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Contents.indd 8
Pharma Bio World
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EXPERT’S TAKE
12
Need for a Smarter Regulatory System to Ensure Access to Affordable Biologics: The Biosimilars – Kiran Mazumdar, Shaw
18
Access to Medicine: Moral Imperative and A New Consciousness Part 1 – Jenik Radon
INTERVIEW
24 12
Aftermath of the Drug Price Control Order 2013 – Dr Gopakumar Nair
FEATURES
20
48
28
Does Antithrombin III Block the Action of a Monoclonal Antithrombin Antibody? – Sophia Kenrick
34
Stem Cell Transplantation from Haplo-identical Donors – Dr Gerez, Dr Rudiger, Dr Roy
40
Recombinant Human Albumin as a Means to Produce Stable Biologic Formulations – Novozymes Biopharma
46
Treating Pharma Effluents – Dr B V Sivakumar
50
Case Study: Productivity Hike Using Crushing and Grinding Line – Roy Housh
52
Pre-filled Syringes: Revolution in Dosage Delivery Trend – Zameer Agarwal
58
Working Towards a Standardised Identification Solution – Ian Parsonage
64
Addressing Complex Needs of Pharmaceutical Stakeholders via Ultra-High-Barrier Thermoformed Packaging – Dr Thomas Dries
66
Current Clinical Trial Scenario of India: Challenges and Solutions – Dr Rajashree Devarakonda
70
Fulfilling Pharmacovigilance Obligations in Innovator Pharmaceutical and Generic Manufacturer Partnerships – Chitra Lele
NEWS UPDATE
75 80 88
In Retrospect Pharma News Biotech News
CORPORATE AFFAIRS
91 95
Product Trends Events Diary
BACKYARD
68
96 98
Bookshelf AD Index
Next Issue Focus: Contracting & Outsourcing
10 July 2013
Contents.indd 10
Pharma Bio World
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Expert's Take Need for a Smarter Regulatory System to Ensure Access to Affordable Biologics: The Biosimilars
Kiran Mazumdar Shaw CMD, Biocon
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Today biologics make for up half of the top 10 best-selling drugs worldwide. With patents for several popular biologics expiring over the next few years, ‘biosimilar’ products that offer the same level of safety and efficacy as innovator molecules can be a cost-effective alternative for patients. Biosimilars can also help governments across the world rein in their burgeoning healthcare spends. The latest available IMS forecast for biosimilars indicates a global market size of US$ 5 billion by 2016. The quality and regulatory requirements for biosimilars are significantly more extensive than those for generic small molecules. Conventional generics are only required to demonstrate simple bioequivalence to the originator product in a small cohort of healthy volunteers, whereas biosimilars have to establish comparable safety and efficacy through
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The use of biologics is fast gaining traction around the globe because they can address medical needs that conventional th e r a p e u t i cs c a nnot , including many cancers, immunological and genetic diseases. Unfortunately, the development of biologics is hugely expensive and the high cost factor makes them inaccessible to a larger patient population.
he global pharmaceutical industry is going through a paradigm change as biologics such as monoclonal antibodies and recombinant proteins find greater acceptance for treating a wide range of chronic diseases.
There is no company today that actually sells bioidentical products. If the same product is manufactured at two different locations even by the innovator, there is a high probability that they will not be ‘bioidentical’.
12 July 2013
Experts Take 12-16.indd 12
fairly large and lengthy clinical trials in patients that make the process complex and expensive. Governments around the world thus need to define a smarter regulatory pathway that reduces ‘cost of development’ and ‘time to market’ for biosimilars. This will ensure that such new age medicines reach a wider swathe of the population, especially the poor. Dealing with Complexity Biosimilars differ from conventional small-molecule generics in that they are target-specific drugs that are large and complex and have a stringent production protocol. Chemically synthesized drugs typically have a molecular weight of less than 700 Daltons, a well-defined structure and are relatively stable. In comparison, a monoclonal antibody weighs about 150,000 Daltons, has complex physicochemical characteristics and is sensitive to heat. A plethora of analytical tools are needed to evaluate the various quality attributes of a protein. As each tool covers only a part of a protein’s complexity, several methods and multicomponent analysis needs to be carried out to arrive at its complete structure and functional attributes. This level of complexity means the time, effort and money needed to analyze and characterize a biologic drug is exponentially higher than a small molecule drug. It takes about 18 to 24 months and costs between US$ 1 million and US$ 4 million Pharma Bio World
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Figure 1: ANDA: An Abbreviated Pathway for Generics
to file an ANDA (Abbreviated New Drug Application) in the U.S. for a small molecule generic (refer Fig 1). In contrast, the complex regulatory path that needs to be traversed for filing for approval of a biosimilar could take as long as five to seven years and cost anywhere between US$ 80 million and US$ 100 million based on the abbreviated pathway proposed by global regulators (refer Fig. 2). The biosimilar manufacturing process starts with fermentation, which is followed by a multi-step purification process to have the right quality product. It is from this stage that the data evaluation process kicks in. The analytical and characterization group evaluates the primary, secondary and tertiary structure of these proteins. However in the case of b io sim ila rs, u n l i k e g e n e r ics, t h e development process does not end at analytics but extends to large and lengthy clinical trials, which adds to the cost of development as well as delays the launch in the market.
Figure 2: Biosimilars: An Abbreviated Pathway (Reality or Mirage)
enough to ensure efficacy and the safety of patients is ensured. Unfortunately, Figure 2 which is highlighted by most regulators as the short pathway for regulatory approval of biosimilars, in reality is not a “pyramid” but a “cube” (as indicated in Figure 3). Although the regulators have indicated that clinical data requirement for biosimilars is abbreviated, when one actually discusses the same with regulators the requirements are nowhere close to the small triangle shown in Figure 2. In reality it takes 7-9 years and costs $100-150 MM, based on current understanding of regulatory requirements. In fact, if one looks at the approvals of some of the innovator biologics, the sample size for their pivotal studies is smaller than the requirements for biosimilars based on current guidelines.
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Experts Take 12-16.indd 14
One of the greatest challenges for biosimilars is to demonstrate whether or not they are substitutable with innovator products. While this is still a very contentious topic, I believe biosimilars will ultimately be substituted for branded products and become part of standard medical practice in the future. There is no company today that actually sells bioidentical products. If the same product is manufactured at two different locations even by the innovator, there is a high probability that they will not be “bioidentical.” We are likely to see at least some variation in most cases because the cell culture process is so complex that there are bound to be batch to batch variations. In fact, innovators making the same biologic at multiple locations are in effect producing biosimilars. Of course, there are acceptable and unacceptable levels of variation. So the question is whether we can use the same yardstick to develop biosimilar drugs? What leeway can be given to companies that are looking to make biosimilars?
T h e h i g h l e v e ls o f co m p le xit y a n d expenses associated with biosimilars make a compelling case for the regulations to balance the aspects of safety and efficacy with affordability. If regulations are made too stringent there may not be enough commercial incentive for companies to develop biosimilars. At the same time, laws should be robust
Demonstration of Biosimilarity
Total Time Incl. Filling: 7-9 Years & Cost $ 100-150 Mn
Figure 3: Biosimilars Requirement: A Reality
The way I see it, ‘biosimilarity’ will hinge largely on comparability between the original and the follow-on product in terms of safety and efficacy. If a biosimilar and an innovator product are comparable on these two parameters it will simplify the task for companies trying to make biosimilars. Pharma Bio World
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Characterisation • • & Analytical • • Phase 1 Study
• • • • •
Post Marketing • • Studies & PV •
Demonstrating comparability based on extensive physicochemical and biological characterisation Using finger printing approach for comparability Harmonising requirements to be similar to comparability exercise done by innovators for “process changes” Preclinical assessment of immunogenicity Replace large safety and efficacy study with PK-PD study Evaluate safety and PK and demonstrate similarity to innovator Comparators sourced from both US and EU Adequate sample size to meet BA/BE criteria for PK Evaluate PD if appropriate marker is available Even large studies are unable to detect rare safety and immunogenicity events Assess safety and immunogenicity as part a comparative post marketing study Robust Pharmaco-Vigilance plan to assess rare events
Figure 4: Clinical Trials: Innovative Regulatory Pathway
The world over, there is a need to create a smarter regulatory environment that not only cuts down the cost of development but also ‘time to market’, which in turn benefits consumers by improving access to affordable drugs. India can play a key role in enabling this process. An innovative regulatory pathway for biosimilars in India could do away with the need for conducting Phase III clinical trials, keeping in mind that high resolution analytics of today provide high end characterization data than before, thereby proving the biosimilarity criteria to a large extent. In light of this, the regulator could give companies a "conditional approval" for these biosimilar drugs based on Phase I comparable Pharmaco-Kinetic (PK) data and give them a year's time to collect "safety and efficacy" data post marketing. The final approval should be given post submission of this data (Refer Figure 4). The current biosimilars regulatory regime stretches approval times to as long as 7
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to 9 years and costs to between $100 million and $150 million, a new regulatory paradigm could drastically bring down timelines to between 30 to 42 months and cut costs up to a tenth. It could thus ensure that local regulatory requirements don’t add to the cost of development and force companies to price their products at a premium. Conclusion The experience of EU with biosimilars has amply demonstrated that the presence of biosimilars enhances existing market competition, increases access to medicine to a larger set of the population and helps stabilize healthcare costs. Biosimilars have been able to command 11% of the total accessible market in EU since their introduction in 2006.
litigations, it is unlikely that there would be a meaningful impact on costs. India therefore should take the lead among the emerging economies to expedite the approval of biologics for use by the public while, at the same time, ensuring that high levels of safety and quality are maintained. Smart regulations and a strong patents regime can help India build an ecosystem that fosters cheaper drug development and gives drug makers the impetus to pass on the benefits to patients without having to take a hit on their bottom line. Contact: seema.ahuja@biocon.com
The urgency for a rational set of biosimilar guidelines is being felt in developed nations. Although US has recently approved a path for biosimilar products, without dealing with issues like interchangeability and substitutability and simplifying the patent
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Journey of New Regulatory Paradigm
The regulator could give companies a "conditional approval" for these biosimilar drugs based on Phase I comparable Pharmaco-Kinetic (PK) data and give them a year's time to collect "safety and efficacy" data post marketing.
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Experts Take 12-16.indd 16
Pharma Bio World
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Expert's Take
Access to Medicine:
Moral Imperative and A New Consciousness Part 1
Jenik Radon Adjunct Professor of International and Public Affairs, Columbia School of International and Public Affairs
Research Associate, Vale Columbia Center for Sustainable International Investment, Columbia University
This series of five articles will address the main issues of the seemingly unending debate, beginning with an introduction of the key concepts and the international agreements that establish, or seek to establish, access to medicine as a human right, and, in the last article, offering a way forward.
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he phrase “access to medicine” has become a catch-all, a mantra and a demand. Supporters want it to become a human right, taking its place along with freedom of speech and freedom from genocide. But it is not clear what the right of access to medicine exactly means or how it can be implemented. Access to medicine has become a headline phrase ever since 1998 when the South African Pharmaceutical Manufacturers Association (PMA) and 39 pharma companies sued the government of South Africa (The Pharmaceutical Manufacturers’ Association of South Africa, et al. v. South Africa, in the High Court of South Africa, Case Number 4138/98). These companies challenged the validity of a South African law that aimed to control South Africa’s AIDS epidemic by importing generic versions of AIDS medicines without the consent of the patent holders. The pharma companies vowed a worldwide legal fight to keep sole control of their intellectual property rights related to these medicines; and they lobbied the US government to support their commercial and legal position. But ultimately, after three years, they retreated under what had become unrelenting negative publicity.
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Maree Newson
Are all persons entitled to the same standard of care and receipt of the same medicine, irrespective of income or citizenship?
18 July 2013
Experts Take 18-22.indd 18
Although access to medicine had been pragmatically codified earlier in 1994 in the Agreement on Trade-Related Aspects of Intellectual Property (TRIPS), the phrase had not yet evolved into a clearly-defined legal concept at the time the pharma companies instituted their lawsuit. Moreover, despite the continued notoriety of this expression and its frequent invocation, there is still no generally accepted agreement to its meaning or scope and it continues to elicit heated debate. The term raises a host of conceptual, commercial and practical questions, as well as, of course, ethical questions. Access to Medicine: What Does it Really Mean? Does access to medicine mean that every person has a right to be treated by a doctor, to be admitted to a hospital, and, the focus of this series of articles, to receive the necessary drugs? Does this apply irrespective of the cost thereof? Are all persons entitled to the same standard of care and receipt of the same medicine, irrespective of income or citizenship? Pharma companies, which have been the primary focus of access to medicine campaigns by NGOs throughout the world, dedicate their business to a very basic and fundamental human concern, namely health. Does this focus give rise to a special societal obligation, or does even impose a burden, to provide their drugs to those in need, no matter where in the world, even if at below cost? Pharma Bio World
8/2/2013 6:00:12 PM
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5) Perhaps most challenging of all, who pays for the development of new drugs? After all, the dev elopm e n t, p r o d u c tio n and provision of drugs, especially new and innov ativ e on e s , imp o s e a significant cost that must be borne by someone. Some of these concerns could potentially be addressed by structuring an appropriate worldwide incentive system to encourage expenditures on continuous drug R&D, manufacturing challenges and costs, and regulatory requirements, which are all necessary parts of developing new, improved drugs. However, this ideal incentive structure remains elusive in practice and is often addressed in terms of rhetoric rather than data.
In order for pharma companies to remain profitable and continue their drug research, should citizens of developed nations, especially the US and EU nations, pay more than citizens of developing nations for new and innovative drugs protected by a pharma company’s patents? Specifically, is access to AIDS medicines a somewhat special situation, as those, afflicted by AIDS would surely die without such medicine? If access to AIDS medicine is the standard by which all other cases are judged, how should arthritis, a disease perceived to be “only” debilitating, be addressed? An endless number of practical and ethical questions continue to be raised. And the 20 July 2013
Experts Take 18-22.indd 20
answers to these questions cannot easily be separated from the emotions they evoke. But they must be openly addressed. Underlying the above questions is a growing consensus that a moral imperative exists to provide appropriate medical drugs to the people of developing nations, as well as of course to poor or poorer people of developed nations. Of course, even that consensus demands that fundamental questions be addressed and answered: 1) Do all drugs have to be provided; 2) Do the drugs have to maintain the same quality or efficacy as those provided in developed countries; 3) At what prices can or should such drugs be provided; 4) Does the pricing have to be uniform or can it be differentiated; in other words, can a system be developed that standardises different pricing for different countries and perhaps even within countries; and
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There is also the related question of how does one calculate the cost of any drug, especially if it based in part on the work of publicly funded research? If so, exactly why do pharma companies have this burden and manufacturers of other lifesaving necessities such as ambulances do not? Moreover, do states and their governments have any public obligations to provide necessary drugs to their citizens? And if so, how and at what cost? Does an economically developed country such as the US have an obligation to help a poorer state secure access to medicine for that state’s citizens?
A viable business model requires the price of any new drug to compensate the research organisations, including pharma companies, for all the costs of their research and development, including research on other products that did not yield marketable products. Thus, the most fundamental question concerning access to medicine arises: What are the principles that should guide pharma companies and the rest of society in balancing the competing demands of drug innovation, profit making, and the moral imperative underlying access to medicine? Will such balance, at least in part, be anchored in modern-day self-interested utilitarianism? After all, unhealthy people and nations do not have the strength to develop good governing structures and have limited capability to prevent the spread of diseases. These articles seek to establish the foundation for such principles by
Current international agreements for intellectual property help to define the parameters of what access to medicine can or should be guaranteed. Pharma Bio World
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portrayed as greedy corporations from rich nations withholding medicine from dying poor patients. Eventually, the companies began offering their medicines at lower prices, lessening the need for parallel imports or compulsory licensing. Ultimately, in April 2001, the plaintiffs withdrew their complaint.
examining the evolution of “access to medicine” since the PMA v. South Africa lawsuit. This discussion will move closer to determining what “access to medicine” means and how it can be put into practice. International Agreements a Landmark Lawsuit
and
Current international agreements for intellectual property help to define the parameters of what access to medicine can or should be guaranteed. During the Uruguay Round of the General Agreement of Trades and Tariffs in 1994, TRIPS was created to guide international enforcement of patent rights, including those applicable to drugs. Article 7 of TRIPS states that protection of intellectual property rights should promote innovation "in a manner conducive to social and economic welfare, and to a balance of rights and obligations.” Article 8 allows for the possibility of suspending intellectual property rights to protect public health and to promote interest in sectors of socio-economic need. The 1994 TRIPS agreement, however, has been vigorously opposed in many sectors on the basis that it is not in keeping with international human rights norms. The agreement created many ambiguities as to when and how the World Trade Organization (WTO) members could suspend intellectual property rights to gain access to needed drugs for their nations. In 1998, these ambiguities were tested under a glaring global spotlight. South Africa, the country at the time with the largest population of individuals living with HIV/AIDS in the world, passed the Medicines and Related Substances Control Act in 1997. The Medicines Act was designed to create access to AIDS medicines at prices lower than those the pharma companies’ had set. Necessary medicine for treating AIDS, including drugs to prevent mother-tochild transmission, antiretroviral therapy, and important antifungal and antibacterial drugs, were all under patent protection and sold at prices that developed nations 22 July 2013
Experts Take 18-22.indd 22
could pay but were too high for the South African healthcare system. Section 15 of the Medicines Act gave the Minister of Health the power to allow lower cost versions of these medicines to be imported from other countries, either through compulsory licensing or through parallel importing. Parallel importing is particularly important when a country lacks the capability of producing the medicines itself. The pharmaceutical industry plaintiffs brought the PMA lawsuit in 1998, which claimed that the Medicines Act violated the TRIPS agreement to enforce patent rights. In this specific instance, the pharmaceutical industry had little to lose financially because they would not have made a profit selling medicine in South Africa regardless. But as a general rule, patent protection is a core principle of the industry, and modern commercial life. The South African law risked setting a precedent that weakened patent protection for new medicines globally. The High Court of South Africa granted the advocacy group Treatment Advocacy Campaign (TAC)’s petition to file a friend-of-the-court brief. Among other arguments in its brief, TAC demanded information about the cost of producing the medicines in order to better debate whether the industry would be able to make a reasonable profit despite South Africa’s law. At the same time, the pharmaceutical industry plaintiffs, who were mostly headquartered in Switzerland, UK and the US, continued to receive extremely negative publicity. The plaintiffs were
In November 2001, during the wake of the PMA case and growing concern about access to medicine as a counterbalance to protecting intellectual property rights, the Declaration on the TRIPS Agreement and Public Health was adopted in Doha by the member nations of the WTO (Doha Declaration). The Doha Declaration emphasises countries’ rights under TRIPS to take measures to protect public health and to determine the grounds upon which to grant compulsory licenses and to declare a health related emergency. In 2005, TRIPS was amended to allow a country that cannot manufacture its own drugs to grant a compulsory license to import drugs from another WTO member country that has the necessary manufacturing capacity. Over the years, TRIPS has focused on trying to balance access to medicine while simultaneously protecting intellectual property rights. What is clear is that, although legal agreements and cases might define rights or provide principles, applying those rules is very difficult and challenging in practice. In the next issue, we explore one of the most important issues that must be addressed if “access to medicine” is to become a reality and a right: Which illnesses demand a universal response, and when is the right to access triggered? Later in the series, we’ll also be looking at the costs and distribution of medicines, the pioneering and humanistic decisions of the Indian Supreme Court, and how the pharmaceutical industry can live up to its standard-bearer responsibilities as a universal medical professional, a doctor, literally for the world, in all but name. Contact: jenik_radon@radonoffices.com Pharma Bio World
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interview
DR GOPAKUMAR NAIR
Aftermath of the Drug Price Control Order 2013
24 July 2013
Interview 24-26.indd 24
The Drugs (Prices Control) Order, 2013 announced on 15 th May 2013 by the Department of Pharmaceuticals, in an attempt to avail drugs at an affordable price to the Indian population has created a stir in the Pharma Industry. Pharma Bio World in an exclusive interview with Dr Gopakumar Nair, Founder, Gopakumar Nair Associates, explores the two sides of this new policy. Gopakumar Nair Associates is a leading legal consultancy firm advising to the biotechnology, chemical, pharma and healthcare industries. Do you support the DPCO 2013 or do you see it as a bad move for the Pharma Industry? Please share your views (pros and cons) about this new Policy with us. Indian Pharma Industry has waited long enough for a new policy. The policies of seventies, eighties and nineties were relatively one-sided. The Government of India had nurtured the Indian Pharma through infancy and the teens. Having reached adulthood, the Government has rightly stressed on the Indian policy of “affordable access” for the masses on a larger canvas than anticancer and anti-HIV drugs. This time, the 2013 Drug Policy is not one sided, having the Courts- including the Supreme Court - massively being pursued (and reasonably succeeded) by the NGOs of the country. The Department of Pharmaceuticals did a commendable job under stress and excessive pressures from the NGOs both directly and through the Apex Court. Kudos to the Policy Makers. That said, the policy needs a few corrections for practical implementation, without undue avoidable litigations. The faulty interpretation and implementation of DEPA of yesteryears have led to very unreasonable demands on the Industry. Impractical conditionalities may leave much room for discretionary actions leading to protracted and multi-locational litigations. Indian Pharma is a survivor. It survived the WTO/TRIPs challenges from outside. This challenge from inside should also be taken head on by India Pharma. Any law which applies to all should be no problem for the Pharma Entrepreneur, who will ride every wave and move on. However, it will be sad, if the erstwhile, 1995 Policy and its provisions are officially not declared as closed in view of the new 2013 Policy. Operating and managing
the 2013 Policy with all the confusingly conflicting provisions of 1995 policy will be unfair to the Industry. According to the new Price Order the price of the bulk drugs is not going to be altered although there is going to be a fall in the cost of formulations. What will you advise the pharma companies so as to cope up with this change to sustain in the industry? The exclusion of Bulk Drugs from pricing was long overdue especially in view of the declining trend in Indian API/Bulk Drug manufacturing operations. In view of built-in provisions and potential exemptions, there is no need for concern on this score. Would you suggest manufacturing outsourcing as an option in this situation? If yes, how does this help? Manufacturing outsourcing is no new phenomenon for India. The DPCO 2013 would not/need not be a catalyst for increased manufacturing outsourcing. This trend in Industry is on the ascend any way. Do you think the new Pricing policy will have adverse effects on the quality of the products manufactured by a company? No. Indian Pharma Industry is the most controlled, regulated industry in the world. Soon, the licences to be obtained by Indian Pharma will exceed 100, at a time when we say the “licence-raj” is a thing of the of past. More over, Indian Pharma is substantially selfregulated. On the contrary, the new DPCO bringing down the disparities in range of prices also acts adversely against spurious players, if any (mostly all unlicenced). Pharma Bio World
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Will you suggest discontinuing the mfg of the scheduled drug formulations/ introducing manufacturing of formulations of unscheduled drugs or none? Discontinuing manufacturing of scheduled drug formulations are in contravention of DPCO 2013. There is no bar on introducing unscheduled formulations. I am sure, the Indian Pharma would consider non-contravening legally valid options for working around to survive economically. Since the DPCO 2013 strives to incentivise indigenous R&D, do you see this as a good opportunity for R&D to survive the competition or is this move going to hinder the further growth of the Indian Pharmaceutical Industry?
Indian Pharma Industry needs to undertake research for patenting and approval for a ‘new drug’ (which can be a new product, new process or novel drug delivery system) from the Drug Controller General (India). A new drug is exempted from the DPCO 2013 for five years from the day of its introduction in the market. It is hoped that Indian Pharma companies will make full use of this golden opportunity through indigenous research and innovation which will add to the growth of this Industry. Do you think the big Indian pharma players will look at India as a potential market or will they now target the foreign market to draw profits? Big Indian Pharma cannot and will not ignore Indian market. They may
strategise for overseas operations for sustaining their ROI, but will continue to cater to Indian market for all the right reasons. Will this step taken up by the Indian Government be successful in ensuring the easy availability of medicines to the weaker section of the society? If not, what else needs to be done in your opinion in order to make it a success? To make this initiative of 2013 Drug Policy a success, the Government will need to treat the transitionary provisions softly and allow the policy to get implemented, with genuine exceptions. The benefits are bound to reach the public at large eventually, improving affordable access, to the larger needy community.
IMS Health’s Analysis on NLEM Policy Based on the DPCO 2013, IMS Health has estimated that the value erosion of the pharmaceutical market would be to the tune of ~` 1600 crores (~2.2 per cent of the current pharmaceutical market), post implementation. Scope of the NLEM pricing policy is likely to cover ~ 18 per cent of the Retail pharmaceutical market. Coupling this with DPCO which is likely to remain in place for some time post NLEM implementation, the scope of the combined price controlled segment would be ~30 per cent of the market, during this period.
erosion in these categories would not substantially change the overall picture. Back-up analysis: Providing below are some highlights of the market
analysis that IMS has conducted internally on the overall impact of NLEM (without DPCO 95) on Medicines (Formulations).
Formulation Listed in NLEM
Original R e v i s e d Value Value Erosion Value Value Erosion % on NLEM
Source: TSA MARCH’13 MAT
` in Crs
` in Crs
` in Crs
%
Grand Total
13033.3
11436.6
1596.7
12%
AMOXICILLIN TRIHYDRATE + CLAVULANIC ACID POTASSIUM SALT Tablets 625mg
637.9
539.8
98.1
15%
Atorvastatin Tablets 10 mg
364.6
310.3
54.3
15%
Notes: • From internal analysis based on IMS Health’s Total Sales Audit, March 2013, we estimate that the contribution from these medicines (~` 13,000 Crs), to the Retail Indian Pharmaceutical market (` 72,762 Crs) is approx ~18 per cent.
Ciprofloxacin Hydrochloride Tablets 500 mg
230.8
179.1
51.8
22%
Omeprazole Capsules 20 mg
212.5
166.0
46.5
22%
Azithromycin Tablets 500mg
300.9
254.5
46.4
15%
Povidone Iodine Ointment 5%
105.8
65.6
40.2
38%
Premix Insulin 30:70 injection Injection 40IU/ml-SR/CR/XR
360.6
323.9
36.7
10%
•
Povidone Iodine Solution 5%
84.2
49.9
34.3
41%
Levothyroxine Tablets 50μg 37%
81.9
51.3
30.6
37%
Hepatitis B vaccine Injection
68.5
39.4
29.2
43%
Tetanus Toxoid Injection
78.7
50.3
28.4
36%
Folic Acid Tablets 5 mg
100.7
72.4
28.3
28%
Some of the medicine (like high-end oncology/hospital products) listed under NLEM do not have adequate representation in our sales audits and are consequently excluded from this analysis. The resultant impact though of price
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Interview 24-26.indd 26
Pharma Bio World
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Does Antithrombin III Block the Action of a Monoclonal Anti-thrombin Antibody? Composition-gradient multi-angle light scattering (CG-MALS) quantifies the affinity and stoichiometry of equilibrium proteinprotein interactions in solution. 1,2 In previous studies, CG-MALS was applied to characterise the equilibrium between human thrombin-α and an anti-thrombin antibody 3 as well as the irreversible association of thrombin-α with antithrombin III. 4 T h is a r t i c l e e x t ends the technique to probe the recognition of the bound thrombin-antithrombin complex by the s a me a n t i body.
M
ulti-angle light scattering (MALS) is a powerful tool for characterising biomolecules and their interactions. Previous studies have described how composition gradient MALS (CG-MALS) quantified the equilibrium interaction between human thrombin-α and an anti-thrombin antibody, revealing the equilibrium dissociation constant, KD = 8.8 nM, and the expected 2:1 stoichiometry. 3 Another study calculated the second order association rate constant for the covalent binding of thrombin to antithrombin III using time-dependent MALS (TD-MALS). 4 This article probes the interactions between three proteins: human thrombin-α (Thr), antithrombin III (AT), and an anti-throm¬bin monoclonal antibody to evaluate whether the antibody recognises AT-inactivated Thr. Materials and Methods Reagents and Instrumentation Human thrombin-α (Thr), human antithrombin III (AT), and mouse monoclonal anti-human thrombin antibody (Ab) were purchased from Haematologic Technologies, Inc. All experiments were
performed with phosphate buffered saline (PBS; 137 mM NaCl, 2.7 mM KCl, 8.1 mM Na 2HPO 4, 1.76 mM KH 2PO 4, pH 7.4). CG-MALS experiments were performed with a modular system (Figure 1) comprising a composition gradient system (Calypso II, Wyatt Technology Corporation) to prepare and deliver protein solutions of varying composition, a MALS detector (DAWN HELEOS, Wyatt) and an online UV/ Vis concentration detector (2487, Waters Corporation). Inline filter membranes with 0.1-μm pore size were installed in the Calypso for sample and buffer filtration. The Calypso software was used to design and control the measurements, acquire and then analyse the data. Size exclusion chromatography (SEC) was performed using a 300 Å pore column (030S5 column, Wyatt), installed on an HPLC system including autosampler (Model 1200, Agilent Technologies). The separation between the covalent Thr-AT complex, Thr and AT monomers was confirmed by SEC coupled with Multi-Angle Light Scattering (SEC-MALS) analysis using a UV detector (Agilent 1200 series),
Sophia Kenrick Wyatt Technology Corporation
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Figure 1: Hardware setup for investigating binding of Ab to Thr-AT complex.
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A powerful set of first-principles, robust techniques makes MALS unique among biophysical characterisation technologies.
DAWN HELEOS, and an online differential refractometer (Optilab T-rEX, Wyatt). Determination of Three-Component Binding In the initial test of Ab binding to bound Thr-AT complex, CG-MALS experiments exposed Ab solution to an unfractionated mixture of Thr, AT, and Thr-AT complex, as follows. Thr and AT were diluted to stock concentrations of 24 μg/mL and 80 μg/mL, respectively, in PBS, and each solution was filtered to 0.02 μm.
Equal volumes of filtered stock solution were combined and allowed to incubate at room temperature for ~2 hr with gentle shaking. Ab was diluted to 22 μg/mL in PBS and filtered to 0.02 μm. The composition gradient consisted of six injections of premixed AT-Thr solution at constant concentration of 25 μg/mL and Ab concentrations from 0 to 8 μg/mL. The increase in measured weight-average molar mass values upon mixing AT-Thr and Ab provided a qualitative indication o f r e c o g n i t i o n o f t h e b o u n d T h r - AT complex by Ab. To quantify the affinity of the Abcomplex binding, a second composition
gradient was performed with multiple compositions of Ab and purified Thr-AT complex. To obtain purified complexes, Thr and AT were diluted to 2 mg/mL each in PBS, mixed at a 1:1 ratio, and allowed to incubate at room temperature 0.5-1 h. Pre-mixed aliquots of 0.1 mL were injected onto an SEC column, and fractions of bound Thr-AT complex were collected at the outlet of the UV detector. Multiple injections were performed and the fractions pooled and filtered to 0.1 μm, with a final purified Thr-AT concentration of ~70 μg/mL. Ab was diluted to 15 μg/mL in PBS and filtered to 0.02 μm. The affinity and stoichiometry of the interaction between Thr-AT and Ab was quantified with a single crossover gradient consisting of eight injections. Results and Discussion The ability of Ab to retain binding activity for the Thr-AT complex was assessed and measured with CG-MALS. Interaction of Ab with unpurified Thr-AT complex In a preliminary experiment, AT and Thr were pre-mixed and the reaction was
Figure 2a: LS and concentration data for a composition gradient with constant concentration of unfractionated Thr, AT, and Thr-AT complex (25 μg/mL total protein) and varying concentrations of Ab.
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allowed to come to completion before loading the unfractionated solution on the Calypso and performing a crossover gradient with this multi-species solution and Ab. Al¬though some degree of binding was evident (Figure 2a), the weight-average molar mass measured by light scattering was significantly less than expected for an interaction between Ab and pure Thr-AT complex assuming 2:1 stoichiometry and KD of 9 nM, the affinity previously measured for Ab binding pure Thr 1 (Figure 2b, green triangles). Previous experiments had shown that ~23 per cent of the Thr was incompetent to bind AT covalently. 4 Hence the observed magnitude of interaction could be explained in two ways: 1) Ab bound the Thr-AT complex with decreased affinity compared to free Thr; 2) Ab did not bind Thr-AT complex, but did form complexes with free Thr in solution. Figure 2 compares the measured Mw with that calculated for Ab binding just this free Thr with affinity KD = 9 nM (blue X symbols). This experiment did not provide sufficient information to discriminate between the two cases. Interaction of Ab with purified Thr-AT complex In order to further refine the analysis, bound Thr-AT complex was separated from unbound Thr and AT via SEC. The fraction of Thr that is incompetent for binding to AT is evident as a secondary peak in the SEC chromatogram of the pre-mixed
Figure 2b: Equilibrium Mw for experiment depicted at left indicated complex formation was occurring but could not differentiate between Thr-AT binding to Ab with decreased affinity, and Ab binding free Thr in solution.
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Figure 3a: Best fit of LS and concentration data for crossover gradient with purified Thr-AT complex and Ab indicates 1:2 (Thr-AT complex):(Ab) stoichiometry with decreased affinity compared to Thr:Ab alone.
solution. After collecting the appropriate peak, an aliquot was re-applied to the column to confirm that no dissociation had occurred and that contamination by free Thr was negligible. A CG-MALS experiment, consisting of a single crossover gradient with Ab and purified Thr-AT complex, revealed complex formation with the expected 1:2 stoichiometry (Figure 3). Since AT was covalently bound to the Thr active site, this location was inaccessible to the Ab, indicating the antibody recognises an epitope on thrombin other than the active site. Previous binding assays also support this assertion. Analysis of the interaction between the antibody and purified thrombin indicates no incompetent fraction of Thr, suggesting that the Ab-binding epitope is always accessible and functional. 3 On the other hand, analysis of the covalent interaction of AT with Thr indicates that ~23 per cent of Thr presented an active site that was incompetent – ie, either not accessible or not properly folded - for binding AT. 4 Taken together, these data confirm that the antibody binds thrombin away from the active site. Although binding of the antibody to the Thr-AT complex is evident, the measured affinity of the antibody for the Thr-AT complex, KD = 250 nM, is ~28x decreased with respect to the affinity for pure Thr. 32 July 2013
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Figure 3b: Molar composition of complexes formed; the molar compositions of unbound Ab and AT-Thr complex have been left off for clarity.
This may indicate that AT imparts some steric hindrance for antibody-binding. Alternatively, the binding of Thr to AT may lock the enzyme in an inactive conformation 5 which has lower affinity for the antibody than the native or allosterically activated Thr.
2. 3.
Conclusion A powerful s et of firs t-princ iples , robust techniques makes MALS unique among biophysical characterisation technologies. SEC-MALS confirmed the irreversible binding of AT and Thr during separation of the purified complex for further characterisation. CG-MALS quantified the affinity and stoichiometry of the multivalent, equilibrium interaction between Ab and the Thr-AT complex, proving recognition of AT-inactivated thrombin by the antibody (but with weaker affinity relative to pure thrombin). TDMALS previously analysed the kinetics of irreversible AT-Thr binding. In combination, these techniques constitute a versatile toolkit for probing complementary aspects of macromolecular interactions without labelling or immobilisation.
4.
5.
10.5772/37240. (http://www.intechopen.com/ books/protein-interactions/characterizationof-protein-protein-interactions-via-staticand-dynamic-light-scattering) Some, D. Biophys. Rev. 5(2), 147-158 (June 2013). doi: 10.1007/s12551-013-0107-1 “Measuring the Interaction Between Thrombin-α and an Anti-Thrombin Antibody.” Wyatt Technology Corp. Published 7 Jan 2013. (http://www.wyatt.com/files/literature/ Calypso-antithrombinantibody.pdf) “Determining the Kinetics of Covalent Thrombin-Antithrombin Association.” Wyatt Technology Corp. Published 7 Jan 2013. ( h t t p : / / w w w. w y a t t . c o m / f i l e s / l i t e r a t u r e / Calypso_covalentantithrombin.pdf) Gandhi, P. S., et al. Proc. Natl. Acad. Sci. 105(6), 1832-1837 (February 2008).
Contact: skenrick@wyatt.com
References 1. Some, D. and Kenrick, S. (2012). Characterization of Protein-Protein Interactions via Static and Dynamic Light Scattering. In Protein Interactions, Cai, J. and Wang, R.E. (Ed.), InTech, doi: Pharma Bio World
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Stem Cell Transplantation from Haplo-identical Donors
Dr L Gerez Project Manager Kiadis Pharma
Dr M Rüdiger CEO Kiadis Pharma
Prof Dr Denis-Claude Roy Scientific Director of Research Hospital Maisonneuve-Rosemont
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F
or patients suffering from high risk hematological malignancies and who do not respond to conventional therapies, Hematopoietic Stem Cell Transplantation (HSCT) is currently the only possibility to achieve cure. To reduce transplant-related complications and increase the likelihood of survival for patients in need of an HSCT, the best strategy is to find an HLA-matched donor to perform such a transplant. Currently, an HLA-matched sibling a donor can only be found for approximately 25 per cent of the patients, and, as family sizes are steadily decreasing in industrialised countries, this number may even drop over the coming years. For patients who cannot find an HLA-matched sibling donor, the second preferred option will be a Matched Unrelated Donor (MUD). The probability of finding a suitable MUD varies quite significantly according to HLAtyping and ranges from 20-80 per cent of the occidentals but drops to only 10 per cent of most ethnic minorities. Moreover, the search to find such a donor can take several months (up to 4 months); time lost which may be critical for the health of thesepatients who are at high risk of relapse. To be able to offer the possibility of an HSCT to all patients in a timely manner, additional alternatives are being developed, such as the use of Umbilical Cord Blood (UCB) and haplo-identical transplantation from haplo-identical donors (family members sharing a HLA-haplotype). UCB has the advantage of allowing greater HLA-antigen mismatching than MUD transplants, and affording shorter timelines in finding a suitable donor when compared
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to MUD. However, UCB transplantion has also its disadvantages, namely the low number of cells in the UCB graft results in delayed hematologic reconstitution and an increased risk of graft failure, especially in adult patients. Therefore, UCB transplantations are mainly performed in children and also result in better survival rates in children when compared to adults. Furthermore, rescue with Donor Lymphocyte Infusions (DLI) from the same donor for the management of disease relapse is not possible. Another option for patients in need of a transplant, for whom a suitable matched related or unrelated donor cannot be identified or not be found in a timely fashion, is the use of a transplant from a haplo-identical family member. This treatment option has the advantage of having a donor virtually always available as parents, children, and half-matched siblings can usually be identified for most patients. In addition, these family members are highly motivated, facilitate work-up procedures and can usually provide immediate access to their stem cells. The use of haplo-identical donors also gives prompt access to DLI in instances where the patient needs additional cells to fight recurring malignancy. Initial haplo-identical transplantations resulted in poor outcome due to graft failure, severe GvHD and TRM. Lately, the haplo-identical transplant procedure has become feasible through the development of methods to remove donor T-cells from the graft, in order to reduce the risk of GvHD. T cell depletion can be done either using immunomagnetic
“
To date Haemopoietic StemCell Transplantation (HSCT) is not the first line of treatment due its significant TransplantRelated Mortality (TRM) most frequently attributable to acute Graft versus Host Disease (GvHD), infections and other toxic complications. This article explores the opportunity to receive stem cell transplantation from a family member to provide rapid and potent protection minimising post transplant risks.
The haplo-identical transplant procedure has become feasible through the development of methods to remove donor T-cells from the graft, in order to reduce the risk of GvHD. Pharma Bio World
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positive selection of CD34+ cells or by removing T and B cells (CD3+/CD19+ cells) with anti-CD3 and anti-CD19 antibodies, the first of the two approaches being more commonly used. Mega doses of T-cell depleted (CD34+ enriched) Hematopoietic Stem Cells (HSCs) from haplo-identical family donors overcome engraftment problems and ensure rapid hematologic reconstitution. However, although such haplo-identical transplants are typical for avoiding refractory GVHD, the downside of this approach is that patients remain severely immune compromised for one year or more with a high risk of life-threatening complications resulting in TRM and low Overall Survival (OS). Several recent developments aim at improving the outcome of haploidentical HSCT. These advances will provide patients with the advantages of immediate/quick donor availability and offer access to more than one donor in many instances, making possible the selection of the best donor on the basis of HLA matching, age, sex and infectious disease status. In addition, solving or reducing the problems associated with haplo-identical transplantations will enable patients to take advantage to benefits of haplo-donor transplantation such as the rapid engraftment afforded by the high number of stem cells infused, and will increase the probability of survival for patients suffering from hematological malignancies.
of additional cells. All these are important factors impacting the outcome of HSCT and it is often a combination of these factors which will determine the success of a haplo-identical HSCT. Some of the new developments are highlighted below. T cell replete haplo-identical transplantation Strategies infusing T cell-replete full haplotype mismatched HSCT in combination with GvHD prophylaxis such as grafts primed with granulocyte colony stimulating factor (G-CSF), post transplantation rapamycin or high dose cyclophosphamide in combination with other immune suppressive agents are being investigated. Selection of the donors Selection of the donor for donor-versusrecipient NK cell reactivity is also under study to promote anti-leukemia activity without causing GvHD. Additional therapy post T-cell depleted (CD34+ selected) HSCT Addition of regulatory T cells (Tregs) Tregs suppress immune reactivity and help maintain tolerance to self-antigens and could therefore suppress lethal GvHD. Tregs are being infused prior to haploidentical HSCT in order to decrease the risk of severe GvHD.
Developments in Haplo-identical HSCT
Addition of anti-pathogen specific cells
Different aspects of the haplo-identical transplantation under investigation are the nature of the conditioning regimen, the composition of the graft, and the infusion
Since patients after a T-cell depleted HSCT remain immunocompromised for a long time and as a consequence are at high risk of opportunistic infections, the
Normal cell Alloreactive cell TH9402
Donor lymphocyte graft
Light
Accumulation of TH9402 in alloreactive cells
Apoptosis of alloreactive cells after light exposure
In Vitro Depletion of Host Alloreactive Cells from Donor Lymphocyte Graft
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Clean donor lymphocytes graft
infusion of specific anti-pathogen T cells lines offer a cellular approach to fight specific offending infectious agents. Selectively allodepleted T cells Ex vivo depletion of alloreactive T cells has been performed using anti-CD25 immunotoxins to specifically eliminate donor T cells activated ex vivo against patient cells. However, CD25 expression on activated T cells is transient and also demonstrates some non-specificity as this antigen is also expressed on the surface of regulatory T cells which reduce alloreactivity. Infusion of donor lymphocytes post HSCT which are ex vivo manipulated to contain a suicide gene (eg, thymidine kinase gene or caspase gene) is being investigated. This suicide gene can be specifically activated upon occurrence of GvHD resulting in the killing of these cells. Another novel approach for the ex vivo depletion of alloreactive T cells is the use of photodynamic treatment (PDT) in combination with a rhodamine derivative TH9402 which accumulates in activated T cells. The Principle of PDT Using TH9402 and its Clinical Application in Haplo-identical Transplantation TH9402 and depletion of host alloreactive T cells from donor T lymphocytes preparations TH9402 is a photosensitiser which is structurally similar to rhodamine. TH9402 enters all cells and preferentially localises to the mitochondria. After internalisation TH9402 is extruded from the intracellular milieu through P-glycoprotein (Pgp) active transport. Pgp is the product of the Multi-Drug-Resistance-1 (MDR-1) gene, which is, amongst others, expressed in T lymphocytes. Most interestingly, Pgp becomes inactivated upon T cell activation. As a consequence activated T lymphocytes fail to extrude TH9402. Taking advantage of the functional inhibition of Pgp on the surface of activated T cells, these cells can specifically be eliminated ex vivo with Pharma Bio World
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the use of TH9402 and visible light since intracellular accumulation of TH9402 renders these cells sensitive to visible light. This principle is being used to specifically eliminate ex vivo host alloreactive T cells from donor lymphocytes; which are the cells responsible for causing GvHD. The main steps in the manufacturing of these of cells can be summarised as follows: - Collection of peripheral blood mononuclear cells PBMC: Donor and patient PBMC are collected by apheresis, followed by enrichment of mononuclear cells using densitygradient centrifugation. - Mixed Lymphocyte Reaction (MLR): To induce an ex vivo alloreactive response of donor cells against patient (host) antigens, donor PBMCs are co-cultured with 50 Gy irradiated patient PBMC in a MLR. - Photodynamic therapy (PDT): At the end of the incubation period of the MLR the cells are incubated with TH9402, followed by an extrusion period. The TH9402 which is taken up by all cells is extruded from resting cells but fails to extrude from donor cells that are host alloreactive cells. At the end of the extrusion period, cells are exposed to visible light, killing those cells which have retained TH9402 and actually represent host alloreactive cells. Using this approach, resting T cells, which consist of cells that can recognise and fight infectious agents and malignant cells, are preserved, while alloreactive cells which can induce GvHD are removed. The safety and efficacy of the above method has been Haploidentical donor Patient
studied in non-clinical studies both in vitro as well as in vivo before initiating the first study in man. The main safety concern of infused T cells is the induction of GvHD due to the large amount of cells infused. Therefore, GvHD is diligently monitored in these studies. Safety and efficacy of host allodepleted cells Preparation of T lymphocytes depleted of host alloreactive cells was tested in vitro using murine cells as well as in vivo in a murine transplantation model. Spleen cells from two different mouse strains were used in these studies, one being the host and the other the recipient. Treatment of the donor cells with TH9402 and PDT after an incubation period in the presence of host cells inhibited anti-host responses by 87 per cent as measured in vitro in a Cytotoxic T-Lymphocyte (CTL) assay, while anti-leukemic responses were preserved (inhibition for 21 per cent only). Infusion of these PDT treated cells in host mice resulted in their survival for more than 100 days while infusion of non treated cells in these mice resulted in the development of severe GvHD and death of all animals within 30 days. These results confirmed the removal of host alloreactive cells using PDT. To study the specificity of this depletion, untreated and PDT treated cells were infused in a third mouse strain (third party response) and in mice inoculated with BCL1 tumor cells. Infusion of both untreated and PDT treated cells in third party mice resulted in the development of GvHD and death of all mice, confirming Patient
Patient
High-dose chemo/radio
Immune reconstitution without (acute) GvHD
Stem cell transplant (CD34 selected graft)
Mix lymphocyte grafts
Infusion TH9402
Light (TheraluxÂŽ )
Alloreactive cells TH9402 selectively Destroyed alloreactive T-cells incorporated into alloreactive T-cells
T-cells depleted of alloreactive cells
Clinical Schema of Infusion of Donor T Lymphocytes from which the Host Alloreactive T Cells have been Depleted
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that PDT exposed cells retain the ability to recognise foreign antigen (not present in the MLR cell mixture). Furthermore, treatment of transplanted mice that were inoculated with BCL1 tumor cells with these PDT treated cells allowed 90 per cent of the recipients to survive more than 100 days without detectable tumor cells or GvHD. In contrast, BCL1 cells were detected in the bone marrow of all mice not receiving any additional cells, killing half of them within 40 days. Mice treated with non-PDT treated cells developed GvHD, with 100 per cent mortality by 50 days. Ex vivo PDT treatment after allostimulation was also tested in vitro on blood from healthy human volunteers. TH9402 was found to be preferentially retained by activated T-cells (both CD4+ and CD8+). When exposed to visible light, these activated T-cells were selectively eliminated while the capacity of quiescent T-cells to respond to third-party cells and pathogens was preserved. These treatment conditions also spared regulatory T-cells cells, which likely confer protection against GvHD.From the results above, we can conclude that the use of TH9402 and PDT for the depletion of host alloreactive cells results in specific depletion of donor cells that are host alloreactive while preserving third party and anti-tumor responses. Safety testing showed a favorable safety profile supporting initiation of clinical studies. The first in man trial was initiated in 2005 and last patient enrolled in this study recently completed the five year follow up period. Currently, data from this study are being collected for analysis and final results will become available later this year. Interim data supported the initiation of a follow up study as part of the clinical development programme. The main objectives of the clinical development programme are to demonstrate that infusion of donor T lymphocytes depleted of host alloreactive cells using TH9402 and PDT after a haploidentical transplantation: - is safe not resulting in grade III/IV GvHD - reduces transplant-related mortality due to GvHD and infections and improves the rate of overall survival. Contact: l.gerez@kiadis.com Pharma Bio World
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Recombinant Human Albumin as a Means to Produce Stable Biologic Formulations Without the application of a half-life extension technology, the biological drugs will require frequent administration, which can lead to a low therapeutic index and ultimately poor patient compliance. The industry looks to find new ways of treating chronic conditions such as diabetes, shifts in dosing paradigms from once daily to weekly and even monthly which provide significant benefits to the patient.
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significant challenge in the development of biological drugs is their characteristically short half-lives. Despite the wide range of available oral medications, many patients fail to achieve appropriate glycaemic control and ultimately require the introduction of injectable insulin.
demands on labelling etc. Albumin is a widely used solution which offers ways to handle these challenges.
A common feature in the advances in dosing regimen made by Liraglutide (shortacting), Albiglutide and CJC-1134 (longacting) is the utilisation of the extended plasma half-life of human serum albumin to achieve an extended therapeutic half-life.
Albumin can also be used as nanoparticle delivery system for poorly soluble drugs, eg, nab particles (Abraxane). Also, albumin can be used as a drug delivery platform for half-life extension for peptides, proteins, GLP-1 and interferon alpha.
The article discusses the application of human serum albumin as a halflife extension technology for GLP-1 therapeutics, and how further developments in recombinant human albumin technology may further change the dosing paradigm.
In the area of small molecule targeting, a l b u m i n f i n d s e ff e c t i v e u s e f o r INNO-206 doxorubicin and methotrexate and in biomaterials it works in wound sealant applications and medical device coating.
Albumin As a Pharmaceutical and Device Ingredient Manufacturers of vaccines in Asia face challenges as markets are expanding with larger populations needing high quality drugs and authorities setting new
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For example, Albumin serves as a stabiliser for vaccine and protein formulations where it reduces non-specific adsorption, antioxidant and protein aggregation.
The Challenges of Using Derived Human Serum
Plasma
For pharmaceutical manufacturers, albumin offers a number of reasons to be used as a key ingredient. It is widely recognised that using plasma derived human serum also holds significant safety and quality risks
Figure 1: Hypothetical model based on knowledge of IgG recycling. The neonatal Fc receptor (FcRn) functions to protect albumin from degradation resulting in prolonged half-life.
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Depending on specific drug delivery requirements, both conjugation and fusion technology can be used with the half-life extension technology.
for producers as well as end users. The challenges of contamination with viruses and TSEs are well known, and at the same time there is regulatory pressure to remove products from pharmaceutical formulations where possible. In 2012 the US FDA moved to require drug products made using plasma derivatives to have a warning label outlining risks of disease transmission allowing the potential for significant batch to batch variability. This requirement also stands for imported pharmaceutical products and the ingredients used in them. Also, supply of plasma derived proteins can be variable which again means a risk of product recall due to infective agents, or perceived risk.
while retaining efficiency. The technology can increase a protein’s half-life from minutes to hours, and hours to days. As a result, it can be used to flexibly control the half-life of the drug so that it stays for longer or shorter periods in the human body, depending on what it is being used for. This flexibility to extend or reduce the half-life of proteins allows drug manufacturers to improve treatment regimes and create novel drugs tailored to the specific needs of patients suffering from chronic or acute conditions, such as diabetes, hemophilia and neutropenia. As there is still only a small number of biologic drugs on the market, companies are looking to adjust and develop those that are available to them.
Industry Changing Advantages The latest advancements in half-life extension technology have been specifically developed to allow users to flexibly tune the pharmacokinetics of a particular target protein or peptide
The technology will allow manufacturers to establish a niche position in the market with more innovative and flexible products. On both a commercial and patient-centric level, the innovation will offer companies a definite competitive advantage due to
Genetic Fusion
Conjugation
Contiguous cDNA encoding target drug plus albumin produces a single protein
Chemically modifies drug to allow covalent attachment to albumin molecules
Flexible options • N- and/or C-terminal • Combinations, linker molecules
Lysine, tyrosine, free thiol (SH) • Free thiolin albumin is the most widely used conjugation route • Specifically reactive with maleimide groups
Applicable to amino acid based products Applicable to complete drug pipeline • Peptides, proteins, antibody fragments • Small molecules, large molecules, nucleic acids Compatible with yeast and mammalian host expression systems
No expression system required
Fusion manufactured at one time and in one host
Each component is manufactured separately
Homogeneous final product
Heterogeneous product or site specific conjugation to produce homogenous product
No additional post-manufacturing costs
Re-purification and additional postmanufacturing costs involved
Table 1: Comparison of albumin fusion strategies. Conjugations v/s Genetic fusion.
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its ability to improve the lives of patients suffering from chronic illnesses. The technology could lead to lower and less frequent dosage levels for patients who need to take regular medication, resulting in increased patient compliance and the possibility for patients to administer their own drugs. Drug Delivery Strategies Depending on specific drug delivery requirements, both conjugation and fusion technology can be used with the halflife extension technology. Table 1 briefly outlines the main features of conjugation and fusion technology. Lysine, tyrosine and the free thiol residues of the albumin molecule are used for chemical conjugation to the drug product with the free thiol at position 34 of albumin being the most widely used conjugation route. This approach is particularly useful for peptides containing maleimide groups, which specifically react with the free thiol, allowing for the formation of a stable thioether bond between albumin and the peptide. Alternatively, proteins can be genetically fused to the N or C terminus or even to both ends of the albumin variant. Using a contiguous cDNA of the target protein or peptide with DNA encoding the albumin variant of choice allows the generation of protein fusions exhibiting the required binding characteristics. A yeast expression system provides a high quality, consistent and reliable supply of the protein of interest when a genetic fusion is applied. To test that the albumin variants maintain their modified FcRn binding affinity when fused to a protein or peptide, a range of albumin protein fusions have been generated. The variants chosen displayed a range of binding affinities from low affinity albumins (HSA K500A) to albumins with a 15-fold increase in receptor binding (HSA K573P). Antibody fragments fused at the C-terminus, N-terminus or bivalent forms as well as fusions to small or large peptides were compared to unfused albumin variants for FcRn affinity by SPR using Pharma Bio World
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Figure 2: Albumin variants selected for their different FcRn receptor affinities were genetically fused to a variety of proteins and peptide. Each fusion was tested was found to maintain similar affinity for FcRn receptor when compared to the unfused variant.
The flexibility of the technology enables proteins and peptides to be bound at either the C- or N-terminus or both, generating fusion molecules with monovalent, bivalent or bispecific affinity. In addition to proteinor peptide-based drugs, the technology also serves as a delivery vehicle for small molecules, providing a broad scope of usability. The technology also enables construction of albumin variants with altered binding affinity to FcRn, making it possible to modulate half-life extension of fused target proteins, offering
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drug developers and control.
enhanced
flexibility
Conclusion Over recent years a range of half-life extension platforms have been developed in response to growing market demand for drugs that work more effectively. However, these platforms are often developed using synthetic materials and are unable to increase and decrease the drug halflife according to the needs of a specific medical condition. Developments in half-life extension technology offer a broadly applicable and easily accessed platform that enables drug manufacturers to differentiate their products from competitive therapies
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Biocore technology (Figure 2). All albumin fusions tested showed distinct differences in receptor affinity correlating to their unfused variant. Each fusion demonstrated the same changes in ScRn binding as the control rHSA variant.
For the first time, the relationship between albumin and its receptor has been resolved, resulting in a new technology that has the potential to revolutionise the healthcare industry.
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by tuning the half-life according to therapeutic requirements. For the first time, the relationship between albumin and its receptor has been resolved, resulting in a new technology that has the potential to revolutionise the healthcare industry. Both small and large pharmaceutical companies started using the technology following its launch to market, particularly in the fields of diabetes, hemophilia and neutropenia. The shift towards the use of this new technology has been driven by the fact that it is based on albumin, a natural non-immunogenic plasma protein which is already naturally present in the human body. As such it offers drug developers a natural, low-cost and safe molecule, in addition to complete control and flexibility of their drug design. By offering the potential to reduce the dosing frequency of a drug from days to weeks, the half-life extension tec hnology c an dramatic a lly imp r o v e patient quality of life. Contact: syke@novozymes.com Pharma Bio World
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Treating Pharma Effluents
Dr B V Sivakumar Chief Scientific Officer Enaltec Labs
46 July 2013
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harmaceutical industries are widely distributed and there is a consistent increase in the use of the chemicals for manufacturing of various drugs which are driven by futuristic drug developments. Thereby, manufacturing of these drugs leads to effluent generation which introduces concerns for environmental contamination. Proper channelling and treatment processes are mandatory to get rid of the adverse effect of these effluents on environment. Many countries had proper sewage systems in place for the effluents generated from industries, which is as early as in late 19 th and early 20 th century. The effluent treatment processes were basically by physical, chemical and thermal methods which were not cost-effective, and were less efficient.As industries scale through, their production strength and the types of drugs being dealt, increase. Effluent Treatment Processes in Indian Pharmaceutical Industry Indian Pharmaceutical industries have been in a boom from the last three decades where the growth rate is indicative for the fact that the future seems to be very challenging and profit-making opportunities. Though there is a substantial happening in Indian pharmaceuticals industry, due to extreme research activities for potent drugs and full-fledged production to meet target requirements; various direct as well as indirect impacts are observed. Out of which, impact on environment is one of the primary concerns. Regulations in India to protect environment from various effluent contaminants are not adequate to
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control the Pharmaceutical manufactures. Environment conscious as well as auditable organisation in-line with GMP compliances follow conventional mode of effluent treatment processes. Conventionally, Effluent Treatment Process (ETP) includes a series of treatments, such as Pretreatment, Primary, Secondary, and Tertiary Treatments. Pretreatment was previously a part of Primary treatment process later made a separate process where a bar screen, usually an automated mechanically raked bar screen or a manually cleaned screen is used to remove large objects. This is performed not to block pipes or moving parts of the treatment plants. During the primary treatment process, pretreated effluent is passed through primary sedimentation tanks where settling of sludge and skimming off of grease and oil occurs. Effluents are neutralised and flash mixed to start coagulation and sedimentation which are later separated by settling tanks. Secondary treatments are employed to substantially degrade the biological content of the effluent. Contamination from short chain organic molecules, sugars, fats are suitably removed during this process. Secondary treatment involves majorly attached-growth and suspended-growth systems. Attached-growth system has been further developed into MBBR (Moving Bed Bio-film Reactors).Suspended-growth system provides higher removal rates as compared to the attached-growth system. In recent times, secondary treatments involve aerobic-granular sludge technique,
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Effluents generated from manufacturing operations, quality control, canteen, warehouse, engineering, and miscellaneous such as floor washes, equipment cleanings, utilities pose a challenge for the treatment processes to be adopted due to the broad categories of various effluents generated. In the recent times, the effluent treatment processes have evolved in many folds to tackle the adverse effects on environment caused due to effluents.
The ultimate goal of effluent treatment is the protection of the environment in a manner commensurate with public-health and socio-economic concerns. Pharma Bio World
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produce renewable energy. As the super critical water oxidation process is itself an exothermic process, the treatment process is auto thermal at very low levels of organic matter. The increasing attention, on Pharmaceutical residues as potential pollutants is due to the fact that they have similar physico-chemical behaviour like other harmful xenobiotics which are capable to produce adverse effects. Some pollutants have very long environmental half-lives and their continuous introductions to environment make them pseudo-persistent. Few self-governed organisations employ risk quotients of various pollutants to categorise and have better treatment processes.
soil bio-technologies, biological aerated filters, rotating biological contractors. Final step of the secondary treatment stage involves settling of biological floc or filter material through a secondary clarifier to produce effluent containing low levels of organic material and suspended matter. Tertiary treatment is carried out to provide a final treatment stage to further improve the effluent quality before it is discharged to the receiving environment, such as sea, river, lake or ground. ETP in Indian Pharmaceutical industry emphasises on Nutrient removal, Nitrogen and Phosphorus removal, addition of Disinfectant and Odor control etc before completing the treatment process. Regulations Processes
for
Effluent
Treatment
In India, effluent treatment processes in Pharmaceutical Industries are governed by either local pollution control agencies as well and central environmental ministry, where the representatives visit to observe and ensure the processes of effluent treatment and record the measures for the released effluents through several check points. Countries like USA, European countries and various other developed 48 ď‚ƒJuly 2013
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nations have their permanent effluent treatment systems for the society as well as mandatory processes for Pharmaceutical industries. Any non-compliance to the established norms leads to cancellation of license. Clean Water Act, established in USA in the year 1972, remarks one of the first steps towards controlling the parameters leading to environmental pollution. Pharmaceuticals come under this as they contribute towards the release of effluents to environment. Several guidelines were amended into the regulations to keep track and under control the release of wastes. Future of Effluent Treatment Processes As the progress continues for Pharmaceutical industries, the need for better effluent treatment systems has been felt for the future. Conventional methodologies for effluent treatment are getting slugged as the strength of industrial waste continues to increase which make them very difficult to breakdown. In recent time, super critical water oxidation processes are employed to have complete destruction of industrial wastes which are cost-effective alternatives to incineration and are energy recovery systems to
A novel approach of effluent treatment being followed is such that the process mimics the natural treatment process, though this process is very much confined to selective industries. Native bacterial populations act through this process by feeding up organic contaminants. Nature based environmental conditions such as predation or exposure to ultraviolet radiations is also processes occurring in the nature’s life cycle. Industries now-a-days employ various productive and cost-effective tertiary treatment processes such as reverse osmosis, dialysis, ion-exchange processes, chemical precipitations to have less to less pollutants in the release effluents to the environment. Conclusion Against the high cost conventional effluent treatment systems, there is an increasing need for low cost methods of treating effluents. So as to counteract this shortcoming and to preserve the high quality environment, a new concept has been practised called as Cleaner Production for effluent pollutant minimisation. The ultimate goal of effluent treatment is the protection of the environment in a manner commensurate with public-health and socio-economic concerns. Low cost methodologies which are very efficient to remove pollutant from the effluent are the need of the hour, which in turn shall ensure the safety, efficacy and quality of the treated effluent. Pharma Bio World
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Case Study: Productivity Hike Using Crushing and Grinding Line This is a case study of ACG Value Links where their partner Frewitt, the Switzerland-based expert for milling and handling of powders, helped with in crushing and grinding line for pre-processing Metformin.
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illions of people worldwide are affected with type 2 diabetes, also known as adult-onset diabetes. Physicians resort to prescribing blood sugar-lowering medications when dietary measures are no longer enough to treat the condition. An innovative producer of pharmaceutical products, and an esteemed customer of ACG Value Links’ partner Frewitt, manufactures medication for this particular kind of diabetes. And owing to a worldwide increase in the demand for blood sugar-lowering medications, the customer was compelled to increase its production capacities at various sites in Europe.
Director of Sales Frewitt S A
50 July 2013
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Solution
From its contract manufacturers, the customer acquires active pharmaceutical ingredients and adjuvants that are usually delivered to the production facility in 25 kg cartons with in liners. The active pharmaceutical ingredient is delivered in various particle sizes and sometimes in block form. It has poor flow properties and tends to form lumps, therefore requiring pre-processing before undergoing further processing (customer-specific process). Because the product cannot be used as delivered, it must undergo a suitable grinding and pre-processing, which is generally a complex procedure. Only after pre-processing, the active ingredients and adjuvants are ready to undergo the actual manufacturing process in the ideal powder state.
Frewitt participated in the evaluation of a new processing line for increasing capacity. The new pre-processing procedure could thus be validated based on preliminary experiments conducted with the newest generation of equipment. Frewitt then reengineered its DelumpWitt crusher and grinding line. Thanks to the DelumpWitt‘s compact construction and two-in-one process, only one, rather than two lines were required for the crushing and grinding process. Active pharmaceutical ingredients and adjuvants in powder and lump form are raised by a pallet lifting column onto a single line, where they are manually fed into the DelumpWitt hopper. The ground product then flows directly into a moveable container placed underneath. The scalemounted container can be loaded with all active ingredients and adjuvants in a single operation before its contents undergo the final blending cycle on a separate lifting column.
Current State
Results
The entire pre-processing line consists of three mechanical procedures – Crushing, Grinding and Blending. The block goods are delivered packaged on pallets. A lifting column raises them up to the infeed hopper of the platform-mounted crusher, where they are hand loaded. The pre-ground product is made to flow into a container placed under the discharge of the crusher. The
The customer highlighted the following advantages of the new DelumpWitt crusher and grinding line: • Up to 70 per cent increase in productivity. • Simplified process cut investments in the new line by approximately 30 per cent. • Compact construction with the new line taking up to 50 per cent less space. • Easy to handle and clean.
Initial Situation
Roy Housh
filled container is then placed on a second lifting column, where it is docked above a milling unit. The product is ground in the milling unit and then made to flow into the container positioned underneath. After other processing agents and adjuvants are added manually, the container is taken by another lifting column to the blender unit. Once the mechanical pre-processing is complete; the blended batch then undergoes further customer-specific processing.
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Pre-filled Syringes: Revolution in Dosage Delivery Trend 95 per cent of India’s pre-filled syringes demand is met t h r o u g h imports and their use is likely to increase considerably. Studies suggest that more than 50 drugs, including antithrombotic agents, vaccines, blood stimulants, interferons, and rheumatoid arthritis treatments, are now available in pre-filled syringe formats.
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re-filled syringes (PFS) are pre-measured single-dose ready-touse injectables for parenteral drug delivery. PFS are a simple, efficient and convenient way for dosage delivery. Tracing its history back to the early 80s, PFS currently are the preferred drug delivery device and there are over 50 types of drug pre-filled syringes available in the market and many more are in pipelines. Till recently, most injectable drugs were mainly supplied to end users in sterile vials and syringes. However, the growing use of biologics and biotechnology drugs, coupled with a staggering increase in the number of patients who self-administer drugs to treat chronic diseases, has forced drug manufacturers to reconsider the vial-and-syringe format, which is prone to dosing errors and low patient-compliance. Because of this, pre-filled syringes — single use, disposable syringes filled with a prescribed unit dose of medication — are rapidly replacing the traditional vial and syringe format to deliver protein-based drugs, sustained release formulations, and other parenteral medications.
There are two types of PFS available in the market, glass based PFS and plastic based PFS. Typically, pre-filled syringes are made of glass and use a conventional plungerbarrel delivery mechanism. These syringes come in a variety of sizes starting with the 0.5 ml to 10ml. Glass PFS has been the preferred as it is strong, chemically inert, dimensionally stable, and easy to sterilise. Further, it is transparent, which allows visible inspection of a dosage form before it is injected. In recent years, syringe manufacturers have introduced plastic pre-filled syringes, mainly in response to the possibility of breakage and plunger failures associated with glass PFS. Using syringe/vial for injection involves 10-12 steps whereas pre-fill involves two to three steps. So it minimises response time during emergency and increases patient compliance and reduces chances of administration errors. Benefits This revolutionary dosage delivery enhances safety of patients as well as
Zameer Agarwal Director Roselabs Bioscience Ltd
52 July 2013
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Pre-filled syringes require just 2-3 per cent overfilling of drug to be delivered as compared to vials which need to be overfilled by 10 to 25 per cent.
healthcare professionals and reduces risks of bacteriological contamination, misidentification and improper dosage delivery. PFS also offer assured sterility, reduce risk of injury and exposure to drug in addition to considerable reduction of medical waste. Because of such benefits, use of PFS is likely to increase considerably. Over 2.5 billion PFS were used in 2011 which is expected to cross 3.5 billion by 2015 and 6.83 billion by 2025. PFS are useful in emergency situations and busy hospitals as the process of transferring a drug from vials & ampoules is eliminated. Most healthcare professionals also prefer PFS to conventional syringes as it reduces the needle struck injuries drastically. As per WHO estimates, every year 3 million accidents occur because of needle stick. Such injuries can involve needles or other sharps contaminated with blood borne pathogens, such as HIV, HBV or HCV. All such accidents can be reduced drastically by using PFS as they are meant for single use and are immediately discarded after injecting the medication.
perspective, pre-filled syringes are easier to handle, store, and ship than vials. Prefilled syringes weigh less and take up less space than vials, so they cost less to ship. PFS occupy less shelf space at distributors and pharmacies, which makes them easier to store than vials, which can also help to reduce costs. Pharma IQ Report "Demand will also gain upward momentum as hospitals, outpatient facilities and other health care establishments adopt stricter safeguards to meet infection prevention standards,” said the report. Market experts estimate that growth of PFS has been over 50 per cent in last 5 years and the segment is expected to grow at over 10 per cent in years to come. With the increased use of biologics and the rise in number of injectable biotherapeutics, growth of PFS as effective dosage delivery system will surge. Further, as demand for pre-filled syringes is increasing it also offers contract manufacturers are taking advantage of this opportunity.
According to a recent iRAP report, PH-1 Nano-Enabled Packaging for the Pharmaceutical Industry—“Global demand for prefillable inhalers and pre-filled syringes will generate the fastest growth opportunities among all pharmaceutical packaging products, based on performance advantages in drug delivery and the introduction of new bioengineered medicines.” While glass remains the industry standard for pre-filled syringes, industry also seen the emergence of plastic pre-filled syringes. Development of this cyclic olefin polymers and copolymers (eg, COC, COP, and CZ) are “glasslike” in appearance; have low extractable, leachable, and protein surface adsorption properties; and are stable over wide pH ranges. Market for PFS According to Global Industry Analysts Inc, pre-filled syringes are finding increased use due to their ability to eliminate risk of cross-contamination, and other risks, such as that of drug counterfeiting and dosing error, that may occur with ampoules or vials. With its pre-dominant use in the US, Europe and Japan, pre-filled syringes with their numerous benefits, are expanding its base in developing countries such as India and China.
Healthcare reform, cost containment, and changing medical practices are also driving the uptake of pre-filled syringes. While pre-filled syringes offer many advantages to end users, they also offer a variety of benefits to drug makers. Along with other benefits it helps drug manufacturers with brand differentiation. Further, pre-filled syringes usually offer drug makers lower overall cost-perdosage-unit as compared with syringe and vial formats. This is because prefilled syringes require just 2-3 per cent overfilling of drug to be delivered as compared to vials which need to be overfilled by 10 to 25 per cent. From a logistical and supply chain management 54 July 2013
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Rapidly-expanding economy, increasing size of the Indian middle class and the aging population are growth triggers for pre-filled syringe in Indian market.
Reports indicate that, PFS command market size of over USD 50 billion – approximately 23 per cent of total injectables market. Notable players in the pre-filled syringe market (Surgical part only) include Becton, Dickinson and Co (BD), Vetter Pharma, SCHOTT, Abbott Laboratories, Ypsomed, Gerresheimer and McGlass. London-based business information company, Visiongain predicts world pre-filled syringe technology revenues will reach USD 3.9 billion in 2015, up from USD 2.7 billion in 2010 in its report ‘ Pre-Filled Syringes: World Market Outlook 2011-2021’. Experts feel that further development of the pre-filled syringe market will be dependent upon developments in syringe technologies and materials. Improvements to performance, product stability, convenience of use, and cost-effectiveness will stimulate increasing use of pre-filled syringes and related devices this decade.
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The Indian pre-filled syringe market, at present, is less than 1 per cent of world syringe market and 95 per cent of demand is imported. Hence it has huge potential for growth. Rapidly-expanding economy, increasing size of the Indian middle class and the aging population are growth triggers for PFS in Indian market. India also has the potential to become a hub for supply of injectable products. New Trends and Pre-Filled Syringes
Innovation
in
Innovation in pre-filled syringes and injection devices has been spurred by a demand for disposable medical supplies on a global scale. Visiongain expects total syringe market (disposable and reusable) could reach USD 11.8 billion by 2017, with much of that being stimulated by the pre-filled syringe.
Despite the commercial availability of a plethora of pre-filled syringe design options, many syringe manufacturers and drug delivery experts believe there is still plenty of room for innovation in the pre-filled syringe market. Microneedle transdermal patches and needleless auto injectors may represent promising areas of innovation. However, for the foreseeable future, it appears that conventional pre-filled syringe formats will remain the method of choice for self-administering biologics and other parenteral drugs. Reference 1) Visiongain is an independent business information provider for the Pharmaceutical, Telecom, Defence, Energy and Metals industries. 2) Pharma IQ, a division of IQPC, is an international online community focusing on providing pharmaceutical professionals with knowledge, information and articles. 3) iRAP (Innovative Research and Products, Inc provides market research and industry analysis on the following subjects including nanotechnology, biotechnology among others.
Contact: zameer@roselabsindia.com In recent years, there has been a shift from glass to plastic syringes, due to advances in materials construction and manufacturing processes.
Pharma Bio World
8/2/2013 6:36:29 PM
Hello India,
For your growing pharmaceutical and healthcare market, Sanner supports you with a new sales office in Pune, near Mumbai. Sanner is a German manufacturer for highquality plastic packaging of pharmaceutical, medical and healthcare products – ranging from standard to customer-specific solutions. Benefit from our high level of expertise in desiccant closures and plastic injection molding at a „Made in Germany“ standard and visit us at: www.sanner-group.com
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Work ing Towa r ds a Identification Solution The US Food and Drug Administration (FDA) has been pursuing the implementation of stringent measures for pharmaceutical companies to implement technology, that will enable medicines to be traced throughout the supply chain on a global scale. Serialisation methods improve traceability and transparency within the supply chain, providing increased confidence that only legitimate products are being taken to market. The pharmaceutical industry has a significant role to play in implementing the right technology into their processes, to protect the supply chain from counterfeit medicines.
St a nda r d is e d
C
ases of counterfeit products in the legitimate pharmaceutical supply chain have highlighted the need to establish more clearly and effectively the identity of each individual medicine pack. Counterfeit drugs represent a significant threat in emerging markets, such as Asia Pacific that are easier to penetrate and the demand for low cost medication is high. The supply chain is becoming increasingly complex with billions of pharmaceutical products being transported and sold globally each year in an increasingly fragmented supply chain. This has resulted in a lack of transparency and increased difficulties in providing a full genealogy of medicines in the market place. To tackle this issue effectively, there needs to be a united effort from the pharmaceutical industry, regulatory bodies, wholesalers and retailers to establish a standardised identification solution. A database where uniquely identifying bar codes on drug packaging can be verified at the point of dispensing would significantly improve the ability to track pharmaceutical products on a global basis. There is an urgent need to improve traceability within the supply chain. Serialisation technology provides the ideal solution to enhancing efficiency in the supply chain, reducing theft, counterfeit products and allowing manufacturers, distributors, retailers, pharmacies and end-users to ensure compliance with industry regulations. Drive to Establish Regulatory Compliance
Ian Parsonage Director, Global Serialisation Services PCI
58 ď‚ƒJuly 2013
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In order to sufficiently protect public health interests and the relationship of trust between patients and pharmaceutical suppliers, the entire production and supply chain needs to be closely regulated. The pharmaceutical industry operates on a global scale and regulatory compliance across multiple geographies is fundamental to ensuring that the supply chain remains safe and secure.
The lack of a standardised system or recognised industry standard for the identification and coding of pharmaceutical products has resulted in the development of coding systems that all differ in terms of the content of each code, through to its physical placement. The lack of a coherent approach to verifying scanned bar codes on drug packaging has undoubtedly contributed to the growing problem of pharmaceutical counterfeiting. Asia accounts for a significant share of the trade in counterfeit medicines and in 2009 the International Medical Products Anti-Counterfeiting Task Force (IMPACT) co-ordinated ‘Operation Storm 2’ in Asia and seized over 12 million pills of counterfeit medicines and medical products. Launched in 2006, IMPACT is committed to combating counterfeit drugs and has been working with international organisations, enforcement agencies, industry and nongovernmental organisations to improve detection capabilities and introduce measures such as secure, high-tech packaging and coding solutions. The World Health Organisation estimated in 2008 that 30 per cent of countries within Asia had either no drug regulation or an ineffective medicine regulatory authority. Although many Asian countries have increased their efforts to combat the issue of counterfeit drugs, the risk of penalties and prosecution remains inadequate and a concerted effort needs to be made to increase education and public awareness around the risks of counterfeit products. The strong drive within the US to establish a nationwide track and trace system throughout the pharmaceutical supply chain demonstrates the importance that is being placed on tackling the issue of counterfeit medicines. In June 2013, the House of Representatives approved legislation, HR 1919, which will introduce a national standard of tracing requirements and create Pharma Bio World
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a transparent process between the FDA and stakeholders to combat the issue of counterfeit drugs. The FDA has also recently announced plans that would require all drug manufacturers to have standard labelling and warning messages. This legislation will have a significant impact on the global pharmaceutical supply chain. Challenges Facing the Pharmaceutical Industry The regulatory changes taking place will have a significant impact at the manufacturing and quality control level and businesses will need to ensure they are compliant with standards throughout all their processes. Counterfeit drugs are estimated to cost between seven to ten per cent of global pharmaceutical market revenue and so there is a strong desire within the industry to implement track and trace technology to help overcome this issue. As well as being potentially life threatening to the patient, counterfeit medicines can damage a business’ reputation and many pharmaceutical companies cannot match the low cost competition, resulting in a loss of revenue, which would otherwise provide funding for further research and development. In addition, pharmaceutical companies must now also find cost effective ways of complying with legislative requirements. As is often the case with the implementation of many new technologies and techniques, there are concerns over the associated capital expenditure and installation of additional equipment throughout the supply chain and in particular, at the point of dispensation. In order for the system to be successful, it will be essential to establish who will be responsible for covering the cost of the new barcode readers for the endsupplier. If smaller independent retailers
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are unable to afford to put the necessary measures in place, the system will not be effective. There are also concerns over the potential disruption to existing production processes, as any time delays in production can result in pharmaceutical companies incurring significant costs. The Track and Trace Solution With industry guidelines stipulating the need for more stringent measures to combat falsified and counterfeit drugs, pharmaceutical companies are increasingly introducing track and trace technology into their production processes. Track and trace is a serialisation method that can help to protect against counterfeiting
The serialisation of pharmaceutical products and the ability to effectively track them is essential to the creation of a truly safe and secure supply chain.
60 July 2013
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and the falsification of medicines by authenticating, monitoring and controlling the flow of medicines throughout the supply chain. Serial numbers can be traced at various points throughout the supply chain which makes it easier to identify where counterfeit products have entered the chain and also allows for full traceability. Ultimately, the primary aim of the technology is to protect the pharmaceutical supply chain and guarantee patient safety. However, there are a considerable number of business and economic benefits that can be gained from the practice helping to overcome a number of challenges faced by pharmaceutical companies. Due to the risk counterfeit pharmaceutical products pose to patients, they can tarnish the reputation of a brand, leading to reduced revenue and market share. Serialisation techniques make it easier to identify counterfeits and help protect genuine pharmaceutical brands. In line with this, secure and traceable products are much more appealing to customers, which can help to create a competitive advantage. Pharma Bio World
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can be provided to meet a client’s specific needs and can be easily integrated to ensure minimum disruption to existing manufacturing lines. PCI has chosen the track and trace solution from Antares Vision to manage the delivery of serialisation at both line and site levels on a global basis. This system will merge information received from PCI’s customers with data held within its own ERP system to deliver the serialisation to the customer’s product. Serial activation and aggregation data can then be sent securely in B2B transactions to enable a customer’s system to prepare for the receipt of serialised product and then perform its onward distribution. Conclusion
Delivering a Secure Supply Chain In response to the challenges facing the pharmaceutical industry, companies such as Packaging Coordinators Inc (PCI) are working to provide secure packaging solutions to support their customers in fully complying with new international standards, to secure the supply chain against counterfeiters. A key priority for pharmaceutical companies is having absolute confidence that only safe products that are compliant with domestic and international packaging requirements are taken to market. Sophisticated security systems can be put in place to monitor product flow throughout the packaging process, from the receipt of incoming bulk product to storage, transfer, processing, and final shipment. The PCI serialisation system for example is an end-to-end, point-of-dispense identification solution which uses a unique identification code on each pack, generated and applied by the packer. The system uses data structures defined by GS1 in their “Global Traceability Standard for Healthcare” to create a ‘license plate’ or serial on each pack. This number, when combined with the Global Trade Item Number (GTIN) creates a globally 62 July 2013
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unique number. Each license plate also contains a 2D data matrix code together with the human readable data contained within, for example; serial number, GTIN, lot number and expiry date. Each pack can then be associated with its bundle and further with the shipping container and finally with the pallet with all of this aggregation information being stored and moved around the supply chain. The product verification process then compares the data held within the data matrix code, with a secure product record on a database shared between the supplier and the customer. This provides confirmation that the product record exists and matches the data held on the product itself, as well as checking that it has not been previously marked as ‘dispensed’ or that it does not contain any warning or advisory notes. This verification process would immediately alert the pharmacist if a packet containing the same number had been released into the supply chain. Track and trace solutions need to accommodate different manufacturing sites and technologies, regulatory regimes and product requirements. Flexible and customisable track and trace solutions
The threat of counterfeit and falsified medicines is a global issue and therefore requires a united global approach to tackle it effectively. The serialisation of pharmaceutical products and the ability to effectively track them is essential to the creation of a truly safe and secure supply chain. The formation of a unified, single-source, global database where scanned bar codes can be verified at the point of dispense is the crucial next step in the creation of true serialisation and supply chain security. The introduction of regulations requiring the implementation of a standardised track and trace system, combined with the commitment of pharmaceutical companies globally to the use of this technology will go a long way in creating a safe, secure and trustworthy supply chain. That is not to say that achieving a harmonised identification solution on a global scale will not represent a significant challenge, but once it has been effectively established, the benefits will be hugely significant. It is imperative that the pharmaceutical companies act now to overcome one of the most significant challenges facing the industry. Contact: info@pciservices.com Pharma Bio World
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Addressing Complex Needs of Pharmaceutical Stakeholders via Ultra-High-Barrier Thermoformed Packaging The pharmaceutical blister packaging is undergoing a period of change. Thermoform blister packaging has become the most prevalent packaging process, as it addresses many of the complexities inherent in worldwide product launches. It is now recognised that pack differentiation offers an ideal opportunity to create a sustainable competitive market advantage. This examines the strategic implications of packaging choice in the pharmaceutical industry and new trends in blister packaging.
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aunching a drug in today’s pharmaceutical environment is more demanding than ever before. The pathway to a successful launch has become more difficult as pharmaceutical companies face a variety of internal and external pressures. Beyond safety and efficacy Pharma companies have to demonstrate treatment effectiveness and improved outcomes of newly launched medicines versus next best alternatives already marketed. At the same time growing external cost pressures are adding to creating a much leaner pharma-internal environment geared to streamlining processes at the boundaries of Drug Discovery, Pharmaceutical Development and Pharmaceutical Operations. “Doing it right the first time!” and “Doing more with less!” have become the name of the game in many companies. In this context, packaging solutions that address multi-stakeholder needs holistically have gained growing importance. This holds true in particular for the packaging of oral solids – still the most preferred dosage form. The high global prevalence of blister packs as observed today is based on a unique combination of value creating features such as flexibility in pack design and processing. A Global Perspective In today’s globalised Pharma environment there are a host of challenges for brand owners around reaching the right patient groups with the right product offering that meets both the regional regulatory requirements but still matches with
Market Development Manager Europe Healthcare & Packaging, Honeywell Performance, Materials & Technologies
64 July 2013
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Dr Thomas Dries
users’ needs in a cultural context. With globalisation, supply chains are getting longer and more complex and logistic costs – both internally and externally – are growing. At the same time, there is a dramatic growth of product site transfers with involvement of countries located in hot and dry or hot and humid regions. Last – but not least – formulations such as Modified Release or solid dispersions are getting more sophisticated and complex and at the same time, dosage sizes are getting bigger. As a result more and more Pharma companies are looking for processing platforms that help to meet users' needs and reduce complexity (costs) whilst maintaining flexibility at all stages – internally and externally from a pack design perspective. Probably this explains why thermoformed blister packs have become the preferred choice even for products that need high and ultra-high moisture barrier protection. Globally, thermoform blister packaging has become the most prevalent packaging process, as it addresses many of the complexities inherent in worldwide product
Pharma companies are looking for processing platforms that help to meet users' needs and reduce complexity (costs) whilst maintaining flexibility at all stages. Pharma Bio World
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These involve reducing: • The need for multiple packaging lines, thereby delaying the need for additional manufacturing space. • Total packaging volume and pallet number resulting in savings of storage space, logistic costs and energy. • The need of additional storage and shelf space at wholesalers and pharmacies. Globalisation is also driving the need for better shelf life. More sophisticated drug formulations such as Modified Release and Solid Dispersions require high levels of moisture barrier protection. To address the key challenges as mentioned earlier there is a growing adoption of high and ultra-high thermoformable moisture barrier films such as Honeywell’s Aclar films. The use of these high-barrier thermoforming films increase the likelihood of achieving sufficient shelf life, even in the most severe climatic zones, allowing the pharmaceutical company to market its product globally on a thermoform platform. Additional global marketing needs, such as user-friendly packs that differentiate the brand, can also be addressed with the use of high barrier films. Proper color coding of the outer carton in combination with clear blister packaging films has proven to be helpful in the effort to prevent medication errors within and across brands. Keep it Simple In parallel with the previously mentioned trends is a movement toward smaller blister pack sizes. To further promote patient compliance, many pharmaceutical companies are looking at reducing the size of blister packs to match patients’ lifestyles without sacrificing product protection. Smaller pack sizes simplify life for patients; they can be concealed in a pocket or handbag and easily taken while on the go. The portability and discretion of a small pack improves the user’s experience, resulting in better patient compliance and more successful therapies. Pharma Bio World
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launches. As a result of highly efficient thermoform processes there are significant gains in “Space productivity” realised both internally and externally.
Proper color coding of the outer carton in combination with clear blister packaging films has proven to be helpful in the effort to prevent medication errors within and across brands.
Furthermore, reducing the size of blister packs can simplify pharmaceutical companies’ internal processes. There is no need to purchase new thermoforming equipment; minor machine adjustments allow the manufacturer to use existing thermoforming processes. By using high barrier thermoforming films, they can achieve a small blister footprint — even with big tablet and capsule sizes. In fact, for very large tablets and capsules, thermoforming can reduce a blister footprint up to 65 per cent versus other blistering materials such as Cold Formed Foil (CFF). Other benefits of smaller thermoformed packs include reduction in material and energy use and productivity gains.
physical and chemical nature of new APIs is also driving the need to optimise packaging choices holistically. At the same time, there are ongoing efforts to develop slimmer packs with smaller footprints that better match users’ lifestyles. These trends result in more restrictive conditions that can impede the introduction of new products. To counteract these constraints, pharmaceutical companies are turning to ultra-high barrier thermoform films, such as Honeywell Aclar Films, that address multiple stakeholder needs. A thermoform platform increases the likelihood of passing stability tests and simplifies patients’ lives as well as the entire pharmaceutical value chain.
To further simplify the pharmaceutical value chain, pharmaceutical developers need to streamline primary packaging selection, adopting one ultra-high barrier thermoform film as a standard for all applications. This can reduce the need to test multiple thermoform packaging materials (analysing test results for multiple packaging materials can be a bottleneck for pharmaceutical companies) for each product to find the optimum solution. Alternatives to high-barrier thermoforming films include aluminum pouch overwraps, alu/alu pouch overwraps, or alu/alu (CFF) blisters. Amber glass bottles with metalscrew caps as well as single- or multi-layer HDPE or PP bottles with CR screw caps also meet high moisture, oxygen and light barrier protection requirements. Conclusion Today’s pharmaceutical manufacturers must reconcile a wide range of disparate needs to successfully launch a drug. Globalisation brings with it the need for better shelf life, simplified supply chains, and greater productivity. The emphasis on the drug formulation pipeline plus the July 2013 65
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Current Clinical Trial Scenario of India: Challenges and Solutions The Indian Clinical Trial Industry, considered as the booming sector and perceived as a potentially upcoming segment, is undergoing turmoil today with a decline of 9.60 per cent in revenues, with further decline because of delay/decreased clinical trial approvals.
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ndia was considered as one of the hubs for conducting major global multinational clinical trials. It still has the potential to establish itself as a hub for global Clinical Trials (CTs). There are several reasons to it, including but not limited to – a large treatment naïve population with diversity in the gene pool with a range of illnesses, many easily accessible tertiary care hospitals, relatively lower cost of clinical trials compared to the western countries, high enrolment rates, good patient compliance/retention, ICH GCP trained healthcare professionals (HCPs), a generation of gifted young medical students, scientists and researchers who are eager to contribute valuably to the advancement of medical science, availability of trained man power and infrastructure and fairly accommodative regulatory environment at least until now. However, the current scenario tells us a different story. The recent amendments to regulation, has contributed to a decline in the Indian Clinical Trial Industry. There are several challenges that the sponsor companies are facing which are diverting them to conduct their trials in countries like
Dr Rajashree Devarakonda General Manager and Director Voisin Consulting Life Sciences
66 July 2013
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China and Taiwan as they are disillusioned with the uncertain regulatory environment here. As well, many companies are as well going for locations like US, European Union, Canada and Malaysia going by the expertise and speedy clearances, which will be cheaper in the long run. Recently few academic NIH trials were also put on hold by US NIH. This trend is a big dent to the Indian CT sector. According to the research firm Frost and Sullivan, the CTs business in India is estimated to be worth around USD 500 million, which projects that it will grow to USD 1 billion by 2016. However, the industry experts have estimated a loss of USD 150-200 million in the past six months due to the changes in the regulations. We will have to wait to see if this is still achievable. Recent Amendments Cosmetic Rules
to
Drug
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In India, Central Drugs Standard Control Organisation (CDSCO) (headed by Drug Controller General of India) is the primary authority and "Drugs and Cosmetics Act, 1940" (along with the rules framed there
122-DAB
The DCR (First Amendment), 2013
- Compensation in case of injury or death during CT. - Free medical management for injury occurring to CT subject. - Requirements for financial compensation to nominee(s) in case of death. - SAE reporting requirements for Sponsor, Investigator & ECs etc.
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The DCR (Second Amendment), 2013
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122-DD
The DCR (Third Amendment), 2013
- Registration of ECs. - Requirements & guidelines for EC registration including application, composition, maintenance of records etc.
Permission of CTs. Approval of ECs before trial initiation. Annual reports of CT status. Ins pec tion of trial s ite and p e r s o n n e l b y CDSCO to check compliance with Schedule Y and GCPs etc.
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Compensation should be limited to the injury or death of the subject, resulting directly or justifiably related to the participation of the subjects in the CTs and not for unrelated events or any injury.
under) is the principal legislation for the regulation of CTs. Schedule Y of the Drugs and Cosmetics Rules (DCR), 1945 provides Rules relating to CTs in India.
bring some stringent regulations and to create a structure similar or stricter than few regulated countries, there still are many lacunas in these amendments.
Since last few years, it was required on the part of the DCGI to formulate new regulations or modify the existing ones in order to streamline the CT process in India. Recently, in January 2013, DCGI amended the DCR 1945 to bring the following three amendments. Few examples of each amendment are provided as well:
Challenges/Gaps in the Recent A mendment(s)
These amendments have brought sudden change to the CT regulations. Many of these amendments were long overdue and were very much required however without too many lacunas and should have been done in consultation with the stakeholders especially while finalising the amendments (Public, Sponsors, CROs, Academia, Ethics Committees, Regulators and Ministry) to avoid the anguish that the CT industry is undergoing currently. The amendment has brought in several good changes (EC/CRO registration, GCP Compliance and other related quality changes), as well as challenges. Bringing these amendments is laudable. However, the current regulation is leaning primarily to guard the safety of trial participants and to improve the much criticised with a justifiable reason, inefficiencies of several Clinical research players including CROs, investigators, ECs, regulators and sponsors in managing properly ethically compliant CT process. Hence, revision of the regulation was very much needed and is much welcomed after years of well-documented ethical lapses in few cases, including informed consent issues, protocol violations, compensation issues by the sponsors among others. Although the DCGI has made an effort to Pharma Bio World
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The language of regulation itself is ambiguous at places and has loopholes, which needs to be clarified. • Compensation for “any injury” or death during CTs due to failure of investigational product to provide the intended therapeutic effect and use of placebo in a placebo controlled trial. Medical coverage and compensation for any type of injury whether it is related or not is a major issue, and there is no clarity for how long and how much compensation need to be provided which will be decided by the regulatory authority and ECs on a case by case basis. If this compensation is not provided, this may lead to the company suspending/losing the license to conduct CT in India on a case-bycase basis. This is acting as a deterrent for many pharma MNCs. • The investigator’s obligation to report any SAE with 24 hours of the occurrence of the event is practically impossible as such information might not be available in the mentioned time period. • The sponsor needs to report any SAE of death to EC and expert committee within 10 days of occurrence, while it is 14 days as per international practice. • 21 calendar day timeline for EC to provide opinion on SAE as well as financial compensations. • The timelines for EC to examine the SAE of death and for DCGI to determine the cause of injury/death are 30 days and 90 days respectively, which looks arbitrary. • The amendments again fail to address issue of variable timelines for CT
approval leading to significant delays and lost trust for the sponsor companies. Challenges of Conducting CTs in India in General 1) Ethical issues a. Even though, India has the manpower, experienced HCPs and infrastructure to handle more CTs, ethical oversight is somewhat missing. International companies are losing trust in the Indian institutes, as there have been cases of unethical practices in the past. b. Until now, the ECs were not required to register with the DCGI. This led to independent working of the ECs leading to in few cases frauds and manipulation of trial data. c. Another important challenge lies with the protection of rights of the subjects in the CTs. d. No transparency in informed consent processing. e. Involvement of major sub group of vulnerable population (illiterates, Villagers with lack of awareness, pregnant women and children) in trials leading to in few cases exploitation of the subjects. 2) Quality Issues a. GCP issues, documentation issues, data quality/data protection/data compromise and fraud issues. b. Different quality standards for local/ global trials/BA/BE studies. c. “Laissez faire” attitude leading to taking lightly some of the key ethical steps in CTs including improper documentation. 3) Regulatory issues a. Delays/Lack of CT approvals: could be mainly due to shortage of technical/ trained staff. b. Lack of standardisation and transparency in CT approvals/audits/ inspections and reason for decisions. 4) Cultural issues a. In India, the personal physician strongly influences patient decisions, as do family and friends, which could raise potential ethical issues with patient recruitment unless the process is transparent. July 2013 67
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b. Informed consent needs to be in local language. This means translation needs to be performed in multiple languages. 5) Media a. There has been lot of negative publicity of CTs in India by media sometimes with biased/inaccurate data on safety related to CTs, which has led to overall negativity/uncertainties in subjects, industry and government leading to development of laws, which are very restrictive rather than supportive. 6) Training/Mentoring a. Lack of practical advanced GCP and CT training of HCPs including regular up gradation and or maintenance of certification is a major issue. b. India has an extraordinary pool of bright, insightful young medical talent who are often given minimal guidance and mentorship, and even less financial support in their endeavors leading to waste of talent. Overcoming the Challenges It is the hope of the clinical trial industry stake holders that the recent amendments to the regulations once lacunas are addressed should be able to address many of the following critical steps leading to solutions to protect the integrity of Indian 68 July 2013
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CT industry leading to India back on as a global hub for global CTs. The amended regulations are great even though very stringent in few aspects and were needed for Mandatory GCP compliance, mandatory AE reporting, EC/ CRO/CT registration including mandatory compensation for the subjects. However, the ambiguity in the regulations has to be clarified soon, as these regulations look more patient/subject friendly and lesser sponsors friendly so that there is a balance in the regulation enabling researchers to conduct CTs in India with integrity as ethically conducted CTs are very much necessary for drug discovery and treatment of rare complex diseases in India or globally. Compensation and safety reporting amendments specially need to be revisited. Compensation should be limited to the injury or death of the subject, which are resulting directly or justifiably related to the participation of the subjects in the CTs and it should not be for unrelated events or any injury. There should be clarity on the compensation amount to be reimbursed. It is important that medical treatment for trial related injury should be covered by the sponsors. However, there should be more clarity on the amount of compensation to be given,
for how long the medical treatment should be given, and industry also should be able to participate in this calculation along with DCGI and ECs. There is urgency in this matter, as we have already seen a decline in the number of CTs in India since last year and companies moving their base to other countries. Positive note is that, the Drug Technical Advisory Board (DTAB), in their recent meeting on May 16 th, 2013, has proposed few changes to these amendments which are still under discussion. For example: including the words “In the case of CT related injury” in the compensation clause to bring clarity that only trial related death/injury needs to be compensated for. Although they have not commented on the amount of compensation to be provided, they have recommended that a qualifying clause may be added “in case there is no permanent injury, the quantum of compensation shall commensurate with the inconvenience, loss of wages, transportation”. The DTAB has recommended the removal of the compensation for the failure of the investigational drug for intended therapeutic effect as well; they have added the clause use of placebo in a placebo controlled trial “if the standard care is denied”. As discussed earlier, the timelines for SAE reporting are also a major concern and needs to be revised. For example, modifying the timelines to meet the international standards : 14 days instead of 10 days for sponsors and investigators, 30 days (instead of 21) for ECs to report SAE, 60 days (instead of 30) Expert committee to examine SAE and 60 days (instead of 90) for the DCGI to determine the cause of injury and decide quantum of compensation. These are few recommendations that the DTAB has provided during their meeting in May. This might help to streamline the timelines and reduce the ambiguity in the regulations. However, it needs to be noted that these are only recommendations at this stage and are not approved yet. It is crucial to increase the technical staff with advanced industry training at the DCGI office as they are currently understaffed/ undertrained which leads to delays in approval of CTs. Further training by international regulator exchange programs Pharma Bio World
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as well as advanced training in clinical trial design, implementation, monitoring, data management, and quality assurance including funding the DCGI’s office might help to improve the consistency of approvals, reduce the time taken for approvals and thereby increase the trust factor of the MNCs in the Indian regulatory system. Once this is concluded, providing more power to DCGI’s office to make the decisions might be useful. As well, planned setting up of technical and regulatory expert committee to support CT application filing, review and related activities should take a priority and be established soon to streamline these activities. Streamlining of, and improved cross-communication and cooperation between the other agencies involved in the CT process approvals will be useful. ECs need to be linked to Institutes, should have appropriate representatives and ideally should be monitored centrally. Constant monitoring and accountability of the ECs as well is the key to ensure quality ethical operation. ECs should do proper monitoring of trials including the consenting aspects, ensuring the diversity of trial populations so as to avoid misuse of vulnerable population including recruitment of poor homogeneous rural communities. CROs when not meeting ICH GCP quality and ethical standards should be removed. A barrier needs to be created between industry and CT investigators to ensure ethical conduct of research. CROs should conduct trials to the internationally recognised standards by conformance to CT protocol and independent monitoring. Independent research in private clinics without supervision should not be allowed. There should be transparency at all levelssponsors, CROs, Investigators, Regulators and ECs. Sponsors should ensure registration of all CTs in the CTs registry. Sponsors should also communicate risks/ benefits of the trials including safety issues related to the drug/device including trial related risks to all the subjects including vulnerable population. Investigators should be transparent about the treatment given, adverse events, relatedness to the trial activities etc. with the public and regulators. Informed consent process need Pharma Bio World
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to be highly transparent and it should be voluntary and documented properly. Transparency by the regulators in the entire process of CT application review with the appropriate reasons for approval or rejection of the application, approval criteria will be very useful. Transparency on CT audit, its process will be useful to build confidence in integrity of the data coming out of India. Increase in the number of Government regulated and funded CT centres, new initiatives for funding translational science/medicine with high-quality training in clinical research management, basic science research and Quality assurance is very much needed. Industry exchange programs should be encouraged at all levels so that Biotech/ pharma/clinical trial experts from developed regulated regions should be allowed to come to India to train our CT community including for regulators vice versa to foster cross-country collaboration initiatives. Clinical research professionals including medical doctors in India need to be appropriately trained on ethics from the beginning during medical school. They need to be educated on the impact of unethical research on the subject, their family, CT industry and the country eventually. There should, not only be ethics courses included in the curriculum from the beginning, but also, annual ethics certification for CRAs and investigators to keep them up to date with the current regulations, GCPs and ethical conduct of CTs. CME credit could be provided to attend these training at least once or twice a year. People should own up responsibilities and the attitude of “Laissez faire” or casual attitude towards consenting, ethical/quality trials process including documentation need to go. The standard of clinical trial should be high irrespective of to which market this drug will go and whether the trial is local or global. Same high ethical and quality ICH GCP standards should be maintained at all levels (Sponsors, Investigator, CROs, Regulators, Ethics committees) Media holds a key responsibility in the process too and it is hence critical for the media to present the right accurate data and not biased data especially on the CT related
activities, adverse events, deaths and injuries related to CTs as presented before in several instances. It is very important for the regulators, the industry and the Government to come together and plan the regulations that protect the interest of the public at all times but, still have regulations that are supportive to the industry leading to the economic growth of the country. Conclusion There is an urgent requirement for readdressing some of the amendments to continue protecting the interests of subjects as a priority however, simultaneously upholding scientific research and development that will be beneficial to society. It is critical that clinical research community at all levels diligently follow the laws that are in place, understand and apply the guidelines and create a transparent trusted environment so that integrity of the Indian CT industry is maintained. It is the hope of Indian CT fraternity that new and reformed regulations once amended further will be able to bring back Indian CT industry to the highest global ethical standards. Insufficient training or mentoring of young scientific community on advanced practical CT activities including practical GCPs is a real loss to Indian scientific community, as India could easily become a centre of basic medical and clinical excellence with a true Evidence-based Integrative Medicine. At every level the sponsor, investigator, monitor, regulator, inspector, CRA, clinical coordinator, there should be a clear focus on integrity and quality for India’s CTs industry to grow. Years may still be required before further clarity if brought in to address the current lacuna in the regulation, quality and ethical standards to effect all transformations, but it is the hope that this year forwards will see a tremendous move forward towards that goal. (Author would like to thank Rushin P Jhala, Dinesh Babu Sukumar and Ravi Rajhans of Voisin Consulting Life Sciences for their valuable support in preparation of this article.) Contact: devarakonda@voisinconsulting.com July 2013 69
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Fulfilling Pharmacovigilance Obligations in Innovator Pharmaceutical and Generic Manufacturer Partnerships
Chitra Lele Chief Scientific Officer Sciformix Corporation
70 July 2013
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he challenging market conditions (which include governmental demands and the weight of supporting global distribution channels) are driving the global pharmaceutical industry to explore new growth opportunities in emerging markets, to focus on operational efficiency and to move towards a mixed portfolio of innovative and generic products. Such changes are responsible for the substantial increase in the number of licensing and supply partnerships between generic manufacturers based in an emerging market and large to mid-sized global pharmaceutical companies – specifically for the marketing of pharmaceutical products. SDEAs & Minimising the Regulatory Risk These mutually beneficial partnerships allow big pharmaceutical companies to attain a mixed portfolio of innovator drugs and generics and expand into emerging markets while providing the generic manufacturers their sought after marketing capabilities. However the increase in regulatory vigilance requires safety reporting responsibility to be clearly outlined and monitored. Pharmaceutical regulators (such as the FDA and EMEA) hold innovator pharmaceutical companies legally responsible for Pharmacovigilance (PV) within such licensing/outsourcing agreements. The Marketing Authorisation Holder (MAH)/Application Holder is ultimately responsible for maintaining
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compliance with the application itself, and applicable laws regarding good manufacturing practices, quality standards and adverse event reporting. Safety Data Exchange Agreements (SDEA) between the partner companies afford an opportunity to manage the risk and are reviewed during regulatory inspections. By defining the responsibilities of each party with reference to each PV activity, these contracts ensure there are written procedures for safety data exchange and that the communication timelines are adequate to ensure regulatory compliance and prevent PV activity duplication. Rooted in the framework of these agreements are the challenges associated with maintaining compliance with safety reporting due to liability on the biopharmaceutical company and responsibility for PV with the generic manufacturer. In a majority of these agreements, the generic manufacturer is based in an emerging market and the regulatory and legal obligations of highly regulated markets are relatively new to them. They often have limited access to safety expertise and resources such as safety databases required for PV compliance. Sourcing Models Challenge
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Mitigating
the
Typically such generic manufacturers are not adequately set up to cope with the intense regulatory requirements.
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Both the reduction in the number of new drug approvals and the increased competition from generic manufacturers due to an increase in patent expiries have put tremendous pressure on innovator pharmaceutical companies. The last decade has been characterised by a severe innovation drought that has seen the number of new medicines fall to little more than half the previous levels (Reuters, 2013), and it is estimated that more than USD 290 billion of prescription drug sales are at risk from patent expirations between 2011 and 2018 (Evaluate Pharma, 2012).
In a majority of SDEA, the generic manufacturer is based in an emerging market and the regulatory and legal obligations of highly regulated markets are relatively new to them. Pharma Bio World
8/2/2013 7:41:21 PM
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model de-risks compliance with long term regulatory obligations. The choice of model also depends heavily on the scale of the partnership (number of products and number of countries/ regions) and projected increase of the complexity of the portfolio.
Figure 1: Implementing the Roadmap
Consultancy and education are essential for mitigating these challenges, and outsourcing PV to a neutral third party offers greater opportunity for its successful management. The main strategic imperatives to consider when adopting a model to ensure a successful path to PV outsourcing are: • Capability – Access to PV and regulatory knowledge to ensure compliance. • Capacity – Access to scalable and resilient sources of talent and infrastructure. • Cost – Ability to establish global PV centers in a low cost destination. Various sourcing models can be considered, with the captive and the fully outsourced models at opposite ends of the spectrum. The fully outsourced model provides an attractive option if the outsourcing partner is competent, flexible enough to accommodate requirements arising from future partnerships of the MAH and if adequate controls are defined and implemented. More control is provided to the MAH in the captive model where global PV operations are set up in-house, but is a high risk and high cost model given the company’s lack of knowledge and resources at the outset. Other intermediate approaches may be considered in place of the fully outsourced Pharma Bio World
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model if the manufacturer wants to retain direct control over specific aspects of the global PV operations or is mandated by the SDEA to do so. Build-OperateTransfer model (BOT) is a relatively low risk and low cost outsourcing model, whereby the third party takes full responsibility of regulatory compliance and safety reporting for a pre-determined period of time before handing over the responsibility to the now-readied generic manufacturer. This model can be challenging for the third party provider unless the generic manufacturer has a few key senior management members with good understanding of safety obligations and who can facilitate and support decisions to enable the provider to act towards attaining compliance. There is also a risk that the company may not be fully ready to bring everything in-house by the agreed time. With the hybrid model, the manufacturer can identify elements which could be managed by third party providers (eg, case processing, aggregate reporting, literature surveillance). For the elements to be retained in-house, either the BOT or captive model can be utilised. Such a model encapsulates the shared approach with continued long-term consultancy. As the responsibility is shared between the generic manufacturer and the third party and is not completely handed back, the
A multi-partner ecosystem is becoming more common and adds a different dimension of complexity requiring high levels of expertise, both on domain and on process. For example, cases received from one partner need to be sent to another partner. Such involvement of multiple parties and multiple hand-offs may result in insufficient turnaround time for cases or even worse, compliance/ reporting risk. Ownership of the global safety database has to be determined upfront and interoperability of different safety databases ensured. There is also a need to drive agreement on document format for receipt (source documents, e2b, MedWatch, CIOMS, etc). Working with a third party provider that specialises in all of these elements may prove to be the best solution is such scenarios. The Hybrid-BOT Model: A Case Study A hybrid-BOT model for PV outsourcing has recently been implemented in a partnership between a well-known global pharmaceutical and an Indian generic manufacturer. The model’s definition and implementation in that specific partnership embodies a roadmap that other similar partnerships may well find useful, specifically highlighting the questions and processes which must be actioned. Firstly, the strategic objectives of the model are identified which should include access to capability, efficiency and leadership. Through the employment of a current state/situational analysis, together with a thorough understanding of organisational limitations, it is then possible to establish the scope involved and what needs and issues require immediate attention. July 2013 73
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Capacity Capability
Cost Adopting Model for Successful PV
With the scope in place, an efficient operating model can be defined by asking questions about the process, technology and organisational changes that are required, and how plans for current initiatives will change on implementation of an operating model. It is essential to employ a change management process in order to meet the set objectives. This may involve establishing a completely new working environment or amending current practices, and must allow for the measurement and management of success through quantifiable metrics around regulatory compliance and operational efficiency. Such issues can be raised through the use of a risk/benefit analysis, which is an important process in identifying the level of investment required, what risks must be managed, and how the probability of realising the objectives can be increased. This initial planning process should take approximately 4-9 months and should be undertaken before implementing the strategy. It is important to ask questions pertaining to what areas should be implemented immediately, which pilot programs should be instigated to ensure the success of the implementation strategy, and if the evaluation process is viable and sustainable.
The implementation of the roadmap involves planning, systems and infrastructure, recruitment and training, and process development, and is summarised in figure 1. In this example, certain responsibilities were transferred to the manufacturer at the end of the agreed period and Sciformix continued to own other tasks and responsibilities such as aggregate reporting, safety surveillance and Quality Assurance. Conclusion – Successful Management of PV It is clear that in any partnership of the type described here, meeting regulatory obligations heavily depends on the successful management of Pharmacovigilance. This success hinges on several key factors, specifically in the context of the partnerships and various sourcing models outlined above. Of paramount importance is clarity and universal understanding that the responsibility for PV obligation fulfilment and its integrity rests with the MAH, and that there should be only a single, global process owner. The requirement for transparency extends to the performance and workflow management systems, and
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Questions should also be asked on which business units or geographies require involvement, and if implementation should occur in certain phases over a given timeframe. In terms of execution, metrics, SLAs and measurement are vital, but it is also imperative to derive a strategy to scale the model across different geographies and the entire organisation. The timeframe is obviously dependent on the scale of activity, which in the case of our partnership example is over a few years.
the need for evaluation is exemplified by the required measurement of key metrics such as compliance and workload. Management commitment must also be evident in ensuring all departments share the same regulatory vision and goals, and the SOPs must be global in true sense with a centralised operation team to ensure consistency in processes and quality criteria across regions. In conclusion, special considerations in terms of regulatory obligations are required in the setting up of global PV operations in the manufacturing and marketing partnerships discussed here. The characteristics of these partnerships are often unique, and although there are some similar considerations taken when addressing PV, there will be unique challenges and complexities which require careful planning. References 1. Reuters (2013). ‘FDA new drug approvals hit 16-year high in 2012.’ Available at http://www.reuters.com/article/2012/12/31/ us-pharmaceuticals-fda-approvalsidUSBRE8BU0EK20121231 Accessed 20/05/13 2. Evaluate Pharma (2012). ‘Patent expirations put more than $290 billion in prescription drug sales at risk through 2018.’ Available at http://www.evaluategroup.com/public/ PressReleases/Patent-Expirations-PutMore-Than-$290-Billion-in-PrescriptionDrug-Sales-at-Risk-Through-2018.aspx Accessed 20/05/13
Contact: susan.najjar@sciformix.com
Special considerations in terms of regulatory obligations are required in the setting up of global PV operations in the manufacturing and marketing partnerships.
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Pharma Bio World
8/2/2013 7:44:18 PM
In retrospect After US and EU Dextropropoxyphene is Now Banned in India The manufacture, distribution and sale of dextropropoxyphene have been banned by the Union Health Ministry, Government of India. Dextropropoxyphene is an opioid analgesic indicated for the relief of mild pain. This drug has been under the scanner since the last few years due to its potential addictive properties and other toxicities even at therapeutic doses. It was being misused by many addicts. Wockhardt and Ranbaxy are some of the major manufacturers of dextropropxyphene in India. The drug has already been withdrawn from the US market and the European Union following reports of cardiac arrhythmia and other adverse effects. India awaits the ban on another analgesic Nimesulide, an NSAID which has been under scrutiny since long and has already been withdrawn in some countries.
InSite Vision, Merck File Joint Patent Infringement Lawsuit Against Mylan InSite Vision Incorporated announced that it will join Merck known as MSD outside the United States and Canada, and Pfizer Inc in filing a patent infringement lawsuit against Mylan Pharmaceuticals, Inc. Mylan recently filed an Abbreviated New Drug Application (ANDA) with the US Food and Drug Administration (FDA) seeking to market a generic version of AzaSite ® (azithromycin 1 per cent ophthalmic solution) before expiration of the patents covering AzaSite and its use. AzaSite is marketed by Merck in the US. The Complaint will be filed in Federal District Court in Trenton, New Jersey. Mylan filed an ANDA application for AzaSite with the FDA of which InSite received notice on May 2, 2013, and InSite has 45 days to file a patent infringement lawsuit. With this filing , that time requirement has been met. This lawsuit also triggers an automatic stay, or bar, of the FDA’s approval of the ANDA for up to 30 months or until a final court decision of the infringement lawsuit, whichever comes first. On May 26, 2011, InSite and Merck filed a similar patent infringement lawsuit against Sandoz Inc. A trial date for the Sandoz ANDA suit has been set for July 11, 2013. The companies have agreed that Merck will take the lead in prosecuting both lawsuits. Each company will be responsible for their own legal costs, with InSite assuming a monitoring role. Merck, with the assistance of InSite and Pfizer, will vigorously defend the five US patents related to AzaSite. InSite owns four US patents covering AzaSite and its use, and an exclusive license to a Pfizer-owned azithromycin patent. Under the license agreement between InSite and Merck, Merck has the exclusive use of these patents in the US in return for a 25 per cent royalty Pharma Bio World
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payable to InSite based on AzaSite net sales. InSite believes that its four patents and the Pfizer patent were properly prosecuted with the US Patent and Trademark Office and are valid, and will provide AzaSite exclusivity until March 2019.
Merck Calls off Development of their Anti Parkinsonian Drug Preladenant, an experimental drug to treat Parkinson’s disease was in the process of development by Merck. The company decided to call off its further development due to insufficient evidence to prove its efficacy over a placebo based on the data obtained from three separate phase III trials. However, the company will continue to work on newer approaches to treat the disease.
GPEI Plans to Make World Polio-free by 2018 GPEI (Global Polio Eradication Initiative) announced a fresh vaccination plan to eradicate Polio footprints globally, at the ‘Global Vaccination Summit’ recently held in Abu Dhabi. Experts have said that by the end of 2018, the world could be free from Polio with a robust USD 5.5 billion vaccination and a monitoring plan. This is the first six year plan made to eradicate all types of polio disease (both wild poliovirus and vaccine derived cases) simultaneously. At the Summit, commitments and pledges helped USD 4 billion of the USD 5.5 billion needed to implement the six year plan.
USFDA Nod for Aurobindo’s Generic Levofloxacin Injection Aurobindo Pharma has received final approval from the US Food and Drug Administration (USFDA) to manufacture and market Levofloxacin injection in strength of 25 mg/ml, packaged in 500 mg/20 ml and 750 mg/30 ml single-use vials.Levofloxacin Injection, 25 mg/ml packaged in 500 mg/20 ml and 750 mg/30 ml Singleuse Vials is the generic equivalent of Janssen Pharmaceuticals Inc.’s Levaquin Injection 25 mg/ml and indicated for the treatment of adults with mild, moderate, and severe infections caused by susceptible isolates of the designated microorganisms such as Pneumonia. Acute Bacterial Sinusitis or Complicated Urinary Tract Infections etc and intravenous administration offers a route of administration advantageous to the patient. These ANDAs have been approved out of Unit IV formulation facility in Hyderabad, India for manufacturing general liquid injectable and ophthalmic products and will be marketed and sold by Aurobindo’s US subsidiary AuroMedics Pharma LLC. Aurobindo now has a total of 175 ANDA approvals (150 Final approvals including 2 from Aurolife Pharma LLC and 25 Tentative approvals) from USFDA. July 2013 75
8/2/2013 5:23:54 PM
Orphan Blood Disease Drugs Set Nanodiamonds could Make Breast Cancer Treatment Better for Growth According to a new report by healthcare experts GBI Research, Physicians treating rare blood disorders are gaining more drug treatments to choose from, which allow patients to avoid demanding surgeries and chemotherapy, and fill the pockets of pharmaceutical companies who can charge top dollar in these untapped markets. The new report looks at the treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH), Idiopathic Thrombocytopenic Purpura (ITP), Myelodysplastic Syndrome (MDS), Myelofibrosis (MF) and Polycythemia Vera (PV), acquired orphan blood diseases which result in a sufferer’s body not producing blood correctly. These diseases have serious risks, and treatments are often limited to symptom management, and improvement of quality of life, with risky surgical procedures offering the only alternative. This bleak outlook makes the orphan disease market a great opportunity for drug discovery and development, as patient populations are small but untapped. Soliris (eculizumab) is a perfect example of a successful orphan blood disease drug.
USP Names Kiran Mazumdar-Shaw to Board of Trustees The US Pharmacopeial Convention (USP) has named Biocon Chairman and Managing Director and founder Kiran Mazumdar-Shaw to its Board of Trustees. In addition to her role on USP’s Board of Trustees, Shaw will serve as a member of the USP Biologics Advisory Group. Biocon Chairman and Managing Director and founder Kiran Mazumdar-Shaw
USP is a scientific nonprofit organization that develops standards for the identity, strength, quality and purity of medicines, medicinal ingredients, botanical medicinal ingredients, dietary supplements, food ingredients, and compounded medicines manufactured, prepared, distributed and consumed worldwide. Headquartered in the United States, USP operates facilities with laboratory and customer support operations in Brazil, India and China, with a sales office in Switzerland. Shaw is the second non-U.S. member of the USP Board of Trustees. The first was Dr Judith Oulton, who served on the USP Board of Trustees in the 2005-2010 cycle. 76 July 2013
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A team of Scientists led by Dean Ho, a professor at the UCLA School of Dentistry and co-director of the school’s Jane and Jerry Weintraub Center for Reconstructive Biotechnology, has developed a promising treatment for “triple-negative” breast cancer that uses nanoscale, diamond-like particles called nanodiamonds. Nanodiamonds are between 4 and 6 nanometers in diameter and are shaped like tiny soccer balls. Byproducts of conventional mining and refining operations, the particles can form clusters following drug binding and have the ability to precisely deliver cancer drugs to tumors, significantly improving the drugs’ desired effect. In the UCLA study, the nanodiamond delivery system has been able to home in on tumor masses in mice with triple negative breast cancer.
No Need for Non-veg, Veg Tag on Drugs: SC Overturning Delhi High Court’s verdict, a Supreme Court bench of Justice GS Singhvi and Justice SJ Mukopadhaya in their order, said symbols to indicate non-vegetarian or vegetarian ingredients are not required to be printed on the package of a cosmetic or a drug. The High Court had in November last directed the central government to amend its rules to mark drugs and cosmetics with V and NV labels in spite of the Centre’s contention that it was not desirable to do so in public interest. The court had asked the Centre to exempt lifesaving drugs from carrying these labels. It was acting on a PIL that sought to press upon the right of a citizen to know the ingredients of all drugs and cosmetics. The Supreme Court bench said it was not an area that was left uncovered by the law and hence the High Court could not have directed the executive to exercise its power to change a law. Opposing the labels, the Centre had said that if you accept that a citizen has the right to know the origins of a drug or cosmetic, a vegetarian could also claim information about the origin of a vegetarian ingredient, depending upon his food habit.
VereFlu can Detect Avian Flu Veredus Laboratories announced that the current version of VereFlu detects the subtype of H7N9 (Avian Flu) that is responsible for the flu outbreak in China. H7N9 is the latest mutation to cause concern and increased surveillance in the region. Launched in 2008 and built on the STMicroelectronics lab-on-chip platform, VereFlu runs on Veredus’ VerePLEX biosystem and is the market’s first test to integrate two powerful molecular biological applications, Polymerase Chain Reaction (PCR) and a microarray, onto a Lab-on-Chip platform. Pharma Bio World
8/2/2013 5:28:57 PM
Cipla’s Hamied to Retire as MD Yusuf K Hamied has decided to retire as Cipla Managing Director. Cipla has been a key player in the domestic ` 1.2-lakh crore pharmaceutical industry, and Hamied has spent over 52 years building it to its present stature. In the global arena, Cipla campaigns for affordable medicines. Its dramatic price cuts on anti-AIDS drugs in the African market in 2001 made history, not just in the pharmaceutical world, but in global business and humanitarian circles as well. In the Indian market, it cut prices of cancer drugs last year. As India moved into the product-patent regime, Cipla is locked in several patent-related battles across the country, challenging what Hamied calls monopolies in the market place. Yusuf K Hamied
He has always batted for the Government to bring in an “automatic compulsory licensing” system, where expensive critical drugs can be made by other companies, on the payment of a royalty to the innovator company — to make the medicine affordable. Over the last several years, Hamied had to field questions on Cipla’s future and whether it was a target for takeover by other companies. On the timing of his “desire to retire”, he said there was no specific reason. “A team has been put in place,” he added. Cipla has a new Chief Executive, Subhanu Saxena, who assumed office recently. About five months ago, Hamied told that Cipla was in restructuring mode, and 12 key people had been appointed, as it stood poised for a ` 8,000-crore turnover. Hamied will continue as Cipla’s Chairman, in a non-executive role.
Adieu Dr Kallam Anji Reddy Padmashri Dr Kallam Anji Reddy, founder of Hyderabad-based drugmaker Dr Reddy’s Laboratories (DRL) and pioneering pharma entrepreneur passed away on March 15, Friday evening. He was suffering from liver cancer. The loss of Dr K Anji Reddy has created a vaccum that can never be filled. A true visionary and philanthropist Padmashri Dr Kallam touched many lives through his pioneering Anji Reddy efforts in the field of affordable medicines. His futuristic approach towards manufacturing and producing affordable medicines and thrust to innovation in developing new products ushered a new era in the Indian pharmaceutical industry which will continue to benefit both the industry and the society. He started his career in the state-owned PSU, Indian Drugs and Pharmaceuticals Limited (IDPL) (1969–1975), and left the job to found Uniloids Ltd in 1976 where he was the Managing Director till 1980, after which he founded Standard Organics Limited, before founding Dr Reddy’s Labs in 1984. Pharma Bio World
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Alchemia, AstraZeneca Partner for Drug Discovery Alchemia Limited, a drug discovery and development company, announces that it has signed a multi-target, drug discovery collaboration with AstraZeneca AB (AstraZeneca). This collaboration includes the use of the proprietary Diversity Scanning Array (DSA) and associated Versatile Assembly on Stable Templates (VAST) chemistry platform to discover and develop novel small molecules against multiple AstraZeneca targets. Alchemia will provide VAST chemistry expertise to develop small molecule clinical candidates for AstraZeneca. By accessing Alchemia’s VAST discovery platform, AstraZeneca will seek novel small molecules to treat diseases across a variety of therapeutic areas including oncology, respiratory, cardiovascular, metabolism, infection and neuroscience. Under the terms of this Agreement, Alchemia will receive an undisclosed upfront payment and is eligible for potential preclinical, clinical and commercial launch payments totalling up to USD 240M, as well as a single digit royalty.
PBS Biotech, SCRUM Inks Distribution Agreement PBS Biotech, a company that designs and manufactures single-use bioreactor systems with the patented Air-Wheel mixing technology, has signed an exclusive distribution agreement with Tokyo-based, SCRUM Inc to market and sell its single-use bioreactor technology in Japan. PBS Biotech makes next generation single-use bioreactors that grow a wide range of cell lines used to develop biological drugs and vaccines. The unique Air-Wheel mixing system and innovative product design provide maximum operation efficiency with minimal space requirement. PBS Bioreactors are fully scalable from three liters to eventually 2500 liters. “We looked for a partner with the expertise and network to bring the PBS Bioreactors to its customers. We are delighted to work with SCRUM to bring our technology to Japan.” said Brian Lee, President of PBS Biotech. “There is a continuing trend in the bio industry to adopt singleuse bioreactors for both R&D and commercial manufacturing. We are flattered to close a distributor agreement with PBS Biotech and to enter the market with innovative Air-Wheel bioreactors.” said Toshiaki Shimada, Vice President of SCRUM. SCRUM Inc is a subsidiary of SEIKO CO LTD, which is one of the biggest dealers in Japan. SCRUM, a Life Science Research and Process support company, brings in novel and innovative product from around the world to the labs in pharmaceutical companies, diagnostic companies, universities, national institutions and other commercial biotech companies. July 2013 77
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Drugs may Cost More Post Excise The Pharma Industry Has Lessons Duty Hike to Learn from Ranbaxy Rating agency Crisil has shared that drug prices will rise marginally as the government’s 2012-13 budget raised excise duty both on active pharmaceutical ingredients by 2 per cent to 12 per cent and finished products from 5 per cent to 6 per cent. Pharma industry manufacturers would not absorb the hike internally, which will mean consumers are likely to face higher drug costs. The budget extends 5 per cent basic customs duty concession to six life-saving drugs or vaccines and for bulk drugs used in manufacturing such life saving drugs. Given that these drugs form a small niche in the pharma sectors, the concession is not impactful.The pharma industry could see marginal benefits from the five-year extension of 200 per cent weighted deduction for in-house research and development expenses. The latter form less than 5 per cent of the total sales of pharma companies. Crisil says that the Indian pharmaceutical sector is poised for healthy growth. It anticipates 13-14 per cent year-onyear growth for 2013-14. This could cause the industry to touch the USD 36-37 billion mark. For 2012-13, the Indian pharma segment could see growth by 16-17 per cent year-on-year.
Soon after Ranbaxy pleaded guilty of violating the regulatory norms and selling their adulterated drugs in the US market, the whole Indian Pharmaceutical Industry was taken by surprise. Daiichi Sankyo Co., a Japan-based pharmaceutical company which now holds the major shares of Ranbaxy has claimed that the former promoters of Ranbaxy, the Singh family had hidden vital information regarding US DOJ and FDA investigations. The Singh family has claimed these allegations as false saying that Ranbaxy settled on an agreement with the US FDA and DOJ according to which the company would cough up a large amount as penalty charges and that this was decided without consulting them. Biocon’s Chairman and MD, Kiran Mazumdar Shaw has termed the Ranbaxy issue a ‘wake-up call ‘for the Indian Pharmaceutical Industry and said that the Industry must learn from this. She also adds that this is an eye opener and calls for the need to come up with stricter drug regulatory norms. Meanwhile the Drug Controller General of India (DCGI) is scrutinizing the legal documents of Ranbaxy filed in the US.
Budget 2013: Not Much to Cheer Cell Surface Glycoproteins’ Behaviour for Biotech Sector Now Discovered The Union Budget for 2013-14 is not encouraging for the biotech sector as proposed by ABLE on behalf of the industry, said Dr P M Murali, President, Association of Biotechnology Led Enterprises (ABLE). Although some measures are announced, overall impression of the budget is not path breaking and is not sending the right pointers for quick growth of this sector as there are no major incentives announced by the government. While the finance minister has recognised the importance of venture capital and tax incentives, the measures announced are far from being adequate to build strong venture capital funds for the sector. The implications of the tax rebates and funds allocated for advanced skills development have to be studied. From the outside one is not able to put any numbers on to this. Exemption from excise/custom duties on life saving medicines as well as on their raw materials and exemption on capital goods and consumables, CRO’s, diagnostic kits have not been considered. More outlay t o AY U S H i s ce rt a in ly a g o o d st e p in t h e right direc tion, Murali remarked. Utkal Chamber of Commerce and Industry president, Ramesh Chandra Mahapatra said the budget has not addressed the problems faced by the Small and Micro Enterprise (SME) sector. 78 July 2013
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Chemists at Simon Fraser University (SFU) have discovered the scientific understanding of the structure and function of glycoproteins, in particular the number and positioning of sugars on them. SFU chemist Bingyun Sun and her colleagues have discovered how nature can vary the amount of a dominant sugar type (N-Glycan) on membrane proteins on a cell surface. The variation helps stabilise these proteins and facilitate their functioning. The researchers verified their observation of a correlation between the number of sugars on a glycoprotein and its function in five animal species ― worms, flies, fish, mice and humans. This led to their realisation that the correlation has been conserved through evolution. To obtain the number of N-Glycans on proteins, the researchers used proteomics, a combination of MS and HPLC. In less than an hour, high-throughput technique identifies the exact place where N-Glycans attach on hundreds of glycoproteins. The scientists analysed cell surface glycoproteins in one type of mouse embryonic stem cells by genetically shutting down the Hypoxanthine Phosphoribosyltransferase (HPRT) gene in the cells. Pharma Bio World
8/2/2013 5:29:09 PM
Pacific Biosciences, Sage Science Zydus Cadila to Launch Lipaglyn Announce Co-Marketing Partnership The Zydus Group announced a breakthrough in its research efforts
Kevin Corcoran, Senior Vice President of Market Development at Pacific Biosciences
Pacific Biosciences of California Inc, provider of the PacBio RS II DNA Sequencing System, and Sage Science, a developer of life science products for improving sample preparation processes in molecular biology applications, announced a co-marketing partnership to provide customers of the PacBio RS II the ability to sequence even longer DNA fragments when performing Single Molecule, RealTime (SMRT) Sequencing.
Soligenix, Intrexon Join Forces to Develop Treatment for Melioidosis Soligenix Inc, clinical stage biopharmaceutical company, will jointly develop a treatment for Melioidosis through a worldwide exclusive collaboration with Intrexon, a synthetic biology company that utilises its proprietary technologies to provide control over cellular function. Under this collaboration with Intrexon, Soligenix intends to develop and commercialise human monoclonal antibody therapies for new biodefense and infectious disease applications for Melioidosis using Intrexon’s advanced human antibody discovery, isolation and production technologies. Melioidosis is an often lethal disease that is endemic in Southeast Asia and Northern Australia. It is also considered a high-priority biodefense threat as defined in the 2012 Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) Strategy established by the US Department of Health and Human Services (DHHS) with the potential for widespread dissemination through aerosol.
GSK, Biological E. Tie up on Polio Vaccine GlaxoSmithKline (GSK) and Biological E Limited (Biological E.), a leading Indian vaccines company, have reached an agreement to form a 50/50 joint venture (JV) for the early stage research and development of a six-in-one combination paediatric vaccine to help protect children in India and other developing countries from polio and other infectious diseases. The partnership reinforces the commitment of both companies to support the World Health Organisation’s (WHO) global polio eradication programme. If approved, the vaccine, which would combine GSK’s injectable polio vaccine (IPV) and Biological E’s pentavalent vaccine for diphtheria, tetanus, whooping cough (whole cell pertussis), hepatitis B, and Haemophilus influenzae type b, could be the first of its kind. The vaccine would enable fewer injections for children thereby improving compliance in immunisation schedules. Pharma Bio World
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with Lipaglyn (Saroglitazar), a novel drug targeted at bridging an unmet healthcare need for treating Diabetic Dyslipidemia or Hypertriglyceridemia in Type II diabetes, not controlled by statins alone. The drug has been approved for launch in India by the Drug Controller General of India (DCGI). With a novel action that offers lipid and glucose lowering effects in one molecule, Lipaglyn is the first Glitazar to be approved anywhere in the world. “Lipaglyn provides patients suffering from diabetic dyslipidemia the option of a once-daily oral therapy that has a beneficial effect on both lipid parameters as well as glycemic control,” said Pankaj R Patel, Chairman and Managing Director, Zydus Cadila. “It has always been our dream to take a molecule right from the concept stage up to its launch. Today, we have realised this dream. It is an important breakthrough and I would like to dedicate this to all the Indian research scientists in the field of drug discovery,” Patel added. World over, it is estimated that 30 per cent of all deaths occur due to cardiovascular diseases (CVD). In India, one out of every five persons is at serious risk of developing CVD. Research has shown that diabetes is one of the major risk factors of CVD.
Life Technologies Sets up International Influenza Network Life Technologies Corporation announced the establishment of the Global Influenza Network, a partnership including scientists at a number of the world’s leading government public health organisations, veterinary agencies and research institutes in a collaborative effort to increase the speed and efficiency of influenza monitoring and vaccine development. Members of the network are sharing tools, experience and data using the Ion Personal Genome Machine (PGM™) semiconductor sequencing platform. “Life Technologies exhibited leadership in infectious disease tracking when our scientists worked alongside federal officials to identify the cause of H1N1 outbreak in 2008,” said Gregory T Lucier, Chairman and CEO of Life Technologies.“We are very proud to now bring together a group of such distinguished organisations to tackle the continued threat of influenza worldwide,” he added. Each year, public health agencies around the world collect samples from infected individuals and share data about flu subtypes circulating in their regions. The pooled data are used by the WHO to determine the strains used to design a vaccine that will be effective against that year’s epidemic. Costs of sequencing, however, have limited data set to about 20 per cent of the patient samples collected. July 2013 79
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pharma news Health Ministry Forbids Manufacture, Honeywell Awarded Indo AmericanCorporate Excellence Award Distribution and Sale of Three Drugs The Health Ministry has banned the manufacture, sale and distribution of analgesic Analgin, anti-diabetic Pioglitazone and anti-depressant drug Deanxit in the country on account of the health risks associated with these drugs after there were reports of serious adverse effects due to their use. Under Section 26A of the Drugs and Cosmetics Act, 1940, the manufacture for sale and distribution of Analgin and all formulations containing the drug has been suspended for human use. The Health Ministry also suspended the manufacture, sale and distribution of Pioglitazone and all formulations containing it. However pioglitazone is likely to be back in pharmacies soon. Sources in the ministry told that the government may call off the ban after a meeting with doctors, a majority of whom felt there was no affordable alternative to the drug which is prescribed for a large number of diabetics in the country.
Bad Habits Add USD 33.9 Billion to Annual Global Cost of Cancer Reducing bad habits such as smoking, alcohol consumption, poor nutrition and physical inactivity could potentially save USD 25 billion each year globally GE Healthcare released secondary research findings indicating that bad habits and lifestyle choices are contributing approximately USD 33.9 billion annually to the costs related to cancer. Furthermore, the same research revealed that by reducing bad habits, global healthcare systems could potentially save USD 25 billion each year. The research conducted by GfK Bridgehead on behalf of GE Healthcare in May and June 2013 focused on four key bad habits; smoking, alcohol consumption, poor nutrition and physical inactivity and their relationship to three types of cancer – breast, lung and colon. The study calculated the cancer costs attributable to bad habits in ten developed and developing markets While it has been long established that tobacco use is linked to the development of lung cancer, the data revealed that other bad habits, such as inactivity and poor nutrition, can also impact the risk of cancer. In seven of ten markets, over 25% of those populations are still regular smokers. Smoking is most prevalent in France and Turkey where 31% of adults over the age of 15 are smokers. French females and Turkish males were ranked highest groups for smokers at 31% and 47% respectively. GE Healthcare provides transformational medical technologies and services to meet the demand for increased access, enhanced quality and more affordable healthcare around the world. 80 July 2013
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Honeywell Automation India Limited was awarded two Indo-American Corporate Excellence awards at a felicitation ceremony organized by the Indo American Chamber o f C o m m e r c e ( I A C C ) . M r. L to R: Anant Maheshwari, MD, Anant Maheshwari, Managing Honeywell Automation India Ltd Director, Honeywell Automation (HAIL) and Country Leader, Honeywell Automation and Control India Limited (HAIL) received Solutions – India; Nanik Rupani, the awards from Shri Prithviraj Regional President, Indo-American Chavan, Honorable Chief Chamber of Commerce; Shri Prithviraj Chavan, CM, Maharashtra Minister of Maharashtra, India, as a part of the pre-American Independence Day celebrations in the presence more than 500 business and government leaders, celebrities, expatriates and the media. Honeywell received the Corporate Excellence Award for Technology and Communications for driving a successful technology enterprise and its contributions to the Indo-U.S. technology sector. The Corporate Excellence Award in Manufacturing recognizes the company for its innovative manufacturing principles using lean manufacturing, Kaizen, and Six Sigma processes, to deliver high quality products to its customers.
Golden Peacock Award for Abbott Abbott, India’s leading health care company, today announced that it was honored with the Golden Peacock Global Business Excellence Award for 2013 at the recentGlobal Convention on Business Excellence in Dubai. The Golden Peacock Global Business Excellence Award recognises Abbott’s strong foundation of stakeholder engagement, a commitment to transparency, a workplace environment that enables its employees to achieve their greatest potential, high standards of ethics and compliance for the company and its partners, and the quality of its involvement with communities. It also recognises Abbott’s broader economic, social and environmental performance. “Abbott is committed to advancing healthcare and improving the lives of millions of patients and customers by partnering with healthcare professionals, governments, non-governmental organisations and other stakeholders,” said Bhaskar Iyer, Divisional Vice President, Established Pharmaceuticals, Abbott in India. “Being a responsible corporate citizen involves more than health care innovation and outreach. Good citizenship also extends to the way we run our business in a sustainable manner to benefit our many stakeholders.” The Golden Peacock Global Business Excellence Award was created by the Institute of Directors to encourage Business Excellence achievements in both manufacturing as well as service organizations globally. Pharma Bio World
8/2/2013 7:50:09 PM
CMDH Endorses Restricted Paediatric Use of Codeine The Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) has endorsed by consensus a series of risk minimisation measures to address safety concerns with codeine-containing medicines when used for the management of pain in children. Codeine is an opioid that is authorised as a painkiller in adults and children. The effect of codeine on pain is due to its conversion into morphine in the patient’s body. T h i s f o l l o w s a r e v i e w o f t h e s e m e d i c i n e s b y t h e E M A’s Pharmacovigilance Risk Assessment Committee (PRAC), which investigated reports of serious and fatal respiratory depression in children after taking codeine for pain relief. Most of the cases occurred after surgical removal of the tonsils or adenoids for obstructive sleep apnoea (frequent interruption of breathing during sleep). Some of the children who had suffered severe side effects had evidence of being ‘ultra-rapid metabolisers’ of codeine. In these patients, codeine is converted into morphine in the body at a faster rate than normal, resulting in high levels of morphine in the blood that can cause toxic effects such as respiratory depression. The CMDh agreed with the PRAC’s conclusions and endorsed the following recommendations: Codeine-containing medicines should only be used to treat acute (short lived) moderate pain in children above 12 years of age, and only if it cannot be relieved by other painkillers such as paracetamol or ibuprofen, because of the risk of respiratory depression associated with codeine use. Codeine should not be used at all in children (aged below 18 years) who undergo surgery for the removal of the tonsils or adenoids to treat obstructive sleep apnoea, as these patients are more susceptible to respiratory problems. The product information of these medicines should carry a warning that children with conditions associated with breathing problems should not use codeine. The risk of side effects with codeine may also apply to adults. Codeine should therefore not be used in people of any age who are known to be ultra-rapid metabolisers nor in breastfeeding mothers (because codeine can pass to the baby through breast milk).
METTLER TOLEDO’s Weighing Standard Ensures USP Compliance On the 3rd June, 2013, United States Pharmacopeia (USP) published the revised mandatory Chapter 41 on balances as well as new updates to the advisory Chapter 1251. With just six months to Pharma Bio World
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comply, METTLER TOLEDO’s global weighing standard, GWP ®, can help pharmaceutical manufacturers and suppliers to meet the new requirements. The new revisions define modified balance test procedures for the US pharmaceutical industry and also apply to companies exporting to the US. With the revised chapters becoming official on 1 st December, 2013, METTLER TOLEDO is providing a free on-demand webinar to explain how balance quality management will be affected, focusing on the determination of minimum weight and execution of routine testing. In addition, METTLER TOLEDO is also offering a wealth of information on their website including a free white paper and a video as well as the opportunity to register for an easy e-learning course. For a long time balance users and manufacturers argued that balance assessment as per USP’s General Chapter 41 (“Balances”) was unclear and difficult to comply with. In addition, they frequently commented that General Chapter 1251 (“Weighing on an Analytical Balance”) no longer represented state-of-the-art weighing practices. The revisions to both chapters in the Second Supplement to USP 36-NF 31 aim to help US pharmaceutical manufacturers and suppliers ensure accuracy and eliminate costly over-testing. METTLER TOLEDO’s Global Weighing Standard: Good Weighing Practice™ (GWP ®) can help consumers put the new standards into practice in a structured and effective way.
N e w O n - d e m a n d We b i n a r f r o m METTLER TOLEDO A new on-demand webinar from METTLER TOLEDO explains how to ensure accurate weighing results in any pharmaceutical quality management system. Out-of-specification results can slow down a production process. Inaccurate weighing results can lead to accidental acceptance of unacceptable products. Those two issues can be easily eliminated by controlling the weighing risk and knowing the minimum weight and measurement uncertainty of each weighing instrument in your process. The right weighing instrument for a process will guarantee the best results. The free webinar explains the cornerstones for evaluating and selecting an appropriate weighing system based on measurement and uncertainty and minimum weight. Upon completion of the webinar, participants should be able to understand the correlation between consistent quality, risk management and efficiency improvement; prove compliance by knowing and documenting the accuracy of your weighing equipment; and avoid surprises during audits. Additionally, the webinar describes the principles of Good Weighing Practice (GWP), the Global Weighing Standard, and how these can be used to establish and maintain sustainable quality and accurate results in your weighing process. It also defines concrete measures for optimizing and documenting accuracy. July 2013 83
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Roche Launches cOmplete His-Tag Purification Column Roche today announced the launch of its new cOmplete His-Tag Purification Column for researchers performing histidine-tagged protein purification from lysates. The new column uses Roche’s proprietary nickel-chelate chemistry and is compatible with commonly used reducing agents (DTT), metalloproteinase inhibiting reagents such as EDTA, and different buffer and salt environments. This allows researchers to choose optimal buffer conditions for the target protein in a convenient pre-packed format. “We have received very positive feedback from pilot users who appreciate the flexibility of being able to purify proteins under protein protecting conditions,” said Ruedi Stoffel, Head of Biochemical Reagents & Custom Biotech. “It enables our customers to apply any buffer required to obtain proteins of high purity, stability and function.” Following the purification step, the new column does not require buffer exchange or resin recharging therefore avoiding a costly and time consuming process. In addition, the resin’s minimized nickel ion leakage not only reduces toxic nickel waste, but also stabilizes the target protein by preventing nickel ions from catalyzing protein oxidation.
Piramal Water Pvt. Ltd honoured with ‘Enabling Technology Award-13’ Piramal Water Pvt. Ltd, an initiative by Piramal Foundation has been awarded with Frost & Sullivan India Electronics Awards for ‘Enabling Technology Award of the Year in the Electronic Security and Auto ID & Data Capture Technologies Market’. This award is a tribute to the company that has developed a technology that revolutionalised the industry for the year 2012. Piramal Water Pvt. Ltd operates through its Water ATM’s in six states with unique RFID, cloud management systems and customized ERP solutions. Its franchisee model helps create local entrepreneurs, who sell water at ultra-affordable prices (30 paisa per litre) and become financially sustainable. The leveraging of technology helps make the service and delivery of drinking water highly transparent. Frost and Sullivan has recognized this initiative that combines technology and sustainable business models that help in delivering drinking water to the last mile. It is also recognized as compatible model for working with Government agencies, NGOs and CSRs. Commenting on the award, Mr. Paresh Parasnis, Head, Piramal Foundation said, “It is a great achievement for Piramal Foundation to receive this industry recognition. Sarvajal has unmatched expertise in delivering safe drinking water under the most difficult circumstances for any size of community. With our initiatives we continue to create replicable solutions to some of our nation’s most pressing challenges.” 84 July 2013
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Sarvajal partners with companies, non-profits, and agencies to deploy end-to-end drinking water solutions for communities, facilities, and institutions. From solutions for patients at public hospitals to water micro-grids in urban settlements, Sarvajal aims to provide clean and safe drinking water for all.
Venus Remedies Among the Best Companies to Work for Venus Remedies Limited, a research-based global pharmaceutical firm is the only company from North India to have made it to the list of Top 100 in the “India’s Best Companies to Work for” study conducted by the Great Place to Work Institute, India in association with The Economic Times. The company is placed at the 72 nd position. Terming the achievement as a matter of great pride, Pawan Chaudhary, CMD, Venus Remedies Limited, said, “We have been getting recognitions in the past from across the globe for our research products. This time, our HR practices have been acknowledged as people-oriented. Now a circle has been completed. We give our employees a conducive environment to learn and work so that they can in turn give great solutions. Employees are our biggest asset and all policies are oriented towards them.” About 550 organisations registered for this year ’s study. The survey, considered to be the most comprehensive and representative study of workplace culture in corporate India, was based on the responses of 98,998 employees in these organisations, which included not only Indian and multinational companies but also public sector and not-for-profit organisations. Hailing the achievement, Dheeraj Aggarwal, chief financial officer and vice-president, HR, Venus Remedies, said, “We did remarkably well on various parameters considered for the survey. We always try our level best to make all our employees feel wanted from the moment they join us. The work timings are employee-friendly. Sitting late at work is not encouraged. Employees are motivated to strike a balance between their personal and professional lives. At Venus, we play light and soothing music to create a relaxing atmosphere for employees. The company has a team of more than 40 in-house faculty members to run the tutor and training programme for employees. This is apart from the technical and non-technical training provided through external agencies. We also seek detailed feedback from employees from time to time on their level of satisfaction.” Only six companies among the top 50 are new entrants this time, down from 14 in the 2012 survey. On the other hand, there are 25 new entrants in the top 100. Pharma Bio World
8/5/2013 10:34:51 AM
A Better Route to Synthesise Hydrocarbazoles A new chemical process developed by researchers at Kanazawa University provides an efficient way of synthesizing diverse organic compounds. This research is also described in the inaugural June 2013 issue of the Kanazawa University Research Bulletin Jun-ichi Matsuo and co-workers in the School of Pharmaceutical Sciences aimed to produce a wide variety of aromatic compounds called hydrocarbazoles, which are found in many natural substances such as strychnine. Hydrocarbazoles contain a benzene ring linked by a six-membered carbon ring and a five-membered carbon ring containing nitrogen. Various methods exist for synthesizing hydrocarbazoles by reacting electron-accepting compounds, called enophiles, with indoles – common aromatic structures that are found in flower scents. Because this reaction involves the addition of a cyclic carbon ring, it is called cycloaddition. Previous cycloaddition methods have been restricted to certain combinations of indoles and enophiles. Moreover, it has been difficult to control exactly where on the molecules the bonds will be formed, and thus what exact chemical structure will come out. The new process developed by Matsuo and co-workers involves a reaction of cyclobutanones with so-called Lewis acids – molecules that can accept two electrons - to produce an intermediary molecule that has positively- and negatively-charged parts, but zero charge overall. This intermediary can react with many different indoles to produce hydrocarbazoles. The choice of indole can lead to different types and structures of hydrocarbazoles. So far, the researchers have synthesized structural parts of strictamine molecules, and demonstrated total synthesis of aspidospermidine. Such an efficient, flexible route to these useful compounds could greatly benefit pharmaceuticals and other industries.
India’s First Pharmaceutical Learning & Development Employee Academy Indegene announces the launch of iAcademy—the company’s learning and development institute to ensure that every employee is trained to competently and effectively meet the changing needs of the global pharma industry. Indegene, a scientific partner to global pharmaceutical and health care organizations, announces the launch of its learning and development academy—iAcademy. As the global pharmaceutical industry continues to transform, it has become evident that the relentless pressures on R&D productivity, sales and marketing effectiveness, operational rigor, and compliance will continue to drive reorganization and innovation initiatives. As the industry continues to evolve, the demand for specialized, scalable, and reliable vendor partnerships is expected only to rise. Pharma Bio World
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Manish Gupta, CEO said “We foresee these transformational changes as important opportunities for Indegene, and for our employees in their learning and growth. iAcademy provides a sophisticated and predictable system for training and developing employees across all functional and domain areas that tie very closely with real changes in the marketplace. The primary benefactor of this initiative will be our clients who will continue to gain access to our highly specialized and multi-skilled talent pool as they continue to traverse this changing global landscape.” iAcademy is built on an integrated curriculum of interactive courses that are linked with the current positions employees hold in the organization (entry-level, team leaders, middle management, senior management); and functionally across content/medical writing, research, analytics, clinical sciences, regulatory & safety, scientific multimedia, multi-channel marketing, technology, and medical affairs. Mr. Gupta added, “iAcademy incorporates L&D best practices, including proprietary technology and instructional systems design (ISD), making this probably the most sophisticated and relevant pharmaceutical services learning and development employee academy in the Asia-Pacific region.” Through the integration of formal and collaborative learning, Indegene is strengthening the core and functional capabilities of its employees and helping clients leverage highly scalable centers of excellence (CoE). Indegene is a leading provider of R&D, commercial, and marketing solutions to global pharmaceutical and health care organizations. Indegene partners with clients to drive both productivity and revenues by delivering better patient outcomes, optimizing cost, enhancing R&D agility, and improving sales and marketing effectiveness. Indegene applies deep scientific knowledge, flexible delivery models, proprietary technology, and a client-centric approach to drive transformational initiatives.
Glenmark Generics Receives ANDA approval for Riluzole Tablets Glenmark Generics Inc., USA the subsidiary of Glenmark Generics Limited has been granted final abbreviated new drug approval (ANDA) from the United States Food and Drug Administration (US FDA) for Riluzole Tablets, 50mg. The Company will commence shipping immediately. Riluzole is indicated for the treatment of amyotrophic lateral sclerosis. Based on IMS Health sales data for the 12 month period ending March 2013, Riluzole garnered sales of USD 64 million. Glenmark’s current portfolio consists of 86 products authorised for distribution in the US marketplace and 52 ANDA’s pending approval with the US FDA. In addition to these internal filings, GGI continues to identify and explore external development partnerships to supplement and accelerate the growth of the existing pipeline and portfolio. July 2013 85
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Cresset Seeks partners for rapid 3D SAR interpretation At Field Based Chemistry Europe, Dr Tim Cheeseright presented a pre-release of Cresset’s new Activity Miner module. The groundbreaking new science in Activity Miner helps researchers optimise their leads by identifying the key 3D structural and electrostatic changes that impact molecular activity. Activity Miner explores the structure activity landscape of a set of molecules. For each pair of molecules, the difference between them in electrostatics, shape and structure is compared to the difference in activity. A small change in structure or electrostatics that results in a large change in activity is known as an activity cliff. Conversely, large structural changes resulting in little or no change in activity indicate bioisosteres. In each case, the comparison indicates an area of interest that merits further research. Activity Miner uses Cresset’s molecular fields so that 3D electrostatic and shape similarities can be analysed as well as 2D structural activity. This makes it meaningful to compare pairs of structurally diverse compounds and gives a more realistic insight into activity relationships. “Based on internal validation experiments, we believe Activity Miner is a powerful tool for guiding lead optimisation and mining the SAR to rapidly generate new and more active structures for experimental evaluation,” said Dr Mark Mackey, Cresset’s CSO. “Activity Miner’s intuitive visualisation makes it easy to identify interesting areas of a dataset. The relationships between molecules can be displayed as a color coded disparity matrix, a table view, a cluster view or the innovative activity view.”
Piramal Enterprises’ Diagnostic Division Has a Host of New Launches After the successful launch of QDx Instacheck in March 2013, Piramal Enterprises’ diagnostic division announced the launch of three new innovative devices in the QDX Range Right-here-Right-now; (a) QDx A1c - India’s first voice guided diagnostic device which measures HbA1c, the diabetes detection marker that measures diabetes QDx HemoStat under 3 minutes (b) QDx HemoStat, detects the level of Haemoglobin in 5 seconds and (c) QDx VitD, the world’s only device that helps detect Vitamin D in 10 minutes. High in features and value for money, QDx A1c measures HbA1c is less than 3 minutes. It is the most reliable diabetes detection marker. The accuracy level of the results is best in the market, which commands less than 2% CV. These tests are performed by diabetologists and endocrinologists in clinics, hospitals, labs etc. 86 July 2013
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The other device, QDx HemoStat is an innovative handheld device to quantify the levels of haemoglobin & hematocrit in blood. It is based on revolutionary electrochemical biosensor technology that helps in monitoring levels of haemoglobin and hematocrit in blood in just 5 seconds. It is used for patients undergoing chemotherapy, dialysis etc. The main USP of the product is its unique strip technology which has a big grip and is more hygienic than its counter parts. Lastly, QDx VitD, world’s first whole blood Vitamin D diagnostic device detects if a person is Vitamin D deficient within 10 minutes. The three ODx devices are portable and affordable, delivering quantitative test results with lab accuracy. The devices can be operated very easily with minimal training requirements. The soft launch for all 3 products is schedule in July and followed by 3 months of Test marketing phase.
German Pharma Packaging Manufacturer, Sanner, Enters India Based in Bensheim, Germany, Sanner GmbH is a family owned enterprise established in 1894 and currently in the fourth generation. Sanner develops and manufactures high-quality plastic packaging and components for pharmaceutical, medical and healthcare products. As a world Holger Frank, CEO, market leader in desiccant closure systems, Sanner-Group Sanner manufactures more than two billion plastic components each year – ranging from standard products to customer-specific solutions. With a workforce of over 450 employees at facilities in Germany, China, Indonesia, Hungary, USA and now India, the company generated sales of more than EUR 50 million in 2012. The company’s product portfolio and customer base increased over the years with the development of plastic materials. In the late 1950s, Sanner introduced the first desiccant cap, a contemporary innovation for medicinal packaging. Manufacture operations at all Sanner sites are subject to uniform quality standards in accordance with the “Made in Germany” principle. To d a y, S a n n e r p r o d u c t s a r e u s e d a l l o v e r t h e w o r l d f o r pharmaceutical products, medical technology and healthcare. The company has gained recognition across the globe for their effervescent tablet and test strips packaging solutions. They place high priority on their completely traceable production chain based on GMP guidelines. State-of-the-art machinery at Sanner production facilities enables best in class for quality standards and great delivery performance. So the Germany based company is the choice when it comes to combining rigorous quality standards with high volume production. Pharma Bio World
8/5/2013 10:35:08 AM
India’s First New Drug, Synriam, Ensocare and Wipro GE Healthcare Wins Innovation Award Enter into a Public Private Partnership Ranbaxy Laboratories Ltd., India’s largest pharmaceutical c o m p a n y, a n n o u n c e d t h a t it has been conferred with the Innovation Excellence Platinum Award at the ASSOCHAM Innovation Awards 2013 in the Science Left to Right) Dr. Nilanjan Saha, & Technology category for Vice President - Medical, Global its new anti-malaria drug, Marketing, Ranbaxy and Umang Chaturvedi, Glo Synriam. The prestigious award was given by Hon’ble Minister for Science & Technology and Earth Sciences, Jaipal Reddy. Synriam is used for the treatment of Plasmodium falciparum malaria, in adults. The company plans to submit New Drug Applications for market authorisation of Synriam in various African countries in 2013. The drug is efficacious and has the advantage of “compliance and convenience”. The course is one tablet a day for three days and costs ` 130. Unlike artemisinin-based drugs, it has a synthetic source, the production of which can be scaled up whenever required and a consistent supply of the drug can be maintained at low cost.
Ensocare by Enso Group, a 7 billion dollar diversified conglomerate in dynamic sectors like Oil & Gas, Infrastructure & Real Estate and GE Healthcare today announced entering into the largest Public Private Partnership (PPP) in the space of healthcare with Government of Maharashtra. Public Health Department, Ensocare (previously named Uber), Government of Maharashtra and Wipro GE Healthcare Pvt Ltd signed this INR 150 Crores PPP project to advance healthcare in the State of Maharashtra. Ensocare is backing the financial investment of 150 cr; the consortium will set up advanced diagnostic facilities at 22 Government district and women hospitals, run operations on 24/7 hour basis and provide services at Government recommended rate cards for the benefit of larger population. The PPP agreement with Government of Maharashtra is the largest in terms of scale. The package includes installation of 4 units of 64 slice CT scanners, 13 units of advance 16 slice CT scanners, 8 units of cutting edge 1.5T Magnetic Resonance Imaging with 16 channels, 22 high end digital radiography systems, 39 color Doppler’s and 39 analog x-ray units. Women’s health is given a special boost with the inclusion of 20 screening mammography units for early breast cancer detection.
Strong Interim Results of CAVATAK FDA Clearance for Carestream’s in Phase 2 Trial Viralytics Limited announced strong interim results from its Phase New X-ray Imaging Technology Carestream Health continued its leadership in medical X-ray imaging technology by announcing FDA clearance for a new wireless digital radiography detector designed to offer high quality, low dose X-ray exams for pediatric, orthopaedic and general radiology applications. The new detector is expected to begin shipping in the third quarter of 2013. In orthopaedic and general radiographic imaging, its smaller size and light weight aids in positioning for tabletop exams such as knee, elbow, skull and other exams that may require a patient to hold the detector or require a smaller field of view. Like Carestream’s DRX-1 and DRX-1C detectors, the new DRX 2530C detector can be used with any member of the DRX family of room-based and mobile imaging systems. This flexibility is part of Carestream’s commitment to enhance productivity and maximize each healthcare provider’s investment in imaging technology. Carestream also offers advanced image processing software that is used to optimize image quality for pediatric patients. The software includes seven patient sizes as specified by FDA guidelines for pediatric exams. Pharma Bio World
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2 clinical trial of CAVATAKTM treatment in late stage melanoma patients. The interim data shows solid progress towards achieving the primary endpoint of the study and strengthens the evidence of the tolerability of CAVATAK™ in late stage melanoma patients. The primary endpoint measured is immune related Progression Free Survival (irPFS) at 6 months after first dose of CAVATAK™. Currently, there are 23 patients who have met the protocol criteria for assessment of the primary endpoint of irPFS at 6 months. 8 of these 23 (35%) have achieved this endpoint. The trial target will be realised if 10 of 54 patients meet the primary endpoint.
30 patients qualified for assessment of the irPFS endpoint at 12 weeks. 18 patients (60%) have achieved an irPFS at 12 weeks, with 7 of these patients currently between the 12 week and 6 months response monitoring timepoints. A further measure in the trial to assess CAVATAK™ activity is the best overall tumour response4 which assesses both injected and non-injected tumours. In the 30 patients who have been on the study for at least 12 weeks, a best response of either a complete or partial tumour response has been seen in 2 and 6 patients, respectively (total of 8 /30 or 27%). July 2013 87
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biotech news Regulatory Submission for New Insulin Glargine Biosimilar Product Eli Lilly and Company and Boehringer Ingelheim announced that the companies’ marketing authorisation application (MAA) for LY2963016, an investigational basal (long-acting) insulin for the treatment of type 1 and type 2 diabetes, has been accepted for review by the European Medicines Agency (EMA). LY2963016 is a new insulin glargine product and has been filed through the EMA’s biosimilar pathway. Lilly and Boehringer Ingelheim have studied LY2963016 in a comprehensive clinical development programme in order to meet the highest standards of safety, efficacy and quality. In addition to pharmacokinetic and pharmacodynamic studies, Phase III studies in patients with type 1 and type 2 diabetes have been conducted and results submitted, using currently marketed insulin glargine as the active comparator. “Long-acting insulin is a mainstay treatment for many people with diabetes, and we anticipate that insulin glargine will continue to be widely used for many years to come,” said Gwen Krivi, PhD, vice president, Lilly Diabetes product development. “We are pleased that the EMA’s acceptance of our application brings us closer to offering a new insulin glargine product to clinicians and their patients, coupled with the expertise they expect from Lilly and Boehringer Ingelheim.”
Dolomite Expertise Brings Microfluidic Product to Market Fledgling spin-out company DropTech has turned to microfluidics s p e c i a l i s t Dolomite for its product development and fabrication skills to help productise the advanced and innovative Robo-Drop technology into the Mitos Dropix, a droplet-on-demand sampler that is set to make it easy to produce extremely miniaturised droplet compartments with excellent control over their contents. Access to this new high-throughput screening format will prove invaluable in basic research, drug discovery and diagnostics applications. The collaboration began when Drop-Tech entered – and won – Dolomite’s Productising Science Competition, sparking discussions and exchanges of ideas between the two development teams. Liisa van Vliet, a Post-doctoral Research Associate at the University of Cambridge and Managing Director of Drop-Tech, explained: “Drop-Tech was formed from an academic collaboration between 88 July 2013
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Imperial College London and the University of Cambridge. In a university environment, finding the time to convert an invention into a product is often difficult, so we welcomed Dolomite’s offer to accelerate product development, fast-tracking the transition from idea to market; Dolomite knows and understands microfluidic droplet technologies and has the engineering expertise to productize the instrument. Drop-Tech’s Technical Director Fabrice Gielen and I met with Dolomite’s product development team to discuss the internal workings of the instrument. Together, we were able to bounce ideas back and forth to incorporate improvements and determine a list of specifications.” The Mitos Dropix sampler allows the creation of nanoliter droplet sequences from up to 24 different samples, with precise control over droplet content and size, as well as the spacing between droplets. It can be used as an add-on for conventional microfluidic chips, delivering droplets for merging, further miniaturization, dilution or any other droplet manipulation, and will also be an invaluable tool to use in conjunction with other analytical and liquid handling systems. The first batch of instruments will be with beta testers by summer 2013, and further collaboration is planned to develop droplet analysis capabilities on upcoming versions of the instrument.
Roche Launches Online Software NimbleDesign Roche today announced the global launch of the NimbleDesign tool, an online software that enables customers to easily design optimised SeqCap EZ Choice Libraries in as little as one hour. The software’s industry-leading design algorithm offers an empirically optimised probe database allowing customers to obtain and review designs in an automated setting before making the purchase decision. “NimbleDesign is based on years of target enrichment design experience from our bioinformatics experts,” said Thomas Schinecker, President of Roche Sequencing Solutions. “Following the very positive feedback we received from pilot users in selected regions we are excited to offer this software tool globally now. It marks another step in our ongoing efforts to improve the customer convenience of our target enrichment portfolio.” The NimbleDesign tool enables customers to take full advantage of Roche’s superior SeqCap EZ library technology, delivering more efficient discovery of Single Nucleotide Polymorphisms and better uniform coverage than many other commercially available technologies. In addition, the easy-to-use interface offers the opportunity to develop multiple designs simultaneously with very quick turnaround time. Adding to the already improved customer convenience with the launch of SeqCap EZ Reagents earlier this year, the NimbleDesign tool further streamlines the design workflow and ordering process. Pharma Bio World
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Cell Metric CLD Success in US Biopharma for Single Cell Cloning Due to the significant time saving advantages of their Cell Metric systems, Solentim, the market-leading developer of innovative tools for shortening steps in the upstream cell line development workflow, have had their best quarter of sales revenues to date. This includes multiple shipments of Cell Metric systems to customers in the US and a repeat order from US biopharma. Cell Metric CLD is a bench-top imaging station, which includes a 10 plate automated plate loader. The system addresses several key stages in the upstream cell line development workflow, including clone screening and documentation of monoclonality (for regulatory submissions), from either seeding single cells into 96 well plates with limited dilutions or by FACS sorting. The Cell Metric CLD also measures clone stability and growth rates by direct non-invasive cell counting in each well without having to remove a sample. Growth data can then be assessed with protein productivity measurements such as ELISA assay data in the same wells. In this way normalised protein productivity and titre can be calculated to identify and rank the best protein producers. The Cell Metric CLD is capable of detecting all cells, even immediately after seeding, affording a significant time advantage. Automated clone imaging and screening have become a routine element of any new cell line development process. Cell Metric CLD has quickly become established as the market-leading clone imager with significantly better optics and automated detection capabilities than previous generation products.
Glythera Receives £700k Funding Boost Glythera Ltd is delighted to announce that it has successfully achieved a number of technical and commercial milestones which has resulted in the release of a second tranche of funding totalling £700k from IP Group and its managed fund, the Finance for Business North East Technology Fund. Glythera, a UK based spin out specialising in a new generation of biological therapeutics through advanced glycosylation technologies, received an initial investment of £600,000 in April 2012.The funds have been used by the company to continue the development of a new generation of biological therapeutics including its core technologies - Permalink and Permacarb. These technologies will be used to create drugs with unprecedented biological stability, bioavailability and therapeutic efficacy. Glythera reached its technical and commercial targets ahead of schedule including the validation of Glythera’s Permalink technology and establishment of partnerships with four pharmaceutical companies. This demonstrates how the company Pharma Bio World
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is effectively managing the financial investment it has received. The third tranche of investment will be made available once further technological progress has been made and commercial traction successfully achieved. Chief Operating Officer Dr. David Simpson said, “We are delighted with the progress that has been made throughout the research and development process so far thanks to the expertise of the Glythera team in the discovery, development and manufacturing of complex biologics. This funding will enable us to continue with the commercialisation of our products and maximise the opportunities available to us in the market.”
Vetter Offers a sWFI Solution with 5 Years Stability Data
Vetter has broadened its portfolio for lyophilized substances. The contract development and manufacturing organization (CDMO) is now offering its filling service for high-quality sterile water for injection (sWFI) syringes with 5 years of stability data. Vetter’s stability data and bracketing concept allows a longer shelf life for drugs, and high flexibility while defining the filling volume. Vetter can also offer ready-to-submit documents for the sWFI service in Common Technical Document (CTD) format. This can considerably abbreviate the approval process. Because innovative drugs are becoming increasingly more sensitive to environmental influences, they are often lyophilized to increase their shelf life. In a freeze-dried state, these drugs maintain their bioactivity for longer periods of time. However, before being administered they have to be reconstituted and dissolved in a solvent, after which they are ready for injection. The filling service for syringes with sterile water-for-injection (sWFI) is Vetter’s intelligent solution for safe and simple handling of the reconstitution process. The system contains the exact defined amount of solvent required by the customer in order to produce the required dosage. This helps to assure patients that they will receive the exact amount of substance needed. Vetter’s filling service for sWFI syringes is an ideal complement to lyophilized drugs in vials and is available in 1.5 ml formats with a volume of 0.5 ml to 1.3 ml, as well as a 3 ml format with a volume of 1.4 ml to 3.0 ml. The syringe features Vetter’s V-OVS ® tamperevident closure, which is designed to give a prefilled syringe system effective protection features. Vetter supports its sWFI filling service with 5 years of stability data and can manufacture batches of up to 120,000 / 140,000 pieces. July 2013 89
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Affordable Enteric Fever Vaccines to Arrive Soon for the Developing World Novartis announced that it has entered into a development and licensing agreement with Biological E Limited (BioE), a biopharmaceutical company based in India, for two vaccines to protect against typhoid and paratyphoid fevers. The agreement advances the Novartis goal to deliver accessible and affordable vaccines that address unmet medical need in endemic regions. In just five years, the Novartis Vaccines Institute for Global Health (NVGH), part of the Novartis Institutes for BioMedical Research, has developed a typhoid vaccine with funding by the Fondazione Monte dei Paschi di Siena and Regione Toscana through the Sclavo Vaccines Association (Italy). In addition, a dual-acting vaccine with components against both typhoid and paratyphoid fevers is being developed with on-going support from the Wellcome Trust. Both could reduce the burden of these diseases in endemic regions.“NVGH uses its innovative know-how to tackle important problems in public health,” said Don Ganem, VP and Global Head of Infectious Diseases, Novartis Institutes for BioMedical Research. “BioE has a proven track record in vaccine manufacture, and capabilities to clinically develop and deliver WHO pre-qualified affordable vaccines to the developing world. We are pleased to be working with them to address this unmet need.” Under the license, NVGH will transfer technology to BioE, which will have financial and operational responsibility for manufacturing, further clinical development, approval and distribution in the developing world. The typhoid vaccine (Vi-CRM197) has achieved Proof of Concept, had successful Phase 2 results, and will be transferred to BioE. A combined typhoid-paratyphoid vaccine will be transferred once Proof of Concept is completed through early, small-scale studies in humans to determine safety and immunogenicity. The Wellcome Trust continues to support the development of the dual-acting vaccine through a Strategic Award that was awarded in 2009.
BioScience Managers Banks on Growth of Anti-infectives Market Leading healthcare fund manager, BioScience Managers, has moved into the rapidly growing anti-infectives market with a US$1m investment into Bulletin Board-listed AmpliPhi Biosciences Corporation. AmpliPhi has a proprietary library of bacteriophage, naturally occurring viruses which seek out and lethally target bacteria. Unaffected by antibiotic resistance these viruses are highly specific and have been proven to be safe for humans, animals, fish and plants. In 2012 AmpliPhi merged with Australian company Special Phage Services, securing additional technology and expertise and adding to the international footprint already established in the USA and the UK. “Resistance to antibiotics is fast emerging 90 July 2013
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as one of the biggest challenges in the modern healthcare environment. We have high expectations for this investment and we’re pleased to be supporting Australian technology and talent in the context of a much larger international opportunity,” commented Chief Investment Officer Matt McNamara. In the US over 50 per cent of hospital-acquired infections are caused by drug resistant bacteria, creating a rapidly growing market with few effective solutions. BioScience Managers has invested USD 1 million in a USD 7 million private placement, alongside RA Capital Management and Third Security LLC, and will take an active role supporting the company as it grows into an international leader in the anti-infectives market. Dr Anthony Atala, editor, Stem Cells Translational Medicine, and director, Wake Forest Institute for Regenerative Medicine, US, said that cells from bone marrow and from fat were equivalent in terms of their potential to differentiate into multiple cell types. The fact that the cells from fat tissue seem to be more potent at suppressing the immune system suggest their promise in clinical therapies.
ARTES, Bio Farma Jointly to Develop Vaccine ARTES and Bio Farma announced to join forces for the development and manufacturing of vaccine candidates. The agreed collaboration involved the strength of both partners. ARTES is specialized in cell line and process development, VLP based vaccines as well as in technology transfer for pharmaceutically relevant production processes whereas Bio Farma is involved in the manufacturing of vaccines, serum and other biological products for the Indonesian domestic and international markets. Under this commitment a first agreement for VLP based vaccine technology transfer was signed on July 1 st in Bandung, Indonesia. “We are extremely delighted about the mutually agreed collaboration. Bio Farma is a strong and reliable pharmaceutical partner and the only vaccine and antisera producer for humans in Indonesia. We are more than confident, that we along with Bio Farma will develop vaccines highly relevant for the Indonesian and neighboring markets. We expect that especially developments based on our Metavax technology will contribute to Bio Farma´s vaccine portfolio”, Dr Michael Piontek, founder and managing director of ARTES Biotechnology. Metavax is a patent protected VLP technology, based on modifications to duck hepatitis B virus. The approach elicits a highly potent immune response and therefore a broader protection than the currently available VLP approaches. ARTES´ Metavax platform is suitable for the development and production of safe and cost-effective vaccines. Meanwhile, Government of Indonesia, represented by Ministry of Health, Ministry of Education and Culture and Ministry of Research and Technology, will assist in aspects of policy to accelerate the development of vaccines in Indonesia. Pharma Bio World
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events diary Pharmac India Dates: 05 – 07 September 2013 Venue: HITEX Exhibition Centre, Hyderabad Hosting by Orbitz Exhibitions Private Limited for three days at HITEX Exhibition Centre, India, Pharmac India is recognised as a focused exhibition for Pharma & Health care industry. It is three day exhibition which is aiming towards highlighting varied related medical products. It will prove to be a large hub of reputed professionals from pharmaceutical formulation, herbal products, veterinary drug, medical & disposal, pharmaceutical machinery and many other sectors. Contact: Orbitz Exhibitions Pvt Ltd 101, Navyug Indl Estate, Sewri (W), Mumbai Tel: +(91)-(22)-24102801/02/03/04/39504586 Fax: +(91)-(22)-24102805
Pharmabiotika Dates: 16 th-18 th September, 2013 Ve n u e : M a h a t m a M a n d i r C o n v e n t i o n & E x h i b i t i o n C e n t r e , Gandhinagar Pharmabiotika is an international exhibition and conference which will bring together US, Europe and Asian Pharmaceutical, Biotechnology, Clinical Research, Vaccine and Contract Research & Manufacturing organizations under one platform. Pharmabiotika exhibition & conference will help in integrating scientific knowledge from the perspectives of design, material synthesis, drug discovery, formulation, processing technology, manufacturing design, clinical trial etc. Contact: Mr. Atanu Bhattacharya Human Crayon Management Services Pvt. Ltd. C-28, Sector -4, Noida - 201301 Mobile: +91-9810303916 Tel +91- 120 – 6528801, +91 - 11-65378800 Email: info@crayon4.com; atanu@crayon4.com Pharma Bio World
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Pharma Bio South 2013 Dates: 9 – 11 October 2013 Venue: Chennai Trade Centre, Guindy, Chennai CHEMTECH announces CHEMTECH World Expo 2013 - SOUTH of its flagship event from 9th to 11th October 2013 in Chennai Trade Centre, Guindy, India. Pharma Bio World Expo & conferences will concurrently be organised during the Expo. The international exhibition will have display of state-of-the-art technologies, equipment, accessories and services from national and international players in each sector. Concurrent International conferences EPC World Expo, ChemPetro World Expo, Industry Automation and Process Control World Expo and WaterEX World Expo will have deliberations on topical issues by industry leaders, experts and influencers and offer high level networking opportunities to take the businesses to newer heights. Contact: Chemtech Secretariat 26, Maker Chambers VI Nariman Point, Mumbai 400 021 Tel: + (91)-(22)-40373737 | Fax: +(91)-(22)-22870502 E-mail: sales@jasubhai.com; conferences@jasubhai.com
India Diagnostic Expo Dates:21– 23 November 2013 Venue: HITEX Exhibition Centre, NAC campus, Madhapur Hyderabad India Diagnostic Expo is going to be held for a period of three days in Hyderabad, India. This expo will attract diagnostic labs, clinical lab professionals, chemists and biochemists from all over the world to discuss about the modern market trends and future market prospective associated with the diagnostic industry. By taking an active part in this expo technical and professional experts related to diagnostic industry will get a scope to share their expertise with the attendees. Contact: SD (India) Corporation 14, Mall Road, 1 st Floor, Hudson Lane, GTB Nagar New Delhi Tel: +(91)-(11)-47034600/43003757 | Fax: +(91)-(11)-47056500 July 2013 95
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bookshelf Real World Drug Discovery: A Chemist’s Guide to Biotech and Pharmaceutical Research [Hardcover] Author: Robert M Rydzewski Price: USD 74.07 No of pages: 512 pages About the book: Real World Drug Discovery: A Chemist’s Guide to Biotech and Pharmaceutical Research demonstrates how the challenge of making new, profitable, drugs has changed in the last few years, as well as the shape of pharmaceutical companies themselves. In a single, readable volume it outlines processes and explains essential concepts and terms for the recent science graduate wondering what to expect in pharma or biotech, the medicinal chemist seeking a broader and more timely understanding of the industry, or the contractor or collaborator whose understanding of the commercial drug discovery process could increase the value of his contribution to it.
Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing (Wiley Series in Biotechnology and Bioengineering) [Hardcover] Authors: Hamid Mollah (Editor), Harold Baseman (Editor), Mike Long (Editor) Price: USD 97.99 No of pages: 416 pages About the book: Risk management is essential for safe and efficient pharmaceutical and biopharmaceutical manufacturing, control, and distribution. With this book as their guide, readers involved in all facets of drug manufacturing have a single, expertly written, and organised resource to guide them through all facets of risk management and analysis. It sets forth a solid foundation in risk management concepts and then explains how these concepts are applied to drug manufacturing. This book is an essential resource for pharmaceutical and process engineers as well as safety and compliance professionals involved in drug manufacturing.
The Impact of Regulation on Drug Development (Pharma, Biotech and Bioscience: Science, Technology and Business) [Hardcover] Author: Heinz Guenter Hennings Price: USD 205.40 No of pages: 250 pages About the book: The impact of regulation on drug development provides the reader with a basic understanding of the evolution of global regulatory standards relevant to the research and development process of medicinal products and the role regulatory science plays, ie, the science of developing new tools, standards and approaches to assess the safety, efficacy, quality and performance of regulated products. This book provides practical guidance on how to obtain such advice efficiently and how it is incorporated in global regulatory planning and strategies.
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PBW Marketing Initiative
Save Energy and Protect Environment without comprising- Usage, Performance and Safety Vishva Protech aims to bring in the best of technological advances from around the globe that will help in preserving the natural resources.
V
ishva Protech Private Limited focuses on GREEN PROJECTS and TECHNOLOGIES. It is a consortium of multi disciplinary Engineering and Project Management firm, promoted by qualified and experienced team of professionals. It is a Mumbai based company with regional office in Bangalore.
Vishva Protech Private Limited entered into an agreement with the Erlab ® Group of France to introduce revolutionary GreenFumehood ® and related products to the Indian market in November 2012. Founded in 1968, Erlab ® Group developed the first Ductless Filtration Fume Hood in the world under the brand name Captair ® in 1971. Engineered with a range of patented innovations, GreenFumeHood ® offers a safe, high performance, energy efficient, fully flexible solution, ideal for virtually any environment from a clean room to a teaching lab. With a unique, modular filtration column and proprietary Neutrodine ® Filtration Technology, it can handle multidisciplinary tasks involving everything from acids and solvents to liquids and powders while exhausting 100 times fewer contaminants than allowed by the official Threshold Limit Value (TLV). With GreenFumeHood ®, saving energy doesn’t mean compromising safety and performance. The system can be left on at times sash up or down without consuming energy or polluting environment. At the same time, it maintains a face velocity of 0.5m/s. GreenFumeHood ® also offers the first ever remote communication software, developed with Microsoft ® Technologies, to provide unprecedented management capabilities for a network of up to 250 fume hoods.
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Features Include: • • • • •
Proprietary Neutrodine® filtration technology Exclusive twin sensor saturation detector User identification and approval system Advanced gGuard® communication technology Electronic filter identification system
Based on the Carbon Molecular Filtration Technology Erlab ® also offers the following products to the Indian Market through Vishva Protech: 1. Captair®Flex®: The revolutionary innovation from the erlab ® R&D laboratory offers onesize ventilation and filtration cartridge (High performances activated carbon filters and H14 filters) which can be stacked vertically to form a multi-layer filtration column, able to easily adapt itself to the various applications to be performed in the lab. The vertical stacking of the modular filtration column uses a foam sealing technology on the whole perimeter of the cartridges, which ensures, by gravity, the perfect air tightness of the filtration column. 2. Captair ®store ®: Range of filtered/vented chemical storage cabinets for labs to filter the harmful smells of the chemical bottles stored inside. This will also filter the lab room air 24 hours, which contains also small quantities of chemicals, harmful on the long term. Therefore eliminating all traces of chemicals which could be inhaled by the chemicals and are dangerous for them on the long term. 3. Captair®bio®: Range of PCR workstations to protect against DNAs/RNAses contamination from the operator, from the room, from the previous experiment. The air is ejected towards the operator, preventing contamination from the operator even when he introduces his hands into the
enclosure. A U.V. lamp controlled by a timer is used to decontaminate the enclosure with C.U.V rays between 2 successive PCR* experiments to avoid cross-contamination. 4. Captair ® flow ® : Vertical laminar flow cabinets, the Captair ® Flow ® cabinets make it possible to perform handlings in an ultra-clean, dust free environment. The housing, which is equipped with a very high quality H14 filter, guarantees 99.995% filtration effectiveness for particles larger than 0.3 μm(according to the MPPS method set forth in the EN 1822-1 Standard). 5. Captair ®pyramid ®: Disposable glove box for the protection of the user and sensitive products. It is a multi-function disposable glove box, made of high quality transparent PVC. Assembled in a few seconds, it can be used anywhere (indoor and outdoor), the slanted shape of the enclosure provides a very ergono-mic working position to the operator. Light, mobile and disposable, Captair ®pyramid ® is an ideal flexible protection tool which can suit many specific protection requirements in each laboratory. For more details please visit website: www.vishvaprotech.com or Contact: Vishva Protech Private Limited H.O: 304, Chawla Complex, Sector 15, CBD-Belapur, Navi Mumbai-400614. Office-022 31923076 Mobile- 9323040973, 9820229591 Regional Office: #298, 2 nd Floor, Opp.IDBI Bank, 24 th main, 6 th phase, J.P Nagar, Bangalore-560078 Mobile-9019783530, 9060821638 Fax: 080-42039776
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