balance between the global priorities for a new product against specific clinical, regulatory and commercial needs in Asia. The earliest possible discussion of and agreement on an Asia Pacific strategy is therefore key as it allows for optimal inclusion within a global development programme.

Agreement on an over-arching strategy requires the in-depth commitment and contribution of experts in clinical development, regulatory affairs and commercialisation. However, it is often the case that resources, both financial and operational, prove to be constraining factors. A compromise usually has to be worked out to ensure that such plans dovetail with the global development and regulatory strategies.

Operationally, a number of areas can be identified for focus in order to overcome challenges and ensure optimization of regulatory performance.

Early Planning is Key

Early planning and decision-making is critical in order to determine the most

effective overall strategy, including country selection. This will ensure that the appropriate personnel are assigned to build an Asia regulatory strategy that takes into account key macro-factors, including: • Sufficient patients allocated to meet regulatory requirements and expectations • Appropriate recruitment windows for the different countries, taking into account regulatory lead times • Epidemiology and prevalence and perceived seriousness of disease in Asia, which can impact the clinical trial submission and approval strategy • Local comparator drug regulations (e.g., in China, comparator drugs must be approved and available) • Future commercial priorities • Perceived ethnosensitivity – clinical relevance of observed differences in Asian populations compared to those of other populations globally • Protocol design, including dose selection (compared to “global” dose), relevance of comparators and endpoints • Future acceptance of data for USA, EU and other regulatory submissions.

Once countries, target numbers of patients, and an overall project plan have been determined, the regulatoryspecific planning and actions need to be developed and executed. Regulatory professionals have to be able to build a plan that manages a number of countries with different requirements, timelines and processes, yet they should deliver appropriate regulatory approvals to meet the scheduled study start up times. In addition, as most of the countries in Asia are actively working on strengthening and improving their guidelines and infrastructure, sometimes with limited resources, there are regular changes to requirements, processes and timelines, not all of which are proactively communicated.

It is important for the regulatory manager of any project to ensure the project team is aware of the likelihood of changes that may take place in the middle of the project.

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Quality Execution and Local Knowledge

Absolutely critical to success in the regulatory management of a clinical study in Asia is quality, up-to-date regulatory knowledge and experience with the local regulatory environment and requirements.

In this respect, there is no substitute for having personnel on the ground dedicated to the planning, preparation, submission and approval of clinical trial applications.

In addition, these team members may also be responsible for the required ethics committee approvals. If not, they should at least be very closely aligned with those responsible for these tasks as there are usually strong process, documentation and timeline links between ethics committee and regulatory authority approvals. Much efficiency can be realised through close coordination of these two key activities.

Local regulatory personnel should also be familiar with the key personnel at local regulatory authorities to ensure they can easily check on the latest processes and perspectives within the agencies, as well as to be able to effectively manage any queries or delays. In some countries, for specific studies, the opportunity may be taken to have formal or informal presubmission meetings with the regulatory authority. The local regulatory personnel should be very familiar with standard practice in this area and be able to effectively organize and coordinate such meetings if needed.

Not every pharmaceutical company will have experienced local staff in all Asian countries, and it may be necessary to use regulatory resources of contract research organisations (CROs) or other third-party providers. Such parties can have experience with a large number and broad range of regulatory applications and can add significant value to the planning and application process.

Globally Integrated Regulatory Personnel

The benefits of quality execution of regulatory strategy by experienced, local regulatory personnel can only be fully realized if they are effectively integrated into an overall regulatory structure, allowing the local execution to dovetail with the global regulatory strategy.

The most effective way to ensure this strategy is by appointing a global regulatory lead for each project who ensures the following: • Effective planning – a comprehensive global regulatory plan, with specific timelines for each key activity by country • A comprehensive inventory of all required documentation for regulatory submissions. Ideally this should have already have been assimilated during the planning phase so that the generation (and required translations) of these documents do not cause unnecessary delays • A seamless relationship and communication link between all regulatory players. This is best achieved through regular progress reports as well as scheduled meetings to ensure close tracking against a project plan • Effective liaison between the regulatory group and other key stakeholders of a

A u t h o r BIO

Along with the rapid growth in clinical studies in the past decade came a need for local regulatory authorities to quickly bring their processes and guidelines up to date and in alignment with the changing clinical trial environment.

drug development program to ensure full alignment and understanding of strategy and outcomes • Flexibility in adjusting a development plan and related actions as a project progresses. Changes are almost inevitable in every project, so the ability of the regulatory lead and local regulatory resources to create and deliver alternative plans according to changing priorities is an important asset to any project. This may also involve the innovative and proactive management of resources and budget in line with project constraints • A special focus on China and its regulatory processes, timelines and requirements, including patient numbers for subsequent drug registrations which have their own unique challenges.

Capable and experienced regulatory resources on-the-ground in China is absolutely essential, especially as more change is expected in this area in the next few years.

Finally as with all regulatory activities, there is usually no such thing as a quick fix or loophole to deliver any regulatory outcome in a way that is not in line with the regulations and practices of local authorities. There is no substitute for strong local knowledge, good teamwork, careful planning and effective delivery.

Any interaction with regulatory authorities should be carried out with integrity, openness and transparency.

Such values will add considerably to the long term development of relationships between pharmaceutical companies, their representatives and regulatory authorities and will help render any regulatory barrier into a much more manageable challenge.

Alistair Davidson is responsible for operations management and strategic development of regulatory services in Asia Pacific.

Previously he held senior regulatory leadership roles in GSK and Quintiles, with a strong record of success with pharmaceuticals and vaccines and extensive, hands-on experience in Emerging Markets, including Asia, Middle East, Latin America and Africa.

www.pharmafocusasia.com

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Pharma Focus Asia portal 2012

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Recent Advances in Analytical Methodologies for the Determination of Impurities in Drugs S

Pharmaceutical industry has great concern towards impurities due to their adverse effects. Regulations alarmed the control of drug substances at lower level based on the threshold of toxicological concern and daily dose.

Advances in analytical technology have improved capability for drug impurity profiling in terms of faster analysis time, better separations and faster method development.

This article briefly explores developments in HPLC -new stationary phases, method development, selected detectors and quality by design (QbD) approach for control of related impurities in drugs and pharmaceuticals.

M V Narendra Kumar Talluri Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research, India

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afety and efficacy of pharmaceuticals are two fundamental issues of importance in drug therapy. The safety of a drug is determined by its pharmacological-toxicological profile as well as the adverse effects caused by the impurities. The impurities in drugs often possess unwanted pharmacological-toxicological effects by which any benefit from their administration may be outweighed. It is quite obvious that the products intended for human consumption must be characterized as completely as possible. The quality and safety of a drug is generally assured by monitoring and controlling the impurities effectively. Thus, the analytical activities concerning impurities in drugs are among the most important issues in modern pharmaceutical analysis.

Regulatory Aspects

The International Conference on the Harmonization of the Technical Requirements for Registration of Pharmaceuticals for Human use (ICH) which took place in Yokohama, Japan in 1995, has released new guidelines on impurities in new drug products.

Analytical procedures should be able to separate all the impurities from each other and the method should be optimised to separate and quantify them in the dosage forms. Such methods are to be validated demonstrating the accuracy, precision, specificity, limit of detection, quantitation, linearity, range and interferences.

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• The validation of analytical procedures i.e., the proof of its suitability for the intended purpose, is an important part of the registration application for a new drug.

• Additional peak tailing, peak resolution and analyte recoveries are important in case of chromatographic methods.

• ICH guidelines serve as a basis worldwide both for regulatory authorities and industries to bring the importance of a proper validation to the attention of all those involved in the process of submission of drug master files (DMF).

The analytical research and development units in the pharmaceutical industry are responsible for preparation and validation of test methods.

Origin of Impurities

• Last intermediate of synthesis • Products of incomplete reactions • Products of over reactions • Impurities originating from starting materials • Impurities originating from solvents • Impurities originating from catalysts • Products of side reactions • Degradation products • Enantiomeric impurities • Residual solvents • Inorganic impurities • Impurities in excipients Analytical Methodology

• The use of strict specifications to control drug quality is possible only when suitable analytical methodology exists.

• Before the advent of modern analytical separation techniques such as HPLC and GC, impurity levels of a few Per cen were considered acceptable.

• Separation methods are developed to detect and measure virtually any impurity, which is present at levels exceeding 0.1 per cent and often can be used at even lower levels of detection.

• For the last few years, the use of HPLC has gone from being a laboratory curiosity to the current state

where HPLC is the workhorse of all analytical facilities.

In the early days of high performance liquid chromatography (HPLC), detection for qualitative or quantitative analyses often was carried out by collecting fractions and analysing them off-line using gravimetric or wet chemical techniques.

It wasn't until the 1940s and 1950s that the first online detectors for liquid chromatography, the refractive index (RI), and conductivity detectors appeared on the scene, and while they were certainly an improvement over off-line approaches, neither detector was particularly sensitive.

In the 1960s, the first ultraviolet (UV) detector for HPLC was introduced, and subsequent improvements in design led to better sensitivity and improvements such as variable wavelength and diode array UV detectors. While a truly universal HPLC detector with the kind of sensitivity achieved in GC–FID is still elusive, many different types of detectors have been developed since the early UV, RI, and conductivity detectors that have been very successful for a wide variety of general or specific HPLC applications.

When Photodiode Array Detector (PDA) is combined with a separating column, three dimensions become available; wavelength, intensity and chromatographic retention. A particular substance appears as a point in this three dimentional space.

Peak Purity Function is useful to detect if a peak is only from one compound or if it contains coeluting peaks. It is done by comparing the similarity of the spectra at different points on the peak. Figure 1 Three dimensions of PDA.

Figure 1 Three dimensions of PDA.

Advantages:

• PDA Detector could analyse a sample simultaneously at many different wavelengths.

• UV Visible spectra are useful for compound identification, checking peak purity, as well as finding the optimum absorbance for the compounds.

• UV Visible spectra of many compounds could be stored in the spectrum libraries, which are useful for compound identification.

• Relatively robust to temperature and flow rate fluctuations • Compatible with gradient elution.

Disadvantages:

• Slightly less sensitive than UV-Visible detector.

• Detection of solutes that possess a significant chromophore.

Light-Scattering Detectors

Recent improvements in the ability to efficiently nebulize an HPLC column effluent has led to increased utility of light-scattering detectors. The most popular detection method of this type is evaporative light scattering detection (ELSD). ELSD works on the principle of evaporation (nebulisation) of the mobile phase followed by measurement of the light scattered by the resulting particles. The column effluent is nebulised in a stream of nitrogen (carrier gas) in a heated drift tube, and any nonvolatile particles are left suspended in the gas stream. Light scattered by the particles is detected by a photocell mounted at an angle to the incident light beam. Carrier gas flow rate and drift-tube temperature must be adjusted for whatever mobile phase that is used. Detector response is related to the absolute quantity of analyte present, and while decreased sensitivity will be obtained for volatile analytes, unlike the UV detector, no chromophores are required and it has orders of magnitude more response than the RI detector. ELSD also has the advantage over RI detection in that the response is independent of the solvent, www.pharmafocusasia.com

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so it can be used with gradients, and is not sensitive to temperature or flow rate fluctuations. Mobile phases of course must be volatile, similar to those used for MS detection. Linearity can be limited in some applications, but is certainly quantitative over a wide enough range if properly calibrated. Recent applications of ELSD also have been extended to UHPLC.

Recent improvements in the ability to efficiently nebulize an HPLC column effluent has lead to increased utility of lightscattering detectors.

Charged-Aerosol Detection

Corona charged aerosol detection (CAD) is a unique technology gaining in its popularity in which the HPLC column eluent is first nebulised with a nitrogen -carrier gas to form droplets that are then dried to remove mobile phase, producing analyte particles [5,6]. The primary stream of analyte particles is met by a secondary stream of nitrogen that is positively charged as a result of having passed a high-voltage through platinum corona wire. The charge transfers diffusionally to the opposing stream of analyte particles, and is further transferred to a collector where it is measured by a highly sensitive electrometer, generating a signal in direct proportion to the quantity of analyte present.

Because the entire process involves particles and direct measurement of

charge, CAD is highly sensitive, provides a consistent response, and has a broad dynamic range, which offers advantages when analysing compounds lacking UV chromophores. Often compared to other universal-type HPLC detection methods, like RI and ELSD, CAD has been shown to be much easier to use, and unlike RI, can accommodate gradients. In addition, CAD response is not dependent upon the chemical characteristics of the compounds of interest, but on the initial mass concentration of analyte in the droplets formed upon nebulisation, providing a much more uniform response as opposed to, for example, UV, where responses can vary dramatically according to the wavelength used and the extinction coefficient. Table I shows some common HPLC detector properties.TABLE

Property

UV-VIS, PDA

RI

Light Scattering

Charged Aerosol

Range of Applications

Selective, Universal at low

Universal

Universal

Universal

Minimal Detectable quantity

Nanograms

Micrograms

High nanograms

Low nanograms

Linear range

105

103

103

104

Key Attributes

Most widely used and accepted, near “universal” at low UV

Original detector for HPLC in many methods, excellent versatility, universal detection, solvent compatibility, nondestructive,

Detects most nonvolatile analytes, works well with gradients HPLC, better sensitivity than RI detection

Highest sensitivity of “universal” type detector, wide dynamic range, detects any nonvolatile or semivolatile, consistent response, ease of use

Requires the use of volatile buffers, optimization, limited dynamic range, reproducibility of methods

Requires the use of volatile buffers

Gradient compatibility Qualitative and quantitative PDA: peak purity/homogeneity, spectral library searches and identification, counter maps and 3D spectral display; nondestructive, low cost, very reliable, easy to use.

Limitations

50

In CAD and in ELSD the effluent of a chromatographic system is nebulised, using a flow of nitrogen, and the resulting aerosol is transported through a drift tube where the volatile components and solvents are evaporated. In the last step in CAD the dried particle stream is charged with a secondary stream of nitrogen that has passed through a high-voltage platinum wire and the resulting charged particle flux is measured by an electrometer. In case of ELSD the signal is proportional to the number of photons scattered from the residual solid fraction that has been introduced into a detection cell. Operation is simple, requiring only setting of few controllable parameters, among them the gas input pressure, the temperature range and signal output range. Like ELSD, CAD system is a mass-dependent detector and the generated response does not depend on the spectral or physicochemical properties of the analyte as in a specific UV detector, which is a concentrationdependent detector. Theoretically this means that CAD and ELSD systems as bulk property detectors generate a similar response for identical amounts of different analytes. CAD generates a nearly constant response under isocratic conditions for compounds at similar concentrations. The relative magnitude of the CAD system

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Must have a chromophore, solvents must be transparent, widely varying response for different solutes

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Low cost, reliable and easy to operate

Sensitivity, gradient incompatible, stability (temperature and flow)

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response correlates with the relative mass of the analytes. The estimated relative response factors (RRFs) of known impurities were comparable with accurate values obtained from linearity data. It could be a fast, convenient, and accurate method to determine RRFs of known and unknown impurities. Important for accurate quatitation of impurities when pure standards cannot be obtained.

Small-particle columns: One area of significant advancement in drug substance impurity analysis is the utilisation of smaller, porous silica particles (<2 µm mean diameter) to improve resolution and/or speed in LC separations. Typical HPLC separations in pharmaceutical analysis in the last decade have used particles with diameters in the range 3–5 µm. With particle diameters of 3.5–5 µm and a typical flow rate of 1 mL/min., many impurity profile methods require long gradient separations (45–60 min.).

This separation time translates into long total analysis times due to the number of injections required. Reducing the particle size from 5 to 1.7 µm will increase N by a factor of 2.9, thereby improving the effective resolution by a maximum of 1.7.

Many of the sub-2-µm particle columns are available in shorter lengths-50 mm, which facilitate their use on conventional LC instruments due to the lower back pressures required. The high pressure instruments (15000 psi) can use longer columns to obtain greater efficiency.

Reversed Phase-Monolithic silica columns have received significant attention for achieving faster analysis times using higher flow rates than are accessible with typical packed columns. Monolithic columns are prepared by polymerization of monomers that result in a continuous porous rod rather than a packed bed of individual particles. This interconnected skeleton provides macro pores (2 µm) with low resistance to flow while mesopores (13 nm) provides high efficiency chromatographic performance. Advantages: Pressure increases for monolithic columns were modest and well within the operating ranges of conventional pumps even at flow rate up to 9 mL/min. Reduced run times

at higher flow rates without loss of resolution (Figure 2). Wu et al found that the monolithics were not as retentive as packed columns and lower solvent strength were required for comparable retention. Good robustness and increased run times Figure 2 Chromatograms obtained at different flow rates on a monolithic column. were observed for methods with intermediate flow rates. No significant column aging effects for monolithics were noted after 22,000 column volumes of use. Gerber et al also reported good separations with

decreased analysis times and good column stability. Several additional applications: chiral separations, hydrophilic interaction chromatography, ion chromatography, capillary chromatography.

Stationary phase development: polar–embedded phases incorporate a polar group (e.g. amide, carbamate, urea or ether) into the alkyl chain. These phases are created to reduce silanol interaction with basic analytes. And found use as stable phases for highly aquous separations and in the intraction of polar

Figure 2 Chromatograms obtained at different flow rates on a monolithic column.

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analytes. Benefit of polar-embedded phases is the alternative selectivity afforded when compared to a standard alkyl phases (C18 or C8). Grumbach et al demonstrated that polar embedded phases are best for retention of polar analytes Mobile Phase pH: significant impact on the retention of acidic and basic analytes. The use of silica based phases above pH 7.5 is not feasible due to dissolution of the silica particles. Stable for pH 12: Zorbax extende (Agilent) –incorporates a bidentate bonding and double end-capping Xterra (waters), which incorporates a hybrid particle that is a combination of silica and organic (methyl silane) components.

Systematic or Automated Method Development

Method development for impurities in pharmaceuticals can require significant time and effort.

Method development HPLC systemsswitching among multiple columns and mobile phases as well as optimising the separations based on the data obtained.

Softwares: Chromsword software (IRIS Technologies) to predict retention using a model derived from analyte structures and column properties. ACD/LC Simulator allows prediction of chromatographic separations based on structure and column chemistry. AMDS (Waters) allows the user to choose columns to screen and then optimizes the separation on one column. DryLab (Rheodyne) LC-modeling software.

a range of 0.05-0.5 per cent relative to the API. Combined accuracy and precision of the method must be within the range of 100 per cent ±10 per cent 2. Method design Phase

Suitability of different techniques such as : LC/UV/MS (HPLC or UHPLC), GC-FID/MS, SFC-UV/MS To meet specificity, sensitivity, accuracy and precision requirements Capability for on/at-line measurements, analysis time and cost, sample preparation Define starting conditions from which method evaluation and optimisation can be performed.

3. Method Evaluation Phase

Risk assessment of the method conditions in order to identify all potential sources of variation in the practice of the intended method. Such as column temperature, gradient profile, buffer concentration, flow rate, sample/standard preparation factors (sonication time/solution volumes), resolution between critical pairs, environmental factors: humidity, reagent source, analyst training-ruggedness assessment.

Inorganic Impurities

Impurities are classified (ICH Q3A guidance) as organic, inorganic, and residual solvents. Some inorganic impurities are toxic at low levels, and these impurities

Analytical Target Profile (ATP) for measurement of impurities present in API. Impurities controlled at 0.2 per cent with reporting threshold of 0.05 per cent.

ATP: The method should be able to quantify impurities in the presence of API, as well as any other potential impurities/degradation products over 52

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ICP-MS Elemental analysis with:

• Wide elemental coverage • Very low detection limits • Fast analysis times (all elements at once) • Wide analytical working range (upto 9 orders) • Simple spectra • Isotopic information • High matrix tolerance Viable alternative to ICP-OES or GF-AAS

ICP-AES 6%

QbD Approach to Chromatographic Method Development: 1. Method objective

should be monitored to ensure safety.

Sources of inorganic impurities include those that are deliberately added to the process (e.g. catalysts), undetected contaminants from starting materials or reagents, leaching from pipes and other equipment from naturally derived plant or mineral sources. The level of each inorganic impurity should not exceed the limit defined or otherwise specified in the individual monograph.

Equipment: One of the following plasma spectrometers is required for an analyst to perform this multi-element analysis: 1. Inductively coupled plasma–atomic (optical) emission spectrometer.

2. Inductively coupled plasma–mass spectrometer.

In addition, a closed-vessel microwave digestion system may be required for the preparation of test materials.

What is ICP-MS: Inductively Coupled Palsma-Mass Spectrometry

CE 11% ICP-MS 61%

AAS 33%

GC 16%

HPLC 68%

IC 5%

Figure 3 Pattern of use of atomic spectrometric techniques in speciation analysis in drugs b) chromatographic techniques coupled with ICP-MS for speciation analysis of metals in drugs

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Is the compound soluble in aqueous solutions?

NO

Is the compound soluble in organic solvents?

NO

Perform closedvessel microwave digestion

YES Prepare sample, monitor solution and USP reference solution according to sample preparation procedure

Perform analysis using user-defined instrument and procedure

USP reference solution recover to within ± 20 per cent ?

NO

Perform analysis using element-specific method or use USP method 1

Report Result

YES Figure 4. USP- Inorganic impurity decision tree ICP-MS can:

• Measure almost any element at ppt to ppm levels in almost any material • Measure all elements in a single analysis • Distinguish different element species (speciation)

soluble in aqueous solutions.

• USP Inorganic Impurities Class 2 Reference Standard for test articles soluble in organic solvents.

• USP Inorganic Impurities Class 3 Reference Standard for closed-vessel microwave digestions.

USP Reference Standards—

• USP Inorganic Impurities Class 1 Reference Standard for test articles

A major trend in LC for the determination of drug impurities is clearly towards faster separations with comparable or improved separation capability. This is indicated by applications of monolithic columns and short, sub-2-µm columns that may be operated at high pressures. Faster analysis times facilitate more efficient method development and exploration of a wide range of mobile phase pH, organic modifier and stationary phase in an automated fashion.

Stationary phase development has focused on columns that provide greater retention for polar analytes, columns that will tolerate operation at pH values above 8 or columns that provide unique selectivity.

Advances in detection include the CAD, which is likely to see increased application for non-UV-absorbing compounds.

The ICP-MS is as an effective tool in impurity profiling of single, multi and speciation analysis of different elements present in bulk drugs and formulations.

The particular advantage of ICP-MS, when compared to other techniques is speciation studies for many elements and separation ability of chromatography coupled to ICP-MS offers a versatile tool for speciation. HPLC was the most widely used chromatographic technique, which occupied nearly 70 per cent of speciation analysis. The use of ICP-MS for elemental specific assays for accurate determination of pharmaceuticals and impurities without the need for standards was also reported.

Collectively, these advances will lead to improved capability for drug impurity profiling.

Please visist www.pharmafocusasia.com for full references.

A u t h o r BIO

Main requirements for pharmaceutical analysis are:

• High sensitivity • Good matrix tolerance • Low levels of interferences • Ease of coupling to separation techniques (CE, IC, LC and GC) for speciation analysis.

Conclusions

M V N Kumar Talluri is a Faculty at NIPER, Hyderabad. Previous positions held by him include Associate Scientific Manager at Biocon. He received PhD degree (pharmaceutical analysis) from IICT. He has published 30 research articles. He is recipient of CSIRResearch fellowship, Institution of Chemists Associateship awards.

He has been in the EditorialAdvisoryBoard of J.Pharmaceutical science-clinical practice and serves as a reviewer for international journals. Science direct declared 4 times his 2007 publication was among “Top 25 hottest articles. The Indian Drug Manufacturer’s Association conferred prestigious “Young Pharmaceutical Analyst Award 2011” for his outstanding research contribution in the field of Pharmaceutical Analysis.

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Books

Medical Informatics: Practical Guide for Healthcare and Information Technology Professionals Fourth Edition Authors: Ann Yoshihashi and Robert E Hoyt No of Pages: 392 Year of Publishing: 2010 Description: Medical Informatics combines information technology (IT) and clinical medicine to improve healthcare delivery, education and research. Our goal is to help healthcare and IT professionals meet the challenge of keeping up to date on the key topics in this rapidly evolving field. This extensively updated fourth edition with over 1300 references includes the following chapters: Overview of Medical Informatics, Electronic Health Records, Practice Management Systems, Health Information Exchange, Architectures of Information Systems, Data Standards, Privacy and Security, Consumer Health Informatics, Online Medical Resources, Search Engines, Mobile Technology, Evidence Based Medicine, Clinical Practice Guidelines, Disease Management and Disease Registries, Quality Improvement Strategies, Patient Safety and HIT, Electronic Prescribing, Telehealth and Telemedicine, Picture Archiving and Communication Systems, Bioinformatics, Public Health Informatics, E-Research, Emerging Trends in HIT. Available also as an ebook.

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Reinventing Discovery: The New Era of Networked Science

Am I My Genes?: Confronting Fate and Family Secrets in the Age of Genetic Testing

Authors: Michael Nielsen No of Pages: 280 Year of Publishing: 2011 Description: In Reinventing Discovery, Michael Nielsen argues that we are living at the dawn of the most dramatic change in science in more than 300 years. This change is being driven by powerful new cognitive tools, enabled by the internet, which are greatly accelerating scientific discovery. There are many books about how the internet is changing business or the workplace or government. But this is the first book about something much more fundamental: how the internet is transforming the nature of our collective intelligence and how we understand the world.

Reinventing Discovery tells the exciting story of an unprecedented new era of networked science. We learn, for example, how mathematicians in the Polymath Project are spontaneously coming together to collaborate online, tackling and rapidly demolishing previously unsolved problems. We learn how 250,000 amateur astronomers are working together in a project called Galaxy Zoo to understand the large-scale structure of the Universe, and how they are making astonishing discoveries, including an entirely new kind of galaxy.

Authors: Robert Klitzman No of Pages: 376 Year of Publishing: 2012 Description: In the fifty years since DNA was discovered, we have seen extraordinary advances. For example, genetic testing has rapidly improved the diagnosis and treatment of diseases such as Huntington's, cystic fibrosis, breast cancer, and Alzheimer's. But with this new knowledge comes difficult decisions for countless people, who wrestle with fear about whether to get tested, and if so, what to do with the results.

Am I My Genes? shows how real individuals have confronted these issues in their daily lives.

Robert L. Klitzman interviewed 64 people who faced Huntington's Disease, breast and ovarian cancer, or Alpha-1 antitrypsin deficiency. The book describes-often in the person's own words--how each has wrestled with the vast implications that genetics has for their lives and their families. Klitzman shows how these men and women struggle to make sense of their predicament and its causes.

They confront a series of quandaries--whether to be tested; whether to disclose their genetic risks to parents, siblings, spouses, offspring, friends, doctors, insurers, employers, and schools; how to view and understand themselves and their genetics; what treatments, if any, to pursue; whether to have children, adopt, screen embryos, or abort; and whether to participate in genetic communities.

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The Creative Destruction of Medicine: How the Digital Revolution Will Create Better Healthcare Authors: Eric Topol M.D. No of Pages: 320 Year of Publishing: 2012 Description: What if your cell phone could detect cancer cells circulating in your blood or warn you of an imminent heart attack? Mobile wireless digital devices, including smartphones and tablets with seemingly limitless functionality, have brought about radical changes in our lives, providing hyper-connectivity to social networks and cloud computing. But the digital world has hardly pierced the medical cocoon.

Until now. Beyond reading email and surfing the Web, we will soon be checking our vital signs on our phone. We can already continuously monitor our heart rhythm, blood glucose levels, and brain waves while we sleep. Miniature ultrasound imaging devices are replacing the icon of medicineâ&#x20AC;&#x201D;the stethoscope. DNA sequencing, Facebook, and the Watson supercomputer have already saved lives. For the first time we can capture all the relevant data from each individual to enable precision therapy, prevent major side effects of medications, and ultimately to prevent many diseases from ever occurring. And yet many of these digital medical innovations lie unused because of the medical communityâ&#x20AC;&#x2122;s profound resistance to change.

Drug Safety Data: How to Analyze, Summarize, and Interpret to Determine Risk Authors: Michael J. Klepper, Barton Cobert No of Pages: 316 Year of Publishing: 2010 Description: Drug Safety Data: How To Analyze, Summarize And Interpret To Determine Risk Was Selected For The First Clinical Research Bookshelf - Essential Reading For Clinical Research Professionals By The Journal Of Clinical Research Best Practices.

Drug Safety Data: How To Analyze, Summarize And Interpret To Determine Risk Provides Drug Safety/Pharmacovogilance Professionals, Pharmaceutical And Clinical Research Scientists, Statisticians, Programmers, Medical Writers, And Technicians With An Accessible, Practical Framework For The Analysis, Summary And Interpretation Of Drug Safety Data. The Only Guide Of Its Kind, Drug Safety Data: How To Analyze, Summarize And Interpret To Determine Risk Is An Invaluable Reference For Pre- And Post-Marketing Risk Assessment. With Decades Of Pharmaceutical Research And Drug Safety Expertise, Authors Dr. Klepper And Dr. Cobert Discuss How Quality Planning, Safety Training, And Data Standardization Result In Significant Cost, Time, And Resource Savings. Through Illustrative, Step-By-Step Instruction, Drug Safety Data: How To Analyze, Summarize And Interpret To Determine Risk Is The Definitive Guide To Drug Safety Data Analysis And Reporting.

Leading Pharmaceutical Innovation: Trends and Drivers for Growth in the Pharmaceutical Industry Authors: Oliver Gassmann, Gerrit Reepmeyer and Maximilian von Zedtwitz No of Pages: 202 Year of Publishing: 2010 Description: Pharmaceutical giants have been doubling their investments in drug development, only to see new drug approvals to remain constant for the past decade. This book investigates and highlights a set of proactive strategies, aimed at generating sustainable competitive advantage for its protagonists based on value-generating business practices. We focus on three sources of pharmaceutical innovation: new management methods in the drug development pipeline, new technologies as enablers for cutting-edge R&D, and new forms of internationalisation, such as outside-in innovation in the early phases of R&D.

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CHINA-PHARM 2012 to Gear Up for New Opportunities Jointly organized by China Center for Pharmaceutical International Exchange and Messe D端sseldorf (Shanghai) Co., Ltd., the 17th China International Pharmaceutical Industry Exhibition (CHINA-PHARM 2012) will be held at China National Convention Center (CNCC) in Beijing from September 24 to 27, 2012 with a brand new look. Numerous renowned pharmaceutical engineering companies home and abroad will attend the exhibition, which is the famous international forefront communication platform in the industry. It is estimated that more than 500 exhibitors will present a broad spectrum of innovative products and services on 35,000 square meters at the CNCC, attracting more than 20,000 visitors worldwide. In order to provide better service to the exhibitors and the visitors, the exhibition will use the new domain name www.china-pharm.net and a new logo this year.

Ever since CHINA-PHARM 2012 started the exhibitor recruitment campaign, the exhibition booths sell

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extremely well. Both new and previous exhibitors all participate actively. At present, almost all the ground floor booths in CNCC have been sold out. The following famous companies have confirmed their participation: Rieckermann, CVC TECHNOLOGIES, INC, NNE, Siemens, Austar, Hunan China Sun Pharmaceutical Machinery Co.,Ltd, TRUKING TECHNOLOGY LIMITED, Colamark (Guangzhou) Labeling Equipment Limited, CHINA ELECTRONICS, SHANGHAIFANUC Robotics Co.,Ltd, BEIJING C&C CAMBCAVI CO.,LTD, Guangzhou SanTuo, Shanghai Macroprocess, Harbin Nano, Beijing Tuobixi, Winifred Group, PHARMAPACK (GUANGZHOU), Qingdao Double Whale, etc. In addition, the national pavilions are also actively under organization. It has been confirmed that the Germany pavilion and UK pavilion will again give support to CHINA-PHARM 2012, embracing the fast development momentum and great potential of China pharmaceutical market.

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aging materials having direct contact with the drugs, improve 100 standards on pharmaceutical excipients and establish 200 standards on pharmaceutical excipients. The plan also emphasizes on control and quality supervision over the whole process including drug R&D, production, transportation and utilization.

As a critical process in the production, clean technology receives more extensive attention. Over the last few years, the pharmaceutical engineering design in China has made a lot of progress in design philosophy and capability with the influence from drug GMP and clean technology development. The implementation of the China’s new drug GMP also poses new requirements on domestic pharmaceutical engineering design and drug production. The good production environment is the foundation of drug production in compliance with drug GMP. Whether the cleaning engineering of the pharmaceutical projects complies with the specific requirements on drug production is the key to drug GMP compliance.

The World Holds High Expectation on China Pharmaceutical Market;

The International Platform Provides Deep Insights While China-Pharm-Clean 2012 to Make Debut Concurrently

Quality and Scale Are Both Important for the Harmonious Development China is the largest emerging pharmaceutical market in the world. Based on the IMS forecast, China will enjoy a higher growth rate than other markets, and will become the second largest pharmaceutical market in the world by 2020, only after the US. By then, the market volume in China will reach $109.5 billion with the market share increasing from 3% to 7.5%. With the estimated continuous growth of the market volume, the government put great emphasis on drug safety and quality management. At February 13th, 2012, the State Council issued the 12th Five-year Plan (20112015) for Pharmaceutical Safety Standard (referred to as the “plan” hereafter). It is the first independent plan for drug safety in China. According to the plan, by the end of the 12th five-year the drug standards and drug quality would be significantly improved; the drug administration system would be more complete; the ability to guarantee the drug safety would be close to the international leading level; and the drug safety and people’s satisfaction on drug safety would be substantially enhanced. The plan has specified the drug standards that need to be improved: improve 6,500 drug standards, improve 139 standards on the packaging materials having direct contact with the drugs, establish 100 standards on the common pack-

As the international annual grand event for pharmaceutical industry, CHINA-PHARM not only provides a platform for domestic and foreign pharmaceutical equipment suppliers to compete, but also a platform to exchange the interpretations of the new drug GMP. Under the new situation, CHINA-PHARM 2012 will integrate the needs and hot topics in different sectors and launch more customized feature zones to provide more promotion opportunities for the exhibitors. Carrying forward the success of last year, the organizer will continue with “CHINAPHARM-Lab Zone”, “China Biological Engineering Zone”, “Excipient and Packaging Materials Zone”, “Fluid Engineering Accessories Zone”, “Engineering Service Consultation Zone” and “RFID, Anti-counterfeiting and Spraying Code Zone” this year.

The 1st China International Pharmaceutical Industry Clean Technology Exhibition & Congress (ChinaPharm-Clean 2012) is to make its debut, in order to promote the communication and development of pharmaceutical clean room technology. It is aimed to provide the pharmaceutical companies with clean production solution and technology in compliance with the new drug GMP. The Exhibition & Congress will be co-organized by the organizers of CHINAPHARM, CCPIE & MDS, as well as the famous industry association, Shanghai Indoor Contamination Control

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Industry Association. Furthermore, the “2012 Pharmaceutical Clean Technology Congress” will be held concurrently, helping the pharmaceutical companies to turn the challenges from the new drug GMP into business success.

Along with the progress of China's reform & opening up and rapid economy development, as well as the implementation of Drug GMP, the drug production conditions have been obviously improved, while scientific and technological level of drug production and equipment have been greatly developed, which played a very important role in ensuring drug quality, protecting public health and guaranteeing the safety and effectiveness of drugs. The newly revised drug GMP stressed that the implementation of the drug GMP need to stick to the principle of “safety, effectiveness, and reliable quality”, and always be honest to the public.

In order to present the achievements of newly revised drug GMP in the past two years, share the successful experience of the outstanding enterprises, Center for Certification of Drug (CCD) will join hands with CCPIE to establish the “Drug GMP Achievements Showcase” Zone during CHINA-PHARM 2012 at the LB1 Exhibition Floor. By vivid case studies and various showcases, this special zone is designed to help

Chinese pharmaceutical manufacturers improve the production conditions and update the production management software, facilitate industrial upgrading and structural adjustment, as well as continuously enhance the pharmaceutical production and quality management capacity and quality control level.

A series of industry high-end forums and events will be held during the exhibition as well, sharing the opinions, experience and insights of the experts and senior elites within the industry and discussing the development trend and opportunities in the industry.

The popular forums in the previous years, such as “ISPE-CCPIE China Conference”, “American Society of Mechanical Engineers (ASME) Seminars”, “World Health Organization (WHO) Pre-qualification Workshop”, “Traditional Chinese Medicine Injection Safety Management Workshop”, will still be on this year’s schedule. Meanwhile, there will be more wonderful Exhibitor Technical Seminars.

Through a nearly 20-year development since 1996, CHINA-PHARM has become one of the famous exhibitions with significant influence in the international pharmaceutical field. With the newly revised drug GMP issued in China and the 12th Five-year Plan for Pharmaceutical Safety Standard, CHINAPHARM will work to provide more business opportunities and premium service to the industry and the exhibitors, establishing the platform for communication and cooperation between China and the world, while contribute to the vigorous development of the pharmaceutical industry in China.

For more information, please visit: www.china-pharm.net

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Drug GMP Achievements Showcase Zone to Present the Achievements of Newly Revised Drug GMP

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

ISSUE - 16 2012

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Products&Services

Company........................................... Page no.

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SuppliersGuide

Xcellerex Inc....................................................... 09 Company...........................................Page no.

BOSCH............................................................... 05 www.boschpackaging.com CCPIE................................................................. 59 www.china-pharm.net DIA...................................................................... 33 www.diahome.org Emirates Sky Cargo........................................OBC www.skycargo.com Fluid-Bag...........................................................IFC www.fluid-bag.com INC Research, LLC.......................................... IBC www.incresearch.com Mikron Group..................................................... 47 www.mikron.com NETZSCH........................................................... 27 www.netzsch-grinding.com/deltavita SHIMADZU (Asia Pacific) Pte Ltd...................... 03 www.shimadzu.com.sg Six Sigma Asia................................................... 29 www.sixsigmaasia.com Subodh Engineering Pvt Ltd.............................. 31 www.subodhfilters.com Thomas Engineering Inc.................................... 11 www.thomaseng.com Wilden Pump & Engineering Company............ 23 www.wildenpump.com Xcellerex Inc....................................................... 09 www.xcellerex.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 Cover 3.OBC: Outside Back Cover www.pharmafocusasia.com

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