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Pharma VOL 8. NO. 6 JANUARY 16-31, 2013

Chairman of the Board Viveck Goenka

CONTENTS

Editor Viveka Roychowdhury*

MANAGEMENT

BUREAUS

Fellowship of the chain: Dietary supplements & nutraceuticals PAGE 24

Mumbai Sachin Jagdale, Usha Sharma, Raelene Kambli, Lakshmipriya Nair, Sanjiv Das

RESEARCH Applying multi-parameter optimisation in drug discovery PAGE 29

Bangalore Neelam M Kachhap Delhi Shalini Gupta

PACKAGING

MARKETING

'We will invest in Triveni in the years to come to foster growth and quality strategy' PAGE 42

Deputy General Manager Harit Mohanty Senior Manager Rajesh Bhatkal PRODUCTION

PHARMA ALLY

General Manager B R Tipnis

SAP hosting services from Netmagic enable Flamingo... PAGE 72 Pharma regulations and their future.... PAGE 73 New data shows value of morphologically ... PAGE 75

Production Manager Bhadresh Valia Asst. Manager - Scheduling & Coordination Arvind Mane Asst. Art Director Surajit Patro Chief Designer Pravin Temble

PHARMA LIFE

Senior Graphic Designer Rushikesh Konka

A Global Manager: Made in India PAGE 78

Photo Editor Sandeep Patil Layout Rakesh Sharma C I R C U L AT I O N Circulation Team Mohan Varadkar Express Pharma Reg. No.MH/MR/SOUTH-77/2013-15 RNI Regn. No.MAHENG/2005/21398 Printed for the proprietors,The Indian Express Limited by Ms.Vaidehi Thakar at The Indian Express Press, Plot No. EL-208, TTC Industrial Area, Mahape, Navi Mumbai 400710 and Published from Express Towers, 2nd Floor, Nariman Point, Mumbai - 400021.

(Editorial & Administra-tive Offices: Express Towers, 1st Floor, Nariman Point, Mumbai - 400021) *Responsible for selection of news under the PRB Act. Copyright @ 2011 The Indian Express Ltd. All rights reserved throughout the world. Reproduction in any manner, electronic or otherwise, in whole or in part, without prior written permission is prohibited.

January 16-31, 2013

MARKET ‘Monopolisation is not the way forward for vaccine industry’

PAGE 11

BioAsia forges prominent partnerships for its 10th edition PAGE 17

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EDITOR’S NOTE

Clinical trials: Edicts and effects Clinical trials and research in India seems to be in danger of getting mired in the quicksand of evolving regulation. And going by past experience, change is going to be the only constant in 2013.

Of course, regulations cannot emerge overnight.

Framing our new drug pricing policy took almost a decade. And could see more tweaking, since NGOs like the All India Drugs Action Network are determined to challenge it yet again by filing an affidavit in the Supreme Court. While industry too was not too happy with the policy, the general consensus was that “it's not perfect, but let's move on”. Restrictive pricing apart, the decade-long process of updating the country's drug pricing policy meant that in one sense, the industry was in limbo with players unable to plan long term strategy.

So are we in for a similar phase in the clinical trials and research segment?

Conducting clinical trials of new drugs in India is set to only become tougher, with increased regulatory oversight, as our Cover story (‘Clinical trials: More regulatory rigour on the cards’) points out. The regulator's directives over the past few months have increased, but while the intent to safeguard patient safety is appreciated and for the most part welcomed by industry, the content of the regulator's orders raises more queries than providing solutions.

Even those solutions already in place seem to be increasing approval timelines rather than streamlining the procedure. For example, since its inspectors were accused of not having the depth of therapeutic expertise required to judge applications for clinical trials, the CDSCO formed 12 committees of experts from government medical colleges and

8 EXPRESS PHARMA

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institutes and now acts on their advice. With one more layer added to the scrutiny process, decision making is delayed and approval timelines could go haywire.

While attempting to more clearly define the roles and responsibilities of the various links in the clinical trial process, from ethics committees to state drug control authorities, the Drug Controller General (India) seems to be sending out the message that each link will be held more accountable. It is the right tune and tone, but industry observers are wary of the nuances of these stated objectives.

From a media perspective, a clinical trials story never fails to make cover page or prime time TV. It has all the angles possible: human interest, business, legal, and ethical. And the coverage too throws up set phrases and images: poor Indian patients being treated like guinea-pigs, a profiteering and uncaring industry, toothless regulators, etc. Added to this mix are vigilante patient groups and it’s no wonder that the industry is worried about the long term impact.

Regulatory oversight is welcome, say industry observers, but it should come with greater clarity and transparency.

And how does the regulator intend to monitor that the edicts are actually being followed, both in letter and in spirit? India’s drug regulatory framework suffers from a dearth of footsoldiers, i.e. drug inspectors, who are crucial to the implementation process. Will the regulator's intent translate into sustained action down the line? Only time will tell.

Viveka Roychowdhury viveka.r@expressindia.com

January 16-31, 2013

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MARKET

W H AT ’ S INSIDE

THE BUSINESS OF PHARMACEUTICALS

‘Monopolisation is not the way forward for vaccine industry’ Panacea Biotec, one of the country’s significant vaccine manufacturers, recently received an order worth ` 187.61 crore from the government to supply polio vaccines till May 2013. Dr Rajesh Jain, Joint Managing Director, Panacea Biotec, in conversation with Shalini Gupta, talks about this welcome development, the challenges facing vaccine manufacturers, competition from China and other trends in the industry What does the recent clearance by WHO mean for India? What are the parameters?

The clearance of the National Regulatory Authority (NRA) or the Drug Controller General of India (DCGI) by WHO has a great significance for the Rs 19,000 crore domestic vaccine industry that we have built over the last three decades. It demonstrates the commitment of the domestic vaccine industry to provide vaccines to those who need it in the developing world. Out of the 133 million children born in the whole world, 121 million are born in the developing world. Out of this, 23.5 million children are born in India alone (˜20% within developing world). Vaccine production in India continues to be of good quality which is good news for the developing world. The fact that it is able to reach these children is also significant.

Looking at Indian statistics, of the six vaccines that we have in the programme, only 61 per cent of children born in India get access to the full immunisation schedule.

Individually, DPT has 80 per cent coverage and OPV has 70 per cent coverage. That's the reach of the government programme. India is now catering to 70 per cent of the volumes of vaccines for the developing world that are of good quality and affordable as well, which is the war cry in the developing world.

WHO looks at how strong is the overview and oversight of NRA or DCGI over the manufacturers in terms of continuance and adherence to GMP standards in the overall safety of the patients. The dynamism of the industry and the regulator alongwith the critical review by the DCGI of manuJanuary 16-31, 2013

INTERVIEW

facturing sites and regulatory dossiers generated by the companies before granting them new drug permissions and renewal of manufacturing licenses is also taken into account. A holistic review of how healthcare is managed per se is what is considered.

China has got a nod from the WHO last year. Given that China offers competition to India in the active pharmaceutical ingredients (API) space, do you see it as a competitor in vaccines as well?

Both the businesses are uniquely different, they are dissimilar and have nothing in common. I agree with you that China definitely has a lead in pharma products as far as APIs are concerned, but in the

final formulation business India wins hands down. The globalisation of Indian pharma or its genericisation happened in the 90s and by late 90s, Indian pharma majors such as Ranbaxy already started filing dossiers in the US. That said, vaccine manufacturing requires far more greater capabilities. A company which cannot make APIs, can still be in the business of pharmaceuticals, supplying to Europe and the US, sourcing APIs from a third party and then getting it manufactured in the final dosage forms from someone. However, in vaccine there is no concept of third party manufacturing as far as final dosage form is concerned.

Vaccine manufacturing is a biological business which www.expresspharmaonline.com

requires competency in both APIs and final dosage forms, China is yet to make a start in the latter. So, China coming up with an NRA is good news for the Chinese industry, but then where’s the industry?

There need to be manufacturers producing the vaccine which are either exported to international markets or audited by WHO. It is when these transactions take place that their preparation level and that of the NRA will be assessed. Only then can we truly say if China is in a competitive space with India or not. In our case the industry was prepared lets say 30 years back. NRA had to catch up pace. In their case industry has to catch up pace. That said when China decides, they deliver. They are going to be a formidable force to be tracked. We need to make sure that India which has a lead over them, continues to maintain that in the interest of the healthcare needs of the children of the developing world. It's not about competition in price, but about delivering good quality healthcare.

Quality, quality, quality will be the mantra.

Panacea is manufacturing products both for the pharma and the vaccine industry What are the differences between the vaccine and pharma business?

In pharma, either the insurance companies or the corporations for whom people work, pay for them while most in the developing world pay from their own pocket. In vaccines, 90 per cent of the market is around kids born in the developing world. Global agencies like GAVI, UNICEF, PAHO, WHO, JICA, DFID as donors influence policy to help governments deliver healthcare. Money is largely brought in by donors not by insurance. The entire logistics in vaccines needs controlled temperature conditions, pharmaceuticals don’t need such stringent logistic conditions.

Packaging and shipping instructions in pharma are

Biocon receives marketing authorisation from DCGI for novel biologic Itolizumab PG14 BioAsia forges prominent partnerships for its 10th edition PG17 Deal Tracker PG18 Event brief PG20

MANAGEMENT 21 RESEARCH 26 PHARMA ALLY 71

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M|A|R|K|E|T lower in terms of adversity than what a vaccine shipment would face. Though both pharma and vaccines need to abide by GMP standards the overall supply chain management is very tough even at the recipient level for vaccines.

Pharma has multi-purpose plants and the switchability of time between one product and another is few hours, the downtime is very less. In vaccines, there are dedicated plants (80-90 per cent) for one product, even if you are undertaking a second product, the down time is huge, from few weeks to almost a month.

The quality control in pharma is two to three days, for vaccines it is 40-45 days. All vaccines can only be released for sale in the market by NRA , in pharma you can do certificate analysis and release the product. In pharma, majority of the products are oral, they do not need aseptic conditions for manufacturing, but vaccines, even if oral, need aseptic conditions. Sterile manufacturing expertise is far more intricate.

These hurdles increase risk of failure. Fixed dose combinations (FDC) do not find supporters in pharma, because of a rigid attitude of regulatory bodies, in vaccines multi-dose combination are a norm (five antigens in one shot is an analogue of FDC in pharma).

Affordability with these challenges is a different ballgame altogether. I am sure China has to grapple with these challenges too, apart from market driven ones.

With drug pipelines drying up and vaccines hard to replicate as opposed to generics, Big Pharma is now foraying into vaccine business. Your views.

For a long time, companies

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did not jump into the vaccines business, since it was financially not viable. Companies did not see much potential in the developing world, donors never came forward, governments were not paying for it, also it was difficult to replicate with regulatory standards not being clear. There were few players in the vaccine industry but intervention from donor agencies and organisations such as the Bill and Melinda Gates Foundation helped bring countries, governments, HNIs and NGOs together to donate money to such social causes.

New vaccines brought in by other companies and research institutes such as Gardasil, Prevnar, etc. have hit blockbuster status. Vaccines were never known to be billion dollar products and not many came up in the past few years.

All these factors have aroused the interest in the industry as well as the investor community about a line of business which can also give returns and have a huge social impact.

New companies entering the market need to think about affordability, a differential pricing system for the developing world. Profit can’t be the only motive, there is a need to work with key enabling organisations including developing country vaccine manufacturers to ensure a global reach of the product. Monopolisation is not the way forward for vaccine industry, there has to be a sense of collective responsibility and shared concern that one can move forward in this business and grow in the future.

What are some of the diseases of the Indian population for which we need vaccines?

Vaccines for Malaria, TB,

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typhoid and cholera are the most needed in India is the next 10 years including epidemic related diseases such as dengue, Japanese encephalitis, chikungunya etc. Of these, dengue has fatal consequences, needs to be taken far more seriously. The concept of a vaccine for flu, needs to pick up in India. A pneumococcal conjugate vaccine is also highly anticipated.

Do you see a shift from paediatric vaccines to vaccines for infectious diseases?

There is huge research being done at academic level as well as applied research at industry level for therapeutic vaccines. They are going to add huge value to the pharma interventions and will grow with time, but to say that they have arrived, would not be the right thing. We haven’t had any great success around therapeutic vaccines, largely because the disease profile is such that pharma need to be given, length of treatment is long and clinical protocols of evaluation are comparative in nature. To evaluate the contributions of a therapeutic vaccine would take more time since real advantages come only in five to seven years, when we talk of chronic diseases like cancer and gastrointestinal diseases like hepatitis B etc. It’s an exciting area but it’s still early days for any meaningful product to come.

Affordable healthcare is the need of the hour. What are the challenges as a vaccine manufacturer to achieve affordability?

Vaccine business aims at keeping healthy people healthy and productive throughout their life cycle.

Affordability here is linked with the R&D cost and the manufacturing capacities that you build when it comes to execution. The market is centred around government and UN organisations, who give us the visibility of the disease, whether countries agree to use this vaccine. So we need to work closely with them to make sure that the capacities that we build are in time with upcoming demand. This is very iterative unlike pharma, where the market size is known, along with which drug is going off patent, so the company just needs to put the dossier and cut the market.

Here, it is driven by unmet needs, facilitated by enabling organisations and increasing awareness within governments, when they adopt, one has to be ready. However, it is not easy to do so, hence you end up with assets ahead of the demand underutilised.

These over the course of time build up cost structures and when the demand comes in, it overshoots the capacities installed. Hence a strong need has been felt for advanced demand planning as compared to what it was 10 years ago. Different models have been worked out to ensure this. For eg. from routine tender inquiries for one or two years, now we have long-term agreements (LTAs) for three years or even four. In some cases advance market commitments (AMC) have worked in, wherein you get commitments ahead of time, they could even be as long as 5-10 years. The whole model from ad hoc demand generation and bidding has moved to more LTAs and advance commitments.

Buyers are working on financing mechanisms to reduce cost. Funding technology at a

January 16-31, 2013

M|A|R|K|E|T research institute, which can then be followed by manufacturing and supply by some company. This saves R&D cost to a company. Better demand planning can help balance whatever investment you have done in the manufacturing through LTAs and AMCs so that you don’t have an underused asset or a demand that you can’t cater to.

Do you think Indian vaccine manufactures are possible target for MNCs? Just because one company was acquired, doesn't make a case for others, but its a good case to be investigated, it might shed light on the challenges that they were facing that made them sell out.

Its about bringing up a company and then at some stage continuing with it or selling it out. But looking from outside in - researching, manufacturing and coming to a point of break even and making profits is a long drawn out process, it is absolutely capital intensive.

With no clarity about demand, no databases, that such a demand is available, financial crunch, the question

January 16-31, 2013

is who would come and invest money in such a venture and how much appetite for patience would one have to continue to wait for results.

While there could be possible motivations, a company which has crossed those minimum benchmarks of sustaining itself as a business entity whether it is around financial viability, capacities, product pipelines, quality standards or supply chain management will become a potential target for an investor, especially for companies who would have missed that piece of business in their growth journey. While Shantha would have had its own share of challenges to come upto that level, a Sanofi, missed a pentavalent vaccine, it did not have that in its portfolio.

Can innovation and affordability go hand in hand?

They are both different. I feel that it is important for a country like India to pay attention to innovation and play a meaningful role in bringing affordable innovative products.

However, I would still like to focus on current products that

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we procure, because we need to ensure that existing medicines are good quality and affordable, that’s the immediate need. Our immediate goal should be to continue to produce already licensed pharma products at good quality and affordable cost for consumption by large masses and then graduate to a level of innovation in the long term.

Collaborations are seen as a better way of risk sharing.

Your views.

The answers would be different from the perspective of each company. A Sun or Zydus Cadila has matured and riding the wave from the front, they don’t need collaborations, as for us, we are followon entrants, for us to compete with them and say a Mylan or Teva is a different ballgame.

We need to think what new value do we want to create, even if we have the value, do we have the muscle to take it to the market? The latter includes research, financials, execution capability in manufacturing, distribution, in short a full chain of events that come together to make us a

vectorial force that moves forward. As a follow on player, I already have a huge task of creating a value proposition.

The business plan needs to be differentiated to fight those formidable ones. To us, collaborations was a better way forward. Our partners had certain strengths they missed for e.g.

R&D manufacturing, we missed the front end. We needed more expertise on how to be successful in the US in the form of a knowledge partner having financial capability and ground presence who could also help us in research, development and regulatory aspects. They lead, we support. This conjugation, we felt could be a formidable alliance that can help us navigate and deliver that differentiated value faster to the market than we would have been able to ourself . For the next few years, this is going to be our business model because it helps us move with right time first approach. There is no second try, whether it is vaccines or pharma, in India as well as other markets. shalini.g@expressindia.com

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COMPANY WATCH M&A activity is showing strong signs of a revival in pharmaceutical industry: Avendus Securities Investors’ reactions to M&A announcements have been mixed

report by Avendus Securities on the pharmaceutical sector has stated that after a subdued three years, the M&A activity has shown strong signs of revival in the industry. While inorganic initiatives were concentrated in the hands of a couple of entities in FY12, participants appear to be more broad based over the nine months of FY13. Along with organic investments, capital deployment is at its highest level, as the industry builds blocks for future growth.

Currently, the industry stays net cash positive.

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However, the situation could alter if the announced acquisitions in the pipeline are concluded. Nevertheless, as a proportion of MCap, the net debt position stays firmly comfortable.

Investors’ reactions to M&A announcements have been mixed—warm, but not overtly so—as the reward to grow inorganically has probably been tempered down, to an extent, by the costly failures of the past.

Nevertheless, the industry’s net cash position, along with scope for fund raising, supports an M&A theme

through 2013.

According to the report, four of the seven deals in the past 15 months were followed by a significant stock out-performance in the immediate four weeks.

However, there has been a subdued reaction to three announcements, indicating that investors’ reward and appreciation towards inorganic initiatives has been probably tempered down, to an extent, by the costly failures of the past.

Challenges in integration pose a prominent risk to M&A, particularly in a cross

border acquisition. In the past, a combination of regulatory and price environment changes have resulted in costly failures in cross border acquisitions. As the industry builds blocks for future growth—in research, technology platforms, manufacturing, plugging portfolio loopholes and establishing a front end—M&A activity is likely to stay high through 2013 and would be among the key guiding posts in determining stock directions.

EP News Bureau-Mumbai

India to exhibit greatest surge in flu vaccine demand over next decade: Global Data Yet despite an AGR of 2.1 per cent, percentage of flu-vaccinated Indians will total only 1.7 per cent of population by 2022 hile US demand for influenza vaccines will remain high in the coming decade, following a post-flu pandemic spike, India is expected to exhibit the greatest surge in vaccine demand over the next 10 years, climbing at a Annual Growth Rate (AGR) of 2.1 per cent. However, despite this relative growth, GlobalData estimates that the percentage of

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influenza-vaccinated citizens in India will total a meager 1.7 per cent of the population by 2022.

GlobalData's Seasonal Influenza Vaccines EpiCast Report provides an overview of risk factors for seasonal influenza and global trends for seasonal influenza vaccination coverage in nine major markets: US, France,

Germany, Italy, Spain, the UK, Japan, India, and China.

According to the report, seasonal influenza vaccine demand will increase from the 142 million expected for 2012 to 158 million in 2022, representing an AGR of 1.2 per cent. After the H1N1 (originally named ‘swine flu’) pandemic claimed thousands of lives across the US in 2009, the number of those vaccinated annually climbed significantly–from 24 per cent in 2007 to 41 per cent in

2010 for citizens aged 5-64 years according to the US Centers for Disease Control and Prevention (CDC). The new GlobalData report says that the primary driver for the predicted growth in influenza vaccine demand will be a general increase in the US population and the corresponding rise in those classed as high-risk, such as the elderly or those with preexisting conditions.

EP News Bureau-Mumbai

Wockhardt launches generic version of Lamictal XR Lamotrigine is used in the treatment of epilepsy ockhardt has received final approval from US FDA for marketing 25 mg, 50 mg, 100 mg, 200 mg and 300 mg extended release tablets of Lamotrigine, which is used in treatment of epilepsy. Lamotrigine is the generic name for the brand Lamictal XR, marketed in the US by Glaxo SmithKline. The product will be amongst the earliest generic versions of this

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product in the market.

Dr Habil Khorakiwala, Founder Chairman and Group CEO, Wockhardt said, “We are continuing our rapid momentum of 2012 into the New Year with this approval of Lamotrigine extended release tablets.

This is the sixth product with drug delivery technology that has received US FDA approval in the last five months, a continuing testiwww.expresspharmaonline.com

mony to the R&D capabilities of Wockhardt.”

According to IMS Health, the total market for

THE PRODUCT WILL BE AMONGST THE EARLIEST GENERICVERSIONS OF THIS PRODUCT IN THE MARKET

this product in the US is about $250 million.

Lamotrigine is used extensively in management of epilepsy. Wockhardt already markets several other products in the US in the CNS segment, especially anticonvulsant drugs.

Wockhardt will be manufacturing the extended-release tablets of Lamotridine at its facility in Aurangabad. The technology was developed in-house.

EP News Bureau-Mumbai January 16-31, 2013

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Suven Life Sciences secures three product patents for NCEs in Eurasia and Canada The patents are valid through 2027 uven Life Sciences announced that the grant of three product patents, two from Eurasia (016594&017007) and one from Canada (2683124) corresponding to the New Chemical Entities (NCEs) for the treatment of disorders associated with neurodegenerative diseases and these patents are valid through 2027.

The granted claims of the patents include the class of selective 5-HT compounds discovered by Suven and are being developed as therapeutic agents and are useful in the treatment of cognitive impairment associated with neurodegenerative disorders like Alzheimer’s disease, Attention Deficient Hyperactivity Disorder (ADHD), huntington’s disease, parkinson and

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schizophrenia. With these new patents, Suven has a total of 10 granted product patents from Canada and 12 granted product patents from Eurasia.

These granted patents are exclusive intellectual property of Suven and are achieved through the internal discovery research efforts. Products out of these inventions may be out-licensed at various phases

of clinical development like at Phase-I or Phase-II. “We are pleased by the grant of these patents to Suven for our pipeline of molecules in CNS arena that are being developed for cog-

nitive disorders with high unmet medical need with huge market potential globally,” says Venkat Jasti, Chief Executive Officer, Suven..

EP News Bureau-Mumbai

An Investment in Drug Protection

Aurobindo Pharma receives US FDA approval for Rizatriptan Benzoate tabs urobindo Pharma has received final approval from the US Food & Drug Administration (US FDA) to manufacture and market Rizatriptan Benzoate tablets 5mg (base) and 10mg (base) (ANDA 202490), which was earlier tentatively approved.

The product is ready for launch.

Rizatriptan Benzoate tablets 5mg (base) and 10mg (base) is the generic equivalent of Merck and Co’s Maxalt tablets 5mg (base) and 10mg (base) and is indicated for the acute treatment of migraine with or without aura in adults and in paediatric patients six to 17 years old. The annual sale of the product is approximately $300 million for the twelve months ending March 2012 according to IMS. The product has been approved out of Unit VII SEZ formulations facility in Hyderabad.

Aurobindo now has a total of 171 ANDA approvals (146 final approvals including two from Aurolife Pharma and 25 tentative approvals) from US FDA.

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EP News Bureau-Mumbai January 16-31, 2013

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Biocon receives marketing authorisation from DCGI for novel biologic Itolizumab Approval paves the way for the launch of Biocon’s Alzumab in India iocon has received marketing authorisation from the Drugs Controller General of India (DCGI) for its novel biologic Itolizumab, anti CD6 molecule, for the treatment of chronic plaque psoriasis.

This approval paves the way for the launch of Biocon’s Alzumab in India, later during 2013.

Alzumab is a differentiated biologic drug with a supe-

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rior safety profile compared to other approved biologic therapies given its very low opportunistic infection rates.

A novel biologic indicated for the treatment of moderate-tosevere psoriasis, Alzumab will be marketed by Biocon’s Immunotherapy Division.

Alzumab, will be manufactured and formulated as an infusion drug at Biocon’s Biopharma manufacturing facility at Biocon Park,

Bangalore.

Kiran Mazumdar-Shaw, Chairman and Managing Director, Biocon said, “We are excited to receive this marketing authorisation for Itolizumab from DCGI which will enable Biocon to introduce this novel, first in class biologic for the treatment of psoriasis patients in India. This is our second novel biologic that we have developed in India, BioMab EGFR, an anti-cancer monoclonal antibody, being the first. This approval paves

the way for us to extend clinical development for other indications like Rheumatoid Arthritis (RA), Multiple Sclerosis (MS) and Vitiligo. We also intend to file a US IND shortly to enable us to embark on a global clinical development plan. This is a defining moment for Biocon as it reaches a significant milestone in its mission of delivering affordable innovation to patients worldwide.”

EP News Bureau-Mumbai

MCC-South Africa approval opens up key African markets for Marck Biosciences Six products from SVP facility at Kheda gets Medicines Control Council-South Africa approval arck Biosciences has received an approval from South African Medicines Control Council for six products manufactured at its Small Volume Parenterals (SVP) facility at Kheda. The South African market, at around USD 3.8 billion (2011), is growing at 6 per cent and is expected to reach $7 billion in 2018, with generics accounting for 60 per cent of the volume.

The MCC approval will also enable Marck Biosciences to achieve immediate access to key markets including Namibia, Botswana, Zimbabwe, Swaziland,

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Lesotho, Zambia, Malawi and Madagascar. MCC approval is expected to result in waiver of inspection by the authorities of these countries and an easier registration of certified products.

For Marck Biosciences, the approval carries the opportunity of accessing some of Africa’s most stable growth economies.

The Medicines Control Council is a statutory body that oversees the regulation of medicines in South Africa. Its main purpose is to ensure that all medicines that are sold and used in South Africa are safe, therapeutically effective and consistently meet acceptable

standards of quality.

MCC-South Africa’s certification is also recognised by 43 participating authorities of the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S). This may facilitate export by Marck Biosciences of certified SVP to PIC/S participating authorities as well as non-PIC/S authorities who accept GMP certificates from PIC/S participating authorities.

Bhavesh Patel, Managing Director, Marck Biosciences, said, “The MCC-South Africa approval for our Kheda facility will provide further impetus to our current expansion efforts in the African region and PIC/S countries. We

would also augment our efforts by our own filing and licensing with new partners in SA. I see strong revenue potential in these underserved markets and we believe that we can make a quantum contribution to healthcare products in these countries.”

Six products have obtained approvals from MCC-South Africa, including Sterile Water For Injections BP 5/10 ml; Ciprofloxacin Eye Drops 5/10 ml; Timolol 0.25 per cent Eye Drops 5/10 ml; Timolol 0. 50 per cent Eye Drops 5/10 ml; Lidocaine Injection BP 1 per cent 5/10 ml and Lidocaine Injection BP 2 per cent 5/10 ml.

EP News Bureau-Mumbai

GVK Biosciences partners with Onconova Therapeutics Joint partnership will be based in the US and will align research priorities and technological expertise VK BIO and Onconova Therapeutics, an USbased biopharmaceutical company have entered into a novel joint partnership to develop new drugs for cancer. The joint partnership will be based in the US and will align research priorities and technological expertise from both companies to facilitate moving certain Onconova oncology assets from early discovery to clinical development stage.

Dr E Premkumar Reddy, Scientific Founder and

G

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Director, Onconova and a world-renowned molecular oncologist, will oversee the biology and biomarker aspects of the partnership.

Onconova will provide two discovery targets with early chemical equity, while GVK BIO will use its multi-disciplinary discovery platform to advance these programmes

GVK BIO WILL GAIN UP TO A 50/50 SPLIT BASED ON ACHIEVEMENT OF MILESTONES www.expresspharmaonline.com

through lead optimisation.

GVK BIO will gain an increasing share of the programmes as they advance, up to a 50/50 split based on achievement of milestones/ funding brought into the joint partnership. Onconova retains the rights to buy back the programmes.

Onconova brings a wealth of knowledge in oncology, with an expertise of disease target pathways, hits, and development capabilities in the US, Europe and India. GVK BIO brings its broad experience of working with over 200 pharma and biotech companies across multiple service

offerings, a strong scientific pool of over 2,000 scientists, and an IP generating capability.

“The demands for integrated and outcome-based research deals are increasing in the service business.

This announcement shows GVK BIO’s commitment to new and innovative models for drug discovery with partners. Onconova is a leading oncology company and GVK BIO is happy to partner with them.” said Manni Kantipudi, CEO, GVK BIO. EP News Bureau-Mumbai

January 16-31, 2013

M|A|R|K|E|T

PRE EVENT BioAsia forges prominent partnerships for its 10th edition Spain joins in as the Country Partner and Victoria (Australia) is the international state partner

The 10th edition of this leading industry event has also received tremendous

response from the industry with Natco, Lonza, Mayar Biotech joining as the indus-

try co-host.

The principal industry host is GVK Biosciences,

industry co-hosts are Natco Pharma, Bharat Biotech, Continued on Pg-19

ioAsia, Asia’s technology and bio-business platform for biotechnology and life sciences announced that Spain will be the Country Partner and GVK Biosciences will be the principal industry sponsor for the 10th edition of BioAsia—BioAsia 2013.

Taking place at the Hyderabad International Convention Centre (HICC), Hyderabad from January 28 to 30, the life sciences dynamic global forum will witness convergence under its cutting-edge theme of Technologies Business Next.

BioAsia 2013, hosted by Government of Andhra Pradesh with the support

B

BIOASIA 2013 WILL BE HELD AT HYDERABAD INTERNATIONAL CONVENTION CENTRE, FROM JANUARY 28 TO 30 AND WILL BE HOSTED BY GOVT OF ANDHRA PRADESH WITH THE SUPPORT FROM FABA AND PHARMEXCIL FABA and Pharmexcil, is going to be the window to the future of lifesciences.

BioAsia 2013 has also joined hands with Victoria (Australia) which is the international state partner for the event this year.

These country and state level partnerships will open up and enhance the bilateral trade in these regions in addition to fostering scientific and technological collaborations.

January 16-31, 2013

www.expresspharmaonline.com

EXPRESS PHARMA

17

M|A|R|K|E|T DEAL TRACKER

M&A activity in pharma market continue to focus on increasing product offerings Indian pharmaceutical sector witnesses no deals during December 2012 M&A (including private equity) trend analysis

Mergers and acquisitions

Source:

Top M&A deals (Dec 2012) Rank

Date

Target

Acquirer

Deal value ($m)

1

12/12/12

YM BioSciences, Inc. (CA)

Gilead Sciences, Inc. (US)

510

2

12/10/12

deCODE genetics, Inc. (IS)

Amgen, Inc. (US)

415

3

12/31/12

JHP Pharmaceuticals, LLC (US)

Warburg Pincus LLC; JHP Holdings LLC

195

4

12/12/12

Incline Therapeutics, Inc. (US)

The Medicines Company (US)

18

5

12/06/12

Amarin Corporation plc (IE)

Pharmakon Advisors, LP (US)

100

6

12/14/12

H. Lundbeck A/S - Product portfolio (DK)

Recordati S.p.A. (IT)

100

7

12/16/12

AbD Serotec (US)

Bio-Rad Laboratories, Inc. (US)

69.78

8

12/20/12

Nuron Biotech (US)

Healthcare Royalty Partners II, L.P (US)

30

9

12/11/12

Somaxon Pharmaceuticals, Inc. (US)

Pernix Therapeutics Holdings, Inc. (US)

25

10

12/10/12

Verenium Corporation (US)

Athyrium Opportunities Fund (US)

22.5

Source:

Venture financing trend analysis

M&A activity in the pharmaceutical sector continued to focus on expanding product pipeline as companies were looking for opportunities to add complementary programmes.

In line with the above trend, US-based Gilead Sciences agreed to acquire YM BioSciences, a Canadabased drug development company, for approximately $510 million. This acquisition represents an opportunity for Gilead Sciences to add a complementary clinical programme in the area of haematologic cancers.

With this transaction, Gilead Sciences will gain access to YM Biosciences’ CYT387, an orally administered inhibitor of both the JAK1 and JAK2 kinases, which have been implicated in a number of haematological and immune cell disorders including myeloproliferative neoplasms and inflammatory diseases as well as certain cancers.

In another key deal, Pernix Therapeutics agreed to acquire Somaxon Pharmaceuticals, a US-based specialty pharma company for $25 million. This transaction is an important step in the growth strategy of Pernix, which is expected to continue to expand its product portfolio.

With this acquisition, Pernix will gain access to Silenor, an approved product for the treatment of insomnia characterised by difficulty with sleep maintenance.

M&A activity in the pharma sector increased in volume terms and decreased in value terms, when compared to the average of previous six months’ (Jun 2012–Nov 2012). According to Datamonitor's Medtrack database, the pharma sector recorded 37 M&A transactions in December 2012, against the previous six months’ average of 33 transactions. In value terms, the sector recorded deals worth $1.7 billion against the previous six months’ average of $4.1 billion.

The Indian pharma sector witnessed no deals during December 2012, against the average of 0.6 deals over the previous six months.

Venture funding Companies in the pharma sector raised $365.1 million during December 2012, against the previous six months’ average of $357.4 million. In terms of volume, the sector recorded 17 venture funded deals, compared to the previous six months’ average of 25 transactions.

Notes and definitions

Source:

Top venture financing deals (Dec 2012) Rank

Date

Target

Investors

Deal value ($m)

1

12/20/12

Ultragenyx Pharmaceutical, Inc. (US)

Adage Capital Management L.P. ; TPG Biotech; Fidelity Biosciences; HealthCap; Pappas Ventures

75.00

2

12/17/12

Regado Biosciences, Inc. (US)

RusnanoMedInvest ; Baxter Ventures ; Edmond de Rothschild Investment 51 Partners ; Domain Associates, L.L.C.; Quaker Partners ; The Aurora Funds, Inc. ; Caxton Advantage Life Sciences Fund, LP

3

12/11/12

23andMe, Inc. (US)

Yuri Milner ; Sergey Brin; Anne Wojcicki; New Enterprise Associates, Inc. ; Google Ventures; MPM Capital

50

4

12/17/12

Naurex, Inc. (US)

Baxter Ventures ; Savitr Capital LLC; Adams Street Partners, LLC; Latterell Venture Partners; Genesys Capital; PathoCapital; Druid BioVentures ; Northwestern University; H Lundbeck A/S; Takeda Ventures, Inc; Shire plc; Undisclosed Investors

38

Novo Ventures; Alta Partners; RiverVest Venture Partners; Roche Venture Fund

32

5

12/17/12

Allakos, Inc (US)

Medtrack is a comprehensive, fully integrated, global biomedical database providing information on companies, products, patents, deals, venture financing, and epidemiology. It is a live database, constantly updated with news, milestones, trial information, etc.

Medtrack’s unmatched coverage is supported by a userfriendly, highly dynamic set of decision support tools and analytics. In-house analysts and researchers add key insights and conclusions to provide you with the primary and secondary information you need. Key uses of the database include competitive intelligence, target identification, screen potential licensing and investment opportunities, patent assessments, product due diligence, royalty valuations, and developmental benchmarking.

For more information, visit us at www.medtrack.com

Definitions 1.Deal value trend is based on transactions where associate values have been disclosed.

2.Trend analysis excludes rumored and terminated deals.

3.Value and volume analysis excludes private equity exits.

Source:

18

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www.expresspharmaonline.com

January 16-31, 2013

M|A|R|K|E|T Continued from Pg 17 Lonza, Mayar Biotech; corporate sponsors are IKS International (Netherlands), Canara Bank; session sponsor is - GE Healthcare; logistic partner is Sequel Logistics; State partners are Karnataka and Madhya Pradesh; partners are APIIC, FICCI and knowledge partner is Grant Thornton.

Department of Biotechnology; Department of Pharmaceuticals; Indian Council of Medical Research; Defense Research and Development Organisation (DRDO) from the Government of India have joined hands with BioAsia 2013 each year.

Commenting on the event S Raghavan, Joint Secretary, Department of Biotechnology, GoI—the apex body for Biotechnology in the country said, “BioAsia is playing an important role in mobilising investments into the biotechnology arena of the country. It has emerged as a prominent platform for facilitating investments, exploring technology opportunities as well as research and innovations for the sector. Department of Biotechnology is happy to support this global event.

The 10th edition of BioAsia has attracted a wider participation from across the industry that will culminate into more holistic discussion, debate and decision making giving the much needed momentum to the growth of the biotech industry.”

Shakthi M Nagappan, Chief Executive Officer, BioAsia, said, “We are delighted with the response from various regions and industry stalwarts like to be part of BioAsia 2013. Our partners, sponsors and participants have recognised the incremental value that BioAsia has added to the industry and we are confident to carry forward the momentum with our 10th edition which is all set to bring excellent opportunities to network with potential business prospects across geographies and deliberate on the growth drivers of future.”

Commenting on the continued partnership with BioAsia, Manni Kantipudi, Chief Executive Officer, GVK Biosciences said, “I have seen BioAsia grow yearover-year for the last five years. It has evolved to be January 16-31, 2013

one of the top conferences in India for bio-pharmaceutical companies and offers a good platform for industry/Government interaction.

Today, BioAsia has a global reach and has participants from over 50 countries. GVK BIO is pleased to be the principal sponsors for BioAsia 2013.”

Dr AKS Bhujangara Rao, President (R&D), Natco

Pharma said, “Bio-Asia has been the ‘mouth- piece’ of the Indian life sciences activities bridging state-ofthe-art academic inventions the industry’s emerging capabilities and the societal health care needs. The Indian bio-pharma industry is grateful to Bio-Asia for its initiatives over the years.”

“BioAsia provides the perfect platform to target the

right persons at the right level. We are pleased to partner with BioAsia and believe that it is a forum to launch and create visibility for our Indian subsidiary,” said Vikas Bhargava, Director (India Operations), IKS International.

“BioAsia as a platform has been evolving consistently each year adding new dimensions to spur the

expansion of the industry with the growing global participation. We see a great potential in this event as it has and continue to help biopharma and life sciences industry to prosper and grow to new heights,” said Deepak Sood, Business Director—South Asia and Middle East, Lonza Biosciences.

EP News Bureau

33-year history of partnership with leading pharma companies

AZITHROMYCIN AZITHROMY CIN active pharmaceutical ingredients & its intermediates* Commercial scale Antitubercular Pyrazinamide# * Isoniazid # *

Antimalarial Artesunate Arteether Artemether# * Dihydroartemisinin Lumefantrine# * Piperaquine

Macrolides

Antihypertensive

Azithromycin Clarithromycin Erythromycin base # # Erythromycin estolate Erythromycin ethyl succinate+ Erythromycin oxime (intermediate) Erythromycin stearate #

Irbesartan # Losartan potassium Telmisartan Valsartan

Antihistaminic

Alendronate sodium Zoledronic acid

Sedative, Hypnotic Zopiclone

#

Antifungal Flucytosine

#

Cetirizine dihydrochloride # Hydroxyzine diydrochlorid + Meclizine diydrochlorid

Antiosteoporotic

#

Antiepileptic Valproic acid

Antidepressant Venlafaxine hydrochloride

Under Development Antiretroviral

Antidiabetic

Hypnotic

Antithrombotic

Ganciclovir Valaciclovir Valganciclovir Maraviroc

Linagliptin Vildagliptin

Eszopiclone

Clopidogrel bisulphate

* WHO APIMF

CEP / COS

*The Technical and Physical manufacturing capabilities exist with us for the above APIs and their intermediates. However these products will be offered only to the markets where any product or process patents are not infringing. During the validity of a patent the research quantities for developing products for regulatory submissions will only be offered to countries where such exemption exists (Hatch Waxman Act / Bolar exemption). While Calyx offers to work with the clients on Patent Status Verification, the final responsibility vests with the buyer. Recipients are requested to make their evaluation and determination as to the patent status prior to their use of the information or materials in their respective jurisdiction.

Products under patent offered only for exempted research, clinical and development purposes. Only non-infringing products and processes are offered, subject to patent status verification by client.

Calyx Chemicals and Pharmaceuticals Limited Reg. Office: Unit No.110, Marwah's Complex, Krishanlal Marwah Marg, Off. Saki Vihar Road, Andheri (East), Mumbai – 400072, Maharashtra, India.

Tel: +91-22-28571191, Fax: +91-22-66466416, Email: sales@calyxindia.com, crams@calyxindia.com USA Contact : 11728 E. Imperial Highway, Norwalk, CA 90650, Tel - 213-291-7773, Email: sales@calyxusa.com, crams@calyxusa.com Website : www.calyxindia.com "Calyx Chemicals and Pharmaceuticals Limited (the “Company”) is proposing to make, subject to receipt of requisite approvals, market conditions and other considerations, an Initial Public Offering of its equity shares (the “IPO") and has filed the Draft Red Herring Prospectus (the “DRHP”) with the Securities and Exchange Board of India (“SEBI”). The DRHP is available on the website of SEBI at www.sebi.gov.in, the website of the BRLMs, i.e. PL Capital Markets Private Limited at www.plindia.com and YES Bank Limited at www.yesbank.in and is also available on the website of the Company at www.calyx-pharma.com. Potential investors should note that investment in equity shares involves a degree of risk. For details, please refer to the DRHP, including the section titled “Risk Factors” of the DRHP. This publicity material does not constitute an offer of securities in any jurisdiction, including the United States of America (“USA”). Securities may not be offered or sold in the USA without registration under the U.S. Securities Act of 1933 as amended, or an exemption therefrom. The Company has not and does not intend to offer any securities to the public in the USA”.

www.expresspharmaonline.com

EXPRESS PHARMA

19

M|A|R|K|E|T

EVENT BRIEF High Potent Drugs 2013 Date: January 23-25, 2013 Venue: Holiday Inn Mumbai International Airport Summary: CPhI’s unique High Potent Drugs 2013 conference, is the only event in India bringing heads of high potent drug manufacturing and R&D together. It will cover complexities at each level of high potent drug R&D and manufacturing and will focus on latest technologies in handling potent drugs, waste disposal and state-of-the-art facility design with practical case study insights. Safebridge, Affygility Solutions, LAT Pharma, Cadila, Famy Care, Rephine and many more will join this conference. Discussions will be held on most successful strategies to develop and manufacture high potent drugs.

Contact details: Tel: +91 (0)22 40461466 Email: conferences-india@ubm.com Website: http://www.highpotentdrugs.com/?utm_ campaign=MEDIAPARTNER&utm_me dium=EVENTLISTING&utm_source=E XPRESSPHARMA

BioAsia 2013 Date: January 28-30, 2013 Venue: Hyderabad Summary: Biotechnology being an emerging industry, game-changing strategies and relevant application of the knowledge-intelligence resource pool, drive the process of growth.

BioAsia seeks to enhance, enrich and encourage newer innovations, pathbreaking discoveries and effective solutions in the industry by offering a vibrant global platform for convergence of the key stakeholders - Biotech & Biopharma companies, research institutions, investors, service providers, policy makers, regulators and analysts.

Contact details: BioAsia Secretariat 204, Imperial Apartments Greenlands Circle, Ameerpet Hyderabad 500016 Andhra Pradesh, India Tel: +91 40-6644 6477 +91 40-6644 6577 Website: info@bioasia.in

STEM 2013 Date: January 31-February 1, 2013 Venue: Fortune Park JP Celestial, Race Course Road, Bangalore

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Summary: STEM 2013 conference will focus on the latest trends in stem cell research and application, regenerative medicine and tissue engineering, inviting leading biotech and pharma companies, research organisations, scientists, companies into instrumentation and support systems, academic institutions, students, investment companies and law firms. The conference will be organised by Society for Regenerative Medicine & Tissue Engineering.

Contact details: Sankar Iyer Organizational Secretary SRMTE (Society for Regenerative Medicine and Tissue Engineering) 3, Lopez Apt, LM Road, Navagaon, Dahisar, Mumbai-400068 Tel: +91 22 2892 6657 Mob: +91 / 7838653861 / 93232 75711

Bangalore INDIA BIO 2013 Date: February 6-8, 2013 Venue: Bangalore, India Summary: Bangalore INDIA BIO is an annual event organised by Department of Science & Technology Government of Karnataka, under the guidance of Vision Group of Biotechnology. Since 2001, Bangalore INDIA BIO has been promoting the Indian biotech industry to the outside world and is one of the biggest event on life sciences.

Bangalore INDIA BIO 2013 will be an opportunity to get insights about the latest trends and biotech business opportunities in India.

It will also deliberate on issues related to the latest innovations in biotechnology and focus on business opportunities that exist for companies in biopharmaceuticals, bio-industrial, bio-services, bio-informatics and agri-biotechnology in the light of the emerging bio economy.

It will also discuss about collaborative and integrative business models as well as policy, regulation, and investment challenges for biotechnology in a global bio-economy and will provide networking and knowledge sharing platform for business leaders, policy makers, research heads and academia.

Contact details: MM Activ #9, UNI Building, 1st Floor, Thimmaiah Road, Millers Tank Bed, Vasanthnagar, Bangalore - 560 052

Tel: +91 80 4113 1912 / 13 Fax: +91 80 4113 1914 Website: enquiry@bangaloreindiabio.in

PHARMA Pro&Pack 2013 Date: April 24—26, 2013

4th Annual Biosimilars Date: March 6-8, 2013 Venue: Mumbai, India Summary: With over 100 attendees in 2012, the 4th Annual Biosimilars is all set to be bigger and better with exclusive focus on process development and analytics to suggest best strategies for developing the first commercially successful molecule.

Designed under the guidance of the strategic advisory members, this three-day strategic meet will be a platform to understand practical solutions to minimise the risks associated with the highest spend areas of the biosimilars development cycle.

Don’t miss this exclusive chance of engaging with the top biosimilars experts in India and across the globe!

Contact details: Tel: +91 (0)22 40461466 email: conferences-india@ubm.com Website: http://www.biosimilarsindia.com/?utm_campaign=MEDIAPARTNER&utm_medium=EVENTLI STING&utm_source=EXPRESSPHA RMA

Global Pharma Regulatory Summit Date: March 11-15, 2013 Venue: Mumbai Summary: 2nd Annual Global Pharma Regulatory Summit will focus on the recent regulatory amendments for 2013.

The conference agenda includes a pre-conference summit on GDUFA, US focused day, EU focused day, ROW focused day and a workshop on eCTD Lifecycle management. Some of the confirmed speakers for this summit include Ashish Kohli - Pfizer UK, Naveen Kumar Jain Dr Reddy’s, Dr Rajkiran Jain - Zydus Cadila, Dr Hoss Dowlat - PharmaBio Consulting, Germany, Jasbir Chohan - PEC, UK and many more.

Contact details: Tel: +91 (0)22 40461466 e-mail: conferences-india@ubm.com Website: http://www.pharmaregulationindia.com/?utm_campaign=MEDIAPARTNER&utm_medium=EVENTLI STING&utm_source=EXPRESSPHA RMA

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Venue: Mumbai Exhibition Centre, Goregaon Summary: PPPE 2013 is an initiative of the Indian Pharma Machinery Manufacturers’ Association (IPMMA), jointly with GPE Expo. The event will offer a single platform for more than 200 exhibiting companies from India and across the world to showcase their products.

Contact details: Paresh Jhurmurwala GPE EXPO Global, Opp. Priyadarshini Tower, Near Judges’ Bungalows, Bodakdev, Ahmedabad 380015, Gujarat Tel: +91 79-2687 1390 +91 79-4000 8253 +91 79-4000 8233 Email: contact@pharmapropack.com

iPHEX 2013 Date: April 24-26, 2013 Venue: Bombay Exhibition Centre Summary: The Pharmaceuticals Export Promotion Council of India (Pharmexcil), has announced the launch of iPHEX 2013, India’s own pharmaceutical show under the support of Ministry of Commerce and Industry, Department of Commerce, and Government of India.

Over 400 leading Indian companies are expected to showcase the best of pharma products at the event.

The organisers claim that iPHEX 2013 will see the presence of 5,000 business visitors including overseas buyers and drug regulators. Huge business opportunities are expected to emerge during the event. Further, the presence of large number of drug regulators from overseas market is expected to help Pharmexcil and its members to promote the quality and affordability aspect as envisaged in ‘Brand India’ pharma campaign. The campaign has been initiated by Ministry of Commerce and executed by Pharmexcil in association with IBEF. Contact details: Sanika Patil ProjectManager – IPHEX 2013 Tel: 91.11.23324288 M: 91.9582758812 E-mail: sanika@falcon-mail.com January 16-31, 2013

MANAGEMENT

W H AT ’ S INSIDE

INSIGHT FOR MANAGING PHARMA

Fellowship of the chain: Dietary supplements & nutraceuticals PG 24

RESEARCH 26 PHARMA ALLY 71 PHARMA LIFE 78 January 16-31, 2013

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M|A|N|A|G|E|M|E|N|T

I

In the past year, the pharmaceutical sector seems to have attracted more than its fair share of attention from the Supreme Court (SC) of India, be it the finalising the drug pricing policy or conducting clinical trials in the country. While it is perusing the pricing policy finally released by the Group of Ministers, the SC seems as determined to keep an eagle eye on the conduct of clinical trials of drugs in the country.

A public interest litigation (PIL) filed in February last year by NGO Swasthya Adhikar Manch, Indore alleged illegal and unethical drug trials involving mentally challenged patients at the MGM Medical College in Madhya Pradesh.

While hearing its PIL, alleging malpractices in clinical trials by Government and non-Government as well as by independent investigators, the SC in its order dated October 8, 2012 had asked either the Secretary, Ministry of Health and Family Welfare (MoH&FW), Government of India or Central Drugs Standard Control Organisation (CDSCO) through Director General of Health Services, Government of India to submit information, from January 2005 to June 2012, on the number of clinical trials approved, number of deaths, if any, recorded during the trials, the number and nature of side

effects recorded and compensation, if any, paid to the victims or their family members.

The SC's most recent missive was on January 3 when it ordered that an additional affidavit filed by the Deputy Drugs Controller (India) in the CSDCO in response to its October 8 order, should be disregarded as it should have been filed by either the Secretary, MoH&FW, Government of India or CDSCO through Director General of Health Services, Government of India. The SC has now given these authorities four weeks to file this information. Meanwhile it has accepted the application filed by Siddharth Luthra, Additional Solicitor General that until further order by this Court, clinical trials of new chemical entity shall be conducted strictly in accord with the procedure prescribed in Schedule 'Y' of Drugs & Cosmetics Act, 1940 under the direct supervision of the Secretary, Ministry of Health and Family Welfare, Government of India.

Damning data As per available data in public domain, the number of serious adverse events (SAEs) resulting in deaths during clinical trials reported in the last three years viz. 2010, 2011 and up to June 2012 were 668, 438 and 211 respectively. However, of these deaths and basis data available with the DCGI, 22 and 16 in 2010 and 2011 respectively were deemed to be due to clinical trials while the rest were found to be due to other concurrent conditions including a natural progression of the disease which is often the case when the sub-

jects were cancer patients, a new illness that patient may have developed, age related disorders or a complication totally unrelated like an accident.

Ghulam Nabi Azad, Minister for Health and Family Welfare had presented the findings of the 59th Report of the Parliamentary Standing Committee on the functioning of the CDSCO to the Rajya Sabha which has raised various issues pertaining to the functioning of the organisation, including alleged approval of drugs without clinical trials. In response to the outcry from parliamentarians as well as health activist groups, the Government constituted a three member expert committee on May 11, 2012 to examine the issues raised by the Parliamentary Committee.

The expert committee comprising Dr VM Katoch, Secretary (Department of Health Research) and Director General, ICMR, Dr PN Tandon, President, National Brain Research Centre, Department of Biotechnology, Manesar and Dr SS Aggarwal, former Director, Sanjay Gandhi Post-graduate Institute of Medical Sciences, Lucknow submitted their report and Azad indicated that it is under consideration.

A consultative approach The regulators seem to have adopted a consultative approach, at least on some fronts. Take for example guidelines on compensation to be given to subjects who suffered SAEs or died during clinical trials. On August 3, 2012, the CDSCO put up its guidelines for compensation, compiled in consultation with rep-

Steps taken to strengthen approval procedures, monitoring mechanism for clinical trials as well to ensure that safety, rights and well-being of clinical trial subjects are protected (1) 12 New Drug Advisory Committees (NDAC) consisting of leading experts from the government medical colleges, institutes from all over the country have been constituted to advise CDSCO in matters related to approval of clinical trials and new drugs.

(2 )Applications of Investigational New Drugs (IND) ; i.e, New Drug Substances which have never earlier been used in human beings, are evaluated by the IND committee, chaired by the Director General, Indian Council of Medical Research.

(3 )Registration of clinical trial in ICMR registry at www.ctri.in has been made mandatory since 15.6.2009.

(4) Every approval / permission for conducting clinical trials now includes a condition that in case of study related injury or death, applicant will provide complete medical

22

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care as well as compensation for the injury or death and statement to this effect would be incorporated in the informed consent form.

(5) Guidelines for conducting inspection of Clinical Trial sites and sponsor /CROs have been prepared and posted on CDSCO website.

(6) Draft rules have been notified to provide for the following: (7) (i) Medical treatment and financial compensation to the trial subjects in case of trial related injury or death; (8) (ii) Procedure for payment of financial compensation; (9) (iii) Enhancement of responsibilities of Ethics Committee (EC), Sponsor & Investigator to ensure that financial compensation as well as medical care is provided to the trial subjects who suffer trial related injury or deaths and such information is provided to the Drugs Controller

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resentatives of industry bodies like the ISCR (Indian Society for Clinical Research), etc. asking for recommendations and suggestions from the public. The guidelines sought to determine quantum of financial compensation to be paid in case of clinical trial related injury or death as well as determine when an SAE or death could be considered trial-related.

In a follow up to the above move, the DCGI's office had issued an another order dated August 16, 2012, which placed more emphasis on informed consent forms (ICF) highlighting that what ought to be valued was the process. It directs the ethics committee (EC) to “exercise particular care to protect the rights, safety and well being of all trial subjects”.

The August 16 order requested all ECs involved in clinical trials in India to “keep vigil on clinical trials being conducted under their jurisdiction”.

Further it allows EC members to make surprise visits (to sites where the trial is being conducted) to ensure that the clinical trial is being conducted as per schedule ‘Y’, GCP guidelines and other applicable regulations.

On December 12, the DCGI issued an another order which addressed all concerned, including ECs and also marked copies to all zonal and sub-zonal offices of CDSCO and State and Union Territory Drugs Control Authorities, to play a watchdog role when it came to approving clinical trial protocols and monitoring ongoing clinical trials in their jurisdiction.

Though there was no direct communication between the DCG(I)'s office

General (India) [DCG(I)].

(10) (iv) Amendment of the format for obtaining informed consent of trial subjects to include the details of address, occupation, annual income of the subject so as to have information regarding socio-economic status of the trial subjects.

(11) Draft rules have been notified to incorporate Rules to have authority for clinical trials inspections by CDSCO and to take administrative actions like restriction on investigators/ sponsors / CROs from conducting future clinical trials in case of non-compliance.

(12) Draft rules have been notified to incorporate Rules and Schedule Y-1 specifying requirements and guidelines for registration of Ethics Committeeanti-malaria programme in India.

Source: Ghulam Nabi Azad, Minister for Health & Family Welfare in a written reply to a question in the Rajya Sabha on Decmber 11, 2012.

January 16-31, 2013

M|A|N|A|G|E|M|E|N|T “As we have issued copies of this letter to State and Union Territory Drugs Control Authorities as well, it is equally their responsibility to keep an eye on clinical trial activities in their territories.”

Industry reactions

Dr SM Sapatnekar Medical Director, Karmic Lifesciences

January 16-31, 2013

Suneela Thatte Executive Director Quintiles Research

Dr Arun Bhatt President, CRO Clininvent Research

to the State and Union Territory Drugs Control Authorities, the fact that they have been copied did not escape the notice of industry observers who pointed out that Madhya Pradesh state authorities had sought to absolve themselves of responsibility for the alleged illegal and unethical drug trials involving mentally challenged patients at the M G M Medical College in Madhya Pradesh, on the grounds that the trials were approved by the DCG(I)'s office at the Centre.

This order was a follow up to the points discussed at the 44th meeting of the Drugs Consultative Committee (DCC) held on July 20, 2012.

In the inaugural deliberations, Sanjay Prasad, Director, Ministry of Health and Family Welfare made the point that the drug regulatory frame work at both the Centre and State levels is an important part of healthcare system.

Confirming this stance, while commenting on the CDSCO order dated December 12, Dr GN Singh, DCG(I) said,

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Analysing the situation, Dr SM Sapatnekar, Medical Director, Karmic Lifesciences, a Mumbai-based CRO, points out that since August 2012, there has been a spate of notices and orders from the office of DCGI. “With mass media outcry on unethical practices, observations of the parliamentary committee and displeasure of the Supreme Court of India, some action from the DCG(I) was anticipated. However, what is notified (and is expected to be enforced) does not seem to be either effective or specific. At their best, these notices and orders are reiterative. At their worst, these are open to contest in the courts on interpretation of statute,” he avers.

Sapatnekar opines, “The order tries to ensure that clinical trials conducted in the country are conducted strictly

in accordance with Schedule ‘Y’ etc. How that is to be attained is left to imagination.

While keeping vigil, if an EC member comes across what is a permissible deviation or objectionable default, the order makes it binding to alert the DCG(I) and take remedial measures too! Is this possible and is this done?

There are doubts.”

Suneela Thatte, President, Executive Director, Customer Operations, Quintiles Research (India) a CRO headquartered out of Bangalore, says, “The order from the DCG(I) appears to serve as a reminder to ECs of their role in according and approving clinical trial protocols and reiterates their responsibility in safeguarding the rights and safety of patients.

The contents of the two orders are not in any variance with what is currently laid down in policies and guidelines that govern the conduct of clinical trials in the country.”

The overall impression seems to be that the DCG(I)'s office would like ECs and their members to take a more proactive rather than passive and reactive stance. But this

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M|A|N|A|G|E|M|E|N|T raises other issues.

For example, Sapatnekar asks, “Do we expect even the mandatory “lay person” and “philosopher” on the EC to keep vigil befitting Schedule ‘Y’ and GCP guidelines?

‘Specificity’ is an important quality of an order; the wording “and applicable regulations” makes it vague. It also raises practical questions. If the EC keeps an “active vigil” it will be carrying out an executive function. In such a case, will the EC act as an auditor?

If so, on whose behalf? Who will decide on a surprise visit?

What is the statutory force for entry to and inspection of the clinical sites? What happens to confidentiality of patient identity? Also, he points out that since the copy is marked to zonal and sub-zonal offices of CDSCO, a question arises about undefined relationship

of EC members vis-à-vis the CDSCO. Dr Arun Bhatt, President of Mumbai-based CRO Clininvent Research too comments that while the December 12 order mandates monitoring of compliance to Schedule Y/GCP, this would require inspection of the clinical trial sites. As per the inspection guidelines released

by CDSCO, CDSCO HQ will issue instruction to the CDSCO Officers/Inspectors to conduct the inspection. Hence, its not clear what is the role of state drug control authorities vis— vis new order, he concludes.

Thatte highlights, “It is not clear from the order what, if any, role is to be played by local drug control authorities within States and Union Territories as they have only been copied on the Order. I believe we will need to wait for more clarity from the

DCG(I)’s Office on this.”

She feels that at a time when the DCG(I)’s office is serious in its intent to tighten the regulatory environment, it is unlikely that the DCG(I) will expect local drug authorities to take on additional responsibility without providing them the resources, both in terms of manpower and expertise.

Thatte points out that there have been questions raised in the past on the role (or lack of) of State and Union Territory drug authorities in clinical trials. Perhaps by copying the order to these authorities, the DCGI expects them to have some oversight of trials in their respective states but again one cannot deduce this from the orders.

“However, in the long run, it would be good to have State and Union Territories’ drug authorities more

involved in clinical trials in their respective regions even if it were only to provide oversight,” she concludes.

The flurry of directives from the DCG(I)'s office as well as critical oversight from the highest court in the land combined with activist NGOs, seems to have put the clinical research industry in India on the defensive.

But of more serious concern is the fact that the industry, specifically CROs, have been left guessing as to the roles of state and centre, as well as the newly envisaged role for EC members. It is clear that 2013 will see more action on this front as regulators try to finetune regulations and responsibilities and industry tries to interpret the new lay of the land. u.sharma@expressindia.com

INSIGHT Fellowship of the chain: Dietary supplements & nutraceuticals Dietary supplements and nutraceuticals were brought under the purview of the Food Safety and Standards Act 2006 (FSSA 2006), changing the manner in which these products are looked at, right from licensing and formulation, to the claims made and marketing. With an increasing number of pharmaceutical companies now entering the nutraceuticals segment, Dr Joseph Lewis, Consultant, MediaMedic Communications analyses the implications egulatory activity and changes are at its peak in India today. While price control, ethical practices are under review, another major change is emerging with dietary supplements and nutraceutical being brought under the purview of the Food Safety and Standards Act 2006 (FSSA). The manner in which these products are going to be looked at from licensing and product approvals to claims rightfully made when marketing these are expected from imminent regulations. Some of the concerns and deliberations that need focus are being explored for consensus.

Like the Act suggests, the focus for these products, are slated for dramatic shifts – the first being safety. If one googles ‘food safety’ today, the FSSA 2006 pops up, to be followed by the Food Safety and Standards Authority of India. No other regulator gets such a prominent position on

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food safety. The primary object of the Act is to ensure safety of consumers a basic human right. To ensure this right of ‘safety’ for the consumers, all producers, traders and marketers of nutraceutical and dietary supplements have to understand that they are a part of the ‘chain’ starting from the ingredient to the final pack, with all steps in manufacturing, transportation and storage included in the chain.

They are all in it together – to put it succinctly.

And this means ‘Quality Assurance’ at every step in the process. While the word ‘quality’ and ‘quality assurance’ is not new to the pharmaceutical industry, the nutraceutical and dietary supplement products are now produced in units having different licensing requirements and ingredients procured from different vendors, who may not understand the requirements of food law. Moreover, nutraceutical ingredients can have variations in quality based on source, which may be a natural extract of variable potency or with contaminants, toxicants gathered along the supply chain. Plant sources bring their own quality issues arising from seasonality, soil conditions, pesticides applied and tested for, extraneous impurities etc.

Such issues are new to this sector and need attention. www.expresspharmaonline.com

Good manufacturing practices of all players in the chain are to be well documented and verifiable by third parties. A few important issues to be considered are as below.

Traceability Safety is all about prevention of an adverse event happening. The Food Safety and Standards Authority of India (FSSAI) has its task cut out with the need to lay down a risk framework to manage the chain – a mandate of the Act. In the ultimate analysis – it’s the chain that assures consumers that the nutraceutical/supplement/functional food they consume is safe, of reliable quality and capable of self correction (traceability).

Nutraceuticals are a new food category that has a rather entangled supply chain from ‘plant to pillbox’. This category of foods leaves complex trails. Apart from the wide spectrum of ingredients, multi-component formulations, it is the globalisation of the industry that has turned traceability into a veritable labyrinth. This is further compounded by imports into the country of vitamins and botanicals from obscure sources. Unlike commodity ingredients which are revealing when sensory attributes distort, dietary supplement ingredients do not – deficiencies lie hidden. Good brands

owe it to their customers to use standard and well characterised ingredients.

To elaborate, many dietary supplements are multi component systems comprising anywhere from 2-20 ingredients, obtained from a few dozen suppliers. Hardly any processing happens at the final manufacturing end except for formulation, mixing, encapsulation and packing. The product safety profile is dependent on the supplier food safety policy.

Special mention may be made regarding metal contaminations that add on to the daily intake.

For example, FAQ/WHO considered that it was not acceptable if 30 per cent or more of the acceptable daily intake of a particular heavy metal derived from food or drinking water or both was accounted for by the additional consumption of dietary supplements. This is a food category that may be patronised by vulnerable groups and thus where contaminants are known to pose high risks; these should be set at a level which is As Low As Reasonably Achievable (ALARA).

Further some of these nutrients may find their way into formulations for infants and young children—it is expected that the chain will establish the lowest levels, which are achievable through a strict selection of the raw materials used for the manuJanuary 16-31, 2013

M|A|N|A|G|E|M|E|N|T facturing of nutrients/supplements for infants and young children. Nutrient suppliers would need to demonstrate up front, their good manufacturing practice, by declaring the maximum limits of metal contaminants or toxins in their product specifications.

Functional foods with enhanced function benefits are another emerging category, which will involve specific nutrients that have proven 'ingredient—health relationships.’ Ingredient must be sufficiently characterised for risk assessment and manufacturers should ensure that only such ingredients are supplied to them where convincing evidence of safety is demonstrated.

Unlike general foods that are mostly sourced locally, dietary supplement ingredients start in all parts of the world and intersect on their way to the final product.

Very few supplements on the market have linear manufacturer- supplier relationships from start to finish. Even a single ingredient can work its way from the original source to final product

January 16-31, 2013

through a series of mixings, additions, and processes sufficient to make traceability a hopeless pursuit.

Botanical extracts or concentrates are even more ‘traceability challenged’ where even the same name could present different histories of cultivation, geographies, extraction techniques, identity uncertainties and purity issues. Ginseng that is found in many supplement formulations could either be sourced from American ginseng (Panax quinquefolium) or Asian ginseng (Panax ginseng) or Siberian ginseng (Acanthopanax senticosis).

They differ in their major chemical constituents and differ in their end benefits. More importantly as an ingredient, their conformance to safety criteria such as microbiological quality, contaminants or heavy metal limits are not yet regulated. Sourcing these plants from several countries could leave pesticide residues that are either illegally present or are at unacceptable limits.

How does one establish the integrity of a batch if its botanical extracts are from several

cultivations spread around the globe? Further, some supplement manufacturers access materials from brokers who aggregate supplies according to price and availability.

Documentation may be inaccessible, unverifiable and traceability a challenge.

In this complex and layered supply chain, dietary supplements and nutraceutical manufacturers are burdened with heightened responsibilities of identifying safe and pure ingredients that they can reliably use in their formulations. A formidable task no doubt, but the need to build safety management systems to overcome this hurdle is a prerequisite for this industry sector.

Reputed brand owners will set up prerequisite systems and obligations on their suppliers and inevitably source from reliable suppliers who can demonstrate verifiable document systems, identity tags, and third party audits.

These manufacturers can raise the bar in the market if their product can demonstrate systems of where the plant was grown or harvested, its purity and safety indices—differenti-

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ating themselves in the market. Traceability can become a subtle and effective way of gaining consumer trust.

Traceability in India is now an essential business activity under the Food Act which requires FBO’s to provide for traceability systems. For example Section 26 requires that all FBOs engaged at all stages of production, processing, import, distribution and sale shall ensure that foods (including nutraceuticals and dietary supplements) satisfy the requirements of food law within the businesses under their control. This provision covers the entire chain including transporters and storage operators and is in accordance of the classical liability rules.

These legal provisions require each FBO in the chain to verify that the ingredient he is receiving is safe and in compliance with the requirements of the Act. There is also another side to it—building confidence in products.

Reliability For decades, the food/supplement manufacturing industries were concerned with

their own Quality Control System without much control on suppliers or other members in the supply chain before HACCP was developed. Most HACCP activity appeared to focus around the processing site where the product was ‘assembled or processed’ for the marketplace. However with emergent categories like dietary supplements and nutraceuticals, it is now likely that HACCP may be focused around the suppliers ‘product’ and less on the ultimate manufacturer to market. When you think ‘chain’ – you see the weakest or the strongest link and where risks and safety lie.

Consumers today are living in anxious times often believing that products bought are safe to consume, and hence ‘Reliable’. There are hardly any marks that help them identify these products with Quality. When outbreaks and recalls occur they understandably panic and refuse to buy any item associated with it. Everyone in the chain suffers – producer to consumer – good reason to shift to a new concept in safety – fellowship of the chain.

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RESEARCH EXPERTISE FOR DRUG DEVELOPMENT

EXPERT SPEAK W H AT ’ S INSIDE

Applying multi-parameter optimisation in drug discovery PG 29 Research updates PG 35

Stem cell therapy and its potential applications in regenerative medicine Dr Aparna Khanna, Dean, School of Science, NMIMS, Mumbai elaborates on the therapeutic potential of stem cells, challenges in harnessing this potential and means to overcome them anoparticles are promising tools for various applications in biomedical research, due to their small size and ability to penetrate cells.

Stem cell research is a rapidly evolving area, despite being fraught with innumerable challenges and hurdles that have yet to be overcome to realise its ultimate potential. There has been a recent spate of activities with respect to the clinical application of stem cells using foetal, cord and adult stem cells. Despite the clini-

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cal data appearing promising, there are severe limitations to stem cell based therapies.

One major obstacle has been monitoring the bio-distribution and homing of implanted or injected stem cells in the human body. Hence, an urgent need exists to develop non-invasive and sensitive imaging techniques, which will prove valuable for optimising cell therapy.

The article outlines the therapeutic potential of stem cells, several hurdles faced by clinicians for optimising cell

therapy and how some of the challenges can be overcome using sensitive non-invasive imaging technology.

Stem cells: Sources, types and clinical application Stem cells have two specialised properties that make them unique and unlike any other cell of the human body.

First, is their indefinite proliferative ability; which simply means that you can have an unlimited and inexhaustible supply of these cells. The second feature of these highly prolific cells, is their inherent capacity to differentiate upon receiving appropriate stimuli, into various cell types of the human body. The most versatile of the stem cells reported are the human embryonic stem cells (hESC). The source of the hESC are surplus embryos (five-day blastocyst), which can be obtained from in vitro fertilisation clinics, with proper informed consent and following national necessary ethical standards.

Subsequently, a hESC line is established from the surplus embryos, brought to the laboratory and warrants a procedure that requires skilled technical expertise and takes about 8-10 months. So, from a five day blastocyst, a hESC line is established, which is said to be virtually immortal and at your disposal, possessing the potential to differentiate into neurons, oligodendrocytes, cardiac cells, pancreatic islet cells, hepatocytes; theoretically, to almost all the 210 cell types found in the human body. Such is the tremendous potential of stem cells and its use in regenerative medicine, January 16-31, 2013

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Dr Aparna Khanna Dean School of Science, NMIMS Mumbai

where damaged or diseases cells can be replaced with the cell types derived from stem cells. The first hESC line established in the world was in 1998, by Dr James Thomson and co-workers at the University of Wisconsin1.

The other commonly reported sources of stem cells are bone marrow, umbilical cord blood, umbilical cord and adipose tissue/lipoaspirates. These sources are termed as “multipotent”, unlike the hESC which are termed as “pluripotent”, because of the restricted differentiation potential associated with adult stem cells.

Adult stem cells are not as versatile as embryonic stem cells. More recently, another source of stem cells were discovered through a breakthrough research. These are

eases, to name a few. Fig 1 depicts a schematic representation of the use of stem cells in regenerative medicine.

Stem cell therapies: Where are we?

The therapeutic potential of stem cells is immense. Two modes of stem cell transplantation exists- patient specific (autologous), and not patient specific, i.e. from one individual to another (allogenic).

One of the earliest examples of stem cell transplantation has been bone marrow transplantation, following which was the cord blood stem cell transplantation. Here, the haematopoietic stem cells (HSC) from an HLA matched individual is injected intravenously, and is widely used in haematological disorders or malignancies like acute

and provided a cell therapy paradigm for neuronal repair in the human brain. This was one of the first published reports and the concept that stem cells could help in neuronal repair emerged.

However, some of the limitations included; donor dependent variation, scarcity of foetal tissue, number of cells required and ethical concerns. Additionally, a fraction of patients suffered from dyskinesia (jerky movements) after transplantation, either due to the stem cells or the procedure (sterotactic surgery). Further, a recent report wherein foetal stem cells were injected into a patient’s brain, who suffered from a rare genetic disorder, ataxia telangiectasia, triggered tumours5. A word of caution is to be aware of the

Institute of Health (NIH).

ClinicalTrials.gov currently lists 4196 ongoing clinical trials using stem cells, with approximately 90 per cent of the studies using adult stem cells.

Similarly, in India all clinical trials being carried out using human participants have to be registered at the Clinical Registry-India, a site maintained by the Indian Council of Medical Research (ICMR). According to the registry, currently there are 29 ongoing studies registered using stem cells. The details are given in www.ctri.nic.in.

Despite, the promising clinical data, a number of unanswered questions with respect to the bio-distribution of stem cells in the human body, homing or movement of the injected stem cells into

Fig 2

the induced pluripotent stem cells (iPSC)2. Here, normal skin cells can be transformed (reprogrammed) into pluripotent stem cells using genetic manipulation. This implies, that if this concept works in a clinical setting, the need for embryos would be eventually removed, and patient-specific stem cells could be made, thus enabling customised therapy. For their pioneering research on reprogramming, this year, the 2012 Noble prize in Physiology and Medicine was fittingly won by Sir John Gurdon, University of Oxford and Dr Shinya Yamanka, Kyoto University, Japan.

The goal of stem cell research is to obtain functional cells which can replace damaged cells in a variety of degenerative or debilitating disorders like Parkinson’s disease, type I diabetes, spinal cord injuries, liver disJanuary 16-31, 2013

and chronic myeloid and lymphoid leukaemia, myelodysplasias, bone marrow failure syndromes, haemoglobinopathies and immune deficiencies. Since the first cord blood transplant was performed in 1988, stem cells derived from umbilical blood have been used in more than 30,000 transplants worldwide to treat a wide range of blood diseases, genetic and metabolic disorders (US Cord Blood Banking Industry Report, 2012).

Cell transplantation has emerged as a potential therapy for Parkinson’s disease and has been under rigorous experimentation, both in animal models and human patients. In two well-defined double blind trials, carried out in the US, in the 1990s, the possibility of using stem cells from aborted foetuses (foetal embryonic transplantation) was investigated3,4 www.expresspharmaonline.com

adverse reaction and associated problems.

Adult stem cells, the mesenchymal stem/stromal cells (MSC) are another population of stem cells found in bone marrow and in a number of other tissues, and have used for stem cell therapy.

The plethora of diseases that can be cured using MSCs are graft versus host disease (GVHD), Crohn’s disease multiple sclerosis (MS), motor neuron disease (MND) and ALS, Parkinson’s disease (PD), diabetes mellitus (DM), chronic obstructive pulmonary disorder (COPD), acute myocardial Infarction (MI), dilated cardiomyopathy (DCM), osteogenesis imperfecta, osteodysplasia and liver failure to mention a few.

The details of the ongoing/completed clinical trials can be obtained from www.clinicaltrial.gov, a registry of the US National

desired organs and their long term effects need to be addressed. These issues can be overcome by developing sensitive non-invasive imaging modalities, which will prove valuable in optimising cell based therapies. The treating physician should be able to address questions with respect to number of cells to be injected, viability of cells after injection and the migration pattern to the targeted organ.

Nanotechnology and biomedical applications Nanoparticles, as the word suggests, are particles with size in the “nanó” range that is 1-100 nm. The advantages of these very small sized particles are that they can traverse through blood vessels, can be administered either intravenously, oral route or inhalation. They can also be targeted to reach speEXPRESS PHARMA

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R|E|S|E|A|R|C|H cific organs or tissues in the human body. For biomedical applications, it becomes essential to ensure that the nanoparticles synthesised possess characteristics such as biocompatiblilty, indicating safety and non-toxicity; otherwise they will be rejected by the body. Further, they have to be retained in vivo for reasonable long periods.

Various methods have been employed to synthesise nanoparticles, which involves basic and inorganic chemistry. With the advancements in synthetic chemistry, nanomaterials can be modified to required size, shapes and properties. Due to their small size and high surface energy, the bare nanoparticles tend to aggregate. Hence, they need to be coated with suitable agents so as to increase their stability and solubility. A number of approaches are used to functionalise nanoparticles, involving the use of materials such as proteins, polysaccharides and synthetic polymers.

Once the nanoparticles are synthesised, detailed characterisation should be performed to understand whether the properties of the nanoparticles with respect to its size, coating are retained.

Detailed characterisation entails sophisticated instrumentation like UV-vis spectroscopy, fourier-transformed infra red spectroscopy (FT-IR), X-Ray diffraction (XRD), transmission electron microscopy (TEM), etc. The ultimate challenge is to design multiplex systems for drug delivery, imaging and therapeutics, using nanotechnology. Fig 2 shows a schematic structure of a functionalised super paramagnetic iron oxide nanoparticle (SPIO) with a tagged fluorophore to allow in vivo imaging.

In vivo imaging technology for tracking stem cells

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Various imaging modalities available for cell tracking are computed tomography (CT), positron emission tomography (PET), magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT) and optical imaging. Each of these methods have their pros and cons. Some of the major hurdles are insensitive contrast agents, short half life, dilution of signal because of cell division, and genetic modification of stem cells, posing regulatory concerns for human stem cell clinical trials. Hence, it is recommended that a multimodality approach that would ensure sensitivity and reproducibility should be used for in vivo tracking.

Such dual optical/MRI have been described using visiblewavelength fluorophores and Gd3+ chelators conjugated to high-molecular-weight scaffolds such as dextran.

Magnetic iron oxide nanoparticles are primarily used in medical resonance imaging (MRI), serving as excellent contrast agents.

Magnetic nanoparticles can be classified into a few groups like superparamagnetic iron oxide particles (SPIO)

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or ultrasmall SPIOs (USPIO) and function by creating local field inhomogeneities that cause decreased signal on T2and T2*-weighted images in a MRI scanner. Besides, they help to distinguish between soft tissues; the iron content is biodegradable and biocompatible and excess iron will be recycled by the cells using biochemical pathways for iron metabolism. Moreover, as the magnetic properties of the cells are retained after coating, these properties can be exploited to deliver the cells at appropriate sites in the human body.

Several clinical studies utilising magnetic nanoparticles to label cells have been conducted. Some of the clinically approved iron oxide particles are Feridex/Endorem (dextran coated SPIO), Resovist (SPIO particles that are coated with carboxydextran).The first report involving magnetically labeled stem cells was from a patient with brain trauma who received an autologous transplant of Feridex-labeled neural stem cells (NSCs) into the damaged temporal lobe6. NSCs were isolated from exposed neural tissue (brain injury region) from the patient. Cells were cultured to select for neural progenitor cells and labeled with Feridex prior to stereotactical transplantation.

The patient was then imaged with a 3.0-T MR scanner weekly for 10 weeks after transplantation. Hypointense signals at the injection sites were only observed after transplantation and the signal persisted for seven weeks.

Although there are a few encouraging results on stem cell tracking, some of the commercially available magnetic iron oxide particles have certain limitations, and the search is on for an ideal

biocompatible nanoparticles for use in stem cell tracking in humans.

Research is underway at the School of Science, NMIMS, in collaboration with IIT, Bombay, where we are in the process of designing novel nanoparticles (SPIO) to be used for long term stem cell tracking. We have been able to synthesise homogenous magnetic iron oxide particles, sized 7-9 nm (see inset) and have performed in-depth characterisation of the generated SPIOs. Further, the detailed cytotoxicity and stem cell-nanoparticle interaction, in vitro are in progress. The ultimate aim of the research is to select the most promising magnetic nanoparticles generated during the in vitro studies, for preclinical studies, to enable tracking of the stem cells in vivo.

References: 1. Thomson, JA; ItskovitzEldor, J; Shapiro, SS; Waknitz, MA; Swiergiel, JJ; Marshall, VS; Jones, JM. Embryonic stem cell lines derived from human blastocysts. Science 1998, 282 (5391), 1145–1147.

2. Takahashi, K; Tanabe, K; Ohnuki, M; Narita, M; Ichisaka, T; Tomoda, K; Yamanaka, S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 2007 131(5), 861-72.

3. Freed, CR; Greene, PE; Breeze, RE; Tsai, WY; DuMouchel, W; Kao, R; Dillon, S; Winfield, H; Culver, S; Trojanowski, JQ; Eidelberg, D; Fahn, S. Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N Engl J Med. 2001, 344, 710-19.

4. Olanow, CW; Goetz, CG; Kordower, JH; Stoessl, AJ; Sossi, V; Brin, MF; Shannon, KM; Nauert, GM; Perl, DP; Godbold, J; Freeman, TB. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease.

Ann.Neuro. 2003, 54, 403-414.

5. Amariglio, N; Hirshberg, A; Scheithauer, BW; Cohen, Y; Loewenthal, R; Trakhtenbrot, L; Paz, N; Koren-Michowitz, M; Waldman, D; Leider-Trejo, L; Toren, A; Constantini, S; Rechavi, G. Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS Med. 2009 Feb 17;6 (2):e1000029.

6. Zhu J, Zhou L, XingWu F. Tracking neural stem cells in patients with brain trauma.

N Engl JMed 2006, January 16-31, 2013

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EXPERT SPEAK Applying multi-parameter optimisation in drug discovery MPO methods have been used in a wide range of fields from engineering to economics and, more recently, drug discovery. In this article Matthew Segall, CEO, Optibrium, discuss how MPO can be applied effectively in drug discovery to guide rigorous and objective decisions on the selection and design of compounds inding a successful drug is a delicate balancing act. It is necessary to simultaneously optimise many, often conflicting, requirements to identify a compound that will ultimately become a safe and efficacious drug. Methods for guiding this process, commonly referred to as multiparameter optimisation (MPO) have been developed1 and in this article we will explore how these can be applied in practice to improve productivity and efficiency in drug discovery.

When searching for a potential drug it is not sufficient to find a highly potent compound against the intended therapeutic target; selectivity against off-targets, appropriate pharmacokinetics and an absence of toxicity at the therapeutic dose are also necessary to reach the market and achieve a strong

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position. Unfortunately, these requirements are often conflicting; for example, increasing lipophilicity will often improve potency but this is also correlated with poor absorption, increased metabolic clearance and a higher chance of non-specific toxicity. The high rate of attrition in pharmaceutical R&D and the increasing cost attest to the challenge that this balancing act presents.

One key to reducing costs and reducing late stage attrition is to simultaneously consider as many compound properties as possible from the earliest stages of drug discovery. By identifying high quality compounds with a good balance of properties as early as possible, resources can be focused on the areas of chemistry with a high chance of downstream success. An overly narrow focus on a single property, typically target potency, early in the optimisation process can be risky. Avoiding this reduces the chance of encountering a dead end, where a critical property cannot be achieved within a potent lead series, leading to many, long iterations in lead optimisation.

The need to generate data on many properties for

Matthew Segall CEO Optibrium potentially large numbers of compounds has led to the development of high throughput in vitro assays and in silico models for a wide range of physicochemical, absorption, distribution, metabolism and elimination (ADME) and toxicity endpoints. However, the avalanche of data that these can generate poses a new challenge for drug discovery scientists; how to analyse this data effectively in order to make good, quick decisions regarding the selection and design of compounds. The human brain is not reliable

when juggling complex data to make decisions.

Unconscious biases can often impact on efficiency and productivity2.

Furthermore, this challenge is heightened by the fact that the data generated in early discovery almost always has significant uncertainty due either to experimental variability or statistical error in predictive models.

This underlying uncertainty brings its own challenge; using even the best experimental or predictive methods in early discovery, it is impossible to say with confidence that a given chemistry will achieve the goals of a project. Furthermore, it is easy to incorrectly discard a compound based on an uncertain piece of data, leading to missed opportunities to find a good drug.

Therefore, while it is important to focus quickly on the best chemistry for a drug discovery project, it is also necessary to first explore broadly. Where possible a range of possible avenues for exploration should be identified, which can be studied in detail to validate the initial hypothesis and confirm the direction the project should take.

Figure 1: An example of a multi-parameter scoring profile defining the properties of interest, the criterion for each property and the relative importance of those criteria. Underlying each criterion is a desirability function defining the relationship between a compound’s property value and how likely it is to achieve the project’s objective. An example is shown to the right, in blue, for the target potency (pKi). This indicates that ideally the pKi would be greater than 8 (Ki lower than 10 nM), below a pKi of 7 (Ki greater than 100 nM) the compound would not be of interest, and between a pKi of 7 and 8 the desirability increases linearly. The histogram in the background shows the distribution of pKi values in the data set January 16-31, 2013

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R|E|S|E|A|R|C|H Multi-parameter optimisation A wide range of MPO methods have been applied to compound optimisation in drug discovery; a detailed review may be found in reference1. Probably the most common approach is the use of rules of thumb, such as Lipinski’s Rule of Five (RoF)3, that provide guidelines for the characteristics of compounds that are similar to those of successful drugs.

These are very easy to interpret and apply, which has lead to their undoubted popularity and positive effect on the quality of compounds.

However, these simple rules have significant limitations: the correlation between the simple characteristics employed by these rules and the complex biological endpoints are not strong; the rules are typically defined for a particular goal, e.g. oral absorption in the case of the RoF, and application to selection of compounds for other objectives may not be appropriate; and, these simple rules are often applied to filter compounds making inappropriately harsh distinctions between compounds, for example a compound with a calculated logP of 5.01 is not significantly worse than one with a logP of 4.99, particularly given that such a calculation typically has an uncertainty of approximately 0.5 log units. These limitations can lead to missed opportunities and wasted effort.

More sophisticated methods for MPO can bring

together data of any type, experimental or predicted, allowing acceptable tradeoffs to be defined and allowing for uncertainty in the underlying data to be rigorously taken into account. For example, the Probabilistic Scoring method, employed by the StarDrop software4, allows a desired profile of property criteria to be defined by a user or project team as illustrated in Figure 1. This ‘scoring profile’ allows the requirements for each property to be defined along with the relative importance of each individual crite-

taking into account the uncertainty in the data due to experimental variability or statistical error in a prediction. The result is a score that estimates the likelihood of success of the compound against the ideal profile of properties and an uncertainty in the overall score. This allows compounds with a good balance of properties to be easily prioritised and makes it clear when compounds can be distinguished with confidence.

This enables the project team to focus effort on chemistries with the highest chance of

rion to the overall success of the project. In addition to simple thresholds or ranges, more subtle relationships between the property value and a compound’s desirability can be defined as a ‘desirability function’, (also illustrated in Figure 1). Once this is defined, the data for each compound are assessed against the scoring profile,

success while avoiding missed opportunities when the data does not support confident rejection of compounds. This is illustrated in Figure 2.

Given the uncertainty in the data and hence in the overall assessment of compound quality, it may also not be appropriate to focus too heavily on a single series

Figure 2: Graph illustrating the output of probabilistic scoring. The compounds in a data set are ordered along the x-axis from the highest to lowest scoring. The score is plotted on the y-axis along with error bars showing the uncertainty (1 standard deviation) in the overall score due to the uncertainty in the underlying data

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of closely related compounds. In particular, early in a project it is also important to explore a broad range of diverse chemistries to mitigate risk, investigate potential backup series and, where predictive models are being used, validate the predicted hypothesis. Achieving this balance between quality and diversity is also a form of MPO and a number of approaches have been developed to assist the exploration of this trade-off. It is not possible to sort compounds by their diversity, the diversity is a property of a set of compounds, therefore achieving a good balance of diversity and quality requires many different selection strategies to be explored; for example there are 3x1025 ways to select 30 compounds from a set of 100. Many of the methods to guide the exploration of this trade-off are based on ‘genetic’ algorithms that use the principles of evolution to ‘evolve’ a population of different selection strategies and identify one that achieves an appropriate balance5. Examples of two such trade-offs can be seen in Figure 3, showing the effects of changing the bias in the selection from quality (score) to diversity.

Practical application of MPO MPO algorithms provide a powerful basis to guide the efficient identification of high quality compounds. But how can they be applied in practice in drug discovery?

The full value of these approaches can only be realised if they are easily accessible to all decisionmakers in a project. The majority of these are experimental scientists responsible for the design, synthesis and testing of compounds.

Analysis by computational experts provides valuable insights into design decisions, however this analysis often introduces a delay before the results can be determined and reported back. The greatest impact on project decisions comes when many strategies can be explored, with instant feedback, before reaching a confident decision. Therefore, it is important that access is via a user-friendly interface through which it is possible to define multi-parameter objectives and then interpret the results in a visual way.

It is also important that the algorithms are not ‘black January 16-31, 2013

R|E|S|E|A|R|C|H boxes’ that accept data and output a result with little or no explanation. The objective is to provide tools to guide the decisions of experts not to automatically make a decision to be accepted blindly.

Therefore, the output of the analysis must provide clearly interpretable results and guidance on potential issues or strategies for improvement.

Some illustrative examples are shown in Figure 4.

MPO methods may be applied throughout the drug discovery process. When designing libraries for use in high throughput screening it is important to cover a wide diversity of chemistry to ensure the greatest chance of finding a potent hit.

However, even here, it is beneficial to select compounds with appropriate properties to provide good starting points for hit-to-lead wherever possible.

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to optimise all of the required parameters simultaneously; too much focus on optimisation of a single property can lead to the sacrifice of other important factors which must then be re-optimised in turn, increasing the number of design-synthesistest iterations.

Early in the drug discovery process, when large libraries of compounds (virtual or synthesised) are often considered, little or no experimental data may be available. In this case, the design and prioritisation of compounds will be primarily guided by data from predictive models. This has been the most common way in which MPO has been applied, due to the quantity and complexity of the data that may be generated. MPO of predicted properties may also be used to guide the exploration of very large numbers of virtual ideas,

focussed library design, the results of virtual screens can be combined with predictions of other important compound properties to provide good quality hits.

During hit-to-lead, the goal is to identify one or more high quality lead series; here it is important to find series with good ADME properties and no overt toxicity in order to give the best chance of rapid progress through lead optimisation. At this hit-to-lead stage, it is important to explore as many options as possible to minimise the chance of getting locked into a lead series with a consistent problem. It can often be difficult to ‘hop’ to a new lead series in order to resolve a problem without sacrificing potency, which can lead to additional, time consuming iterations, increasing the cost and time of lead optimisation. Finally, during lead optimisation, MPO can help

automatically generated from a starting structure in order to increase the breadth of the search for optimisation strategies around hit or lead compounds6 7 and prioritise the most interesting ideas for detailed consideration by an expert.

However, with the increasing quantity of in vitro ADME and toxicity data that is now routinely generated, even in the earliest stages of drug discovery, MPO has become equally valuable for the effective use of these experimental data to select compounds for further investigation. An example application of MPO to a data set comprised only of in vitro data, to identify compounds with improved in vivo disposition in lead optimisation, is described in8.

Examples Many examples of the application of MPO to the

a

b Figure 3. Examples of two selections of 20 compounds from a set of 267. For each selection, the ‘chemical space’ is plotted to illustrate the diversity of the full data (the diversity is defined by Tanimoto similarity of 2D fingerprints) and each point is coloured by score from high (yellow) lo low (red). A similar graph to that shown in Figure 2 is also plotted for each selection. (a) illustrates a selection biased towards score in light blue. This shows that the compounds are selected from the highest-scoring, but that they are focussed on a few small regions of similar chemistry. (b) illustrates a selection biased more towards diversity, selecting a wider range of both diversity and score January 16-31, 2013

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R|E|S|E|A|R|C|H challenges of drug discovery have been discussed elsewhere1 8. Here we will summarise two recent examples.

MPO-Guided automatic idea generation

Reference 7 illustrates the application of MPO, coupled with automatic idea generation, to the lead compound that ultimately led to the discovery of the serotonin reuptake inhibitor Duloxetine, using the Nova tool in StarDrop. A library of 206 ‘medicinal chemistry transformations,’ representing typical compound optimisation steps, were applied iteratively to the lead structure to create three ‘generations’ of related compounds. This could have generated approximately 1.7 million compounds if all possible combinations had been enumerated. Therefore, to control this, only the top 10 per cent were selected from each generation, based on a probabilistic score calculated from properties predicted using quantitative structure activity relationship (QSAR) models of target potency and key ADME properties. After three generations this resulted in a total of approximately 2,200 compound ideas that explored the ‘chemical space’ around the initial lead and proposed a diverse range of interesting structures, as illustrated in Figure 5.

Among the top-scoring compounds in the final gen-

a

b

Figure 4. Two examples of visual feedback that help to guide the redesign of compounds in order to improve the overall chance of success. The histogram in (a) indicates the impact of each individual property on the overall score; a high bar indicates a high confidence that the property is good while a low bar indicates a significant negative impact of a property value (the colours correspond to the key in Figure 1).

This suggests that the most significant risks for this compound are due to high logP and hERG inhibition. (b) is an example of the Glowing Molecule that shows the key structural influences on a predicted property of a compound, in this case logP. The red regions are those that have a significant impact increasing the predicted property, while the blue regions correspond to regions with a significant impact decreasing the property value eration was the drug Duloxetine; its score was statistically equivalent to the top-ranked compound and was predicted to be better than the lead with a confidence of approximately 90 per cent. Furthermore, the second-ranked compound generated was very similar to another clinical candidate, Litoxetine, differing only in

the substitution point of the side chain on the core naphthalene ring and the addition of a single methyl.

This demonstrated that the combination of idea generation using medicinal chemistry transformations with predictive models and MPO can propose relevant and interesting structures for consideration during drug discovery.

Quantitative estimate of drug likeness

Bickerton et al.9 introduced a metric that estimates the similarity of a compound’s characteristics to those of known drugs. The quantitative estimate of drug likeness (QED) they propose is a generalisation of simple rules of thumb such as the RoF to provide a single numerical measure of ‘druglikeness’.

The QED was constructed by examining the frequency distributions of molecular weight, lipophilicity, numbers of hydrogen bond donors and acceptors, polar surface area, number of rotatable bonds, number of aromatic rings and number of

structural alerts (i.e. undesirable substructures) for 771 known drugs. Desirability functions were fitted to each of these distributions, such that compounds with a value for which a high frequency of known drugs are observed will receive a high desirability score. The overall QED can then be calculated for a compound by combining the desirability scores for its individual characteristics into a single desirability value by taking a weighted geometric mean, which indicates the similarity of the compound to known drugs.

Unlike rules of thumb which classify compounds as ‘good’ or ‘bad’, the QED provides a measure of ‘drug likeness’ on a continuous scale.

The authors found that the value of the QED correlated with the subjective view of medicinal chemists on the suitability of a compound as a starting point for a medicinal chemistry project over a set of 17,117 diverse compounds.

Furthermore, a benchmarking study also found that drugs were, on average, more likely to have a

Figure 5 An illustration of the chemical space explored around the initial lead that led to the discovery of the drug Duloxetine. The points are coloured by score, from the lowest (0.29) in red to the highest (0.69) in yellow. The initial lead is shown as a dark blue diamond, Duloxetine as a green diamond. The top-three scoring compounds are shown as purple diamonds along with their structures. In this plot, each point represents a compound and the distance between two points indicates their structural similarity; close points are structurally similar while distant points are structurally diverse

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January 16-31, 2013

R|E|S|E|A|R|C|H high QED than a general set of small molecule protein ligands. However, while avoiding ‘non-drug like’ compounds will reduce the risk of failure, it should be noted that a ‘drug like’ compound is far from guaranteed to have suitable physiochemical and biological properties to be a successful drug.

Conclusion The application of MPO to drug discovery can help to efficiently explore many potential avenues for research and quickly and confidently focus synthetic and experimental efforts on those areas of chemistry most likely to yield a high quality drug.

This, in turn, reduces the cost and time for drug discovery while improving the chance of downstream success and reducing the chance of missing valuable opportunities.

For MPO to have a strong impact on key decisions in drug discovery, it must be accessible to all members of a drug discovery project team to provide intuitive guidance on design and selection of

January 16-31, 2013

THE APPLICATION OF MPO TO DRUG DISCOVERY CAN HELP TO EFFICIENTLY EXPLORE MANY POTENTIAL AVENUES FOR RESEARCH AND CONFIDENTLY FOCUS SYNTHETIC AND EXPERIMENTAL EFFORTS ON THOSE AREAS OF CHEMISTRY MOST LIKELY TO YIELD A HIGH QUALITY DRUG compounds. Software that supports MPO in a visual and user friendly environment can facilitate collaboration between computational scientists, chemists and biologists to bring consistency and objectivity to decision-making in order to quickly achieve the objectives of a drug discovery project.

References 1.Segall, M. D. MultiParameter Optimization: Identifying high quality compounds with a balance of properties. Curr. Pharm. Des. 2012, 18, 1292-1310, Preprint may be downloaded from http:///www.optibrium.com/co

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mmunity.

2.Chadwick, A. T.; Segall, M. D. Overcoming psychological barriers to good discovery decisions. Drug Discov. Today 2010, 15, 561-569.

3.Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 1997, 23, 3-25.

4.Optibrium. http://www.optibrium.com/sta rdrop, visited on 7th January 2012.

5.Fonesca, C. M.; Fleming, P. J. Genetic algorithms for multiobjective optimization: for-

mulation, discussion and generalisation. Genetic Algorithms: Proceedings of the Fifth International Conference, San Mateo, CA, 1993; 416-423.

6.Stewart, K.; Shiroda, M.; James, C. Drug Guru: a computer software program for drug design using medicinal chemistry rules. Bioorg. Med. Chem. 2006, 14, 7011-7022.

7.Segall, M. D.; Champness, E. J.; Leeding, C.; Lilien, R.; Mettu, R.; Stevens, B. Applying medicinal chemistry transformations to guide the search for high quality leads and candidates. J. Chem. Inf. Model. 2011, 51, 2967–2976.

8.Segall, M.; Beresford, A.; Gola, J.; Hawksley, D.; MH, T. Focus on success: using a probabilistic approach to achieve an optimal balance of properties in drug discovery. Expert Opin. Drug Metab. Toxicol. 2006, 2, 325337.

9.Bickerton, G. R.; Paolini, G. V.; Besnard, J.; Muresan, S.; A.L., H. Quantifying the chemical beauty of drugs. Nature Chemistry 2012, 4, 90-98.

The author can be reached at matt.segall@optibrium.com

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CLINICAL UPDATE US FDA, EMEA accept GE Healthcare’s review applications for [18F] Flutemetamol New imaging agent may aid in evaluation of Alzheimer's disease E Healthcare announced that regulatory bodies in the US and Europe have accepted its applications for review of the investigational positron emission tomography (PET) amyloid imaging agent [18F]flutemetamol, a PET imaging agent.

A New Drug Application (NDA) was submitted to the US Food and Drug Administration (US FDA) for [18F]flutemetamol use in the visual detection of beta amyloid in the brains of adult patients with cognitive impairment who are being evaluated for Alzheimer's disease (AD) or other cognitive disorders. Additionally, a Marketing Authorisation Application (MAA) was submitted to the European Medicines Agency for [18F]flutemetamol use in the visual detection of beta amyloid in the brains of adult

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patients who are being evaluated for AD. William E Klunk, Codirector, Alzheimer Disease Research Center, Distinguished Professor of Psychiatry and Neurology at the University of Pittsburgh, said, “In clinical trials, [18F]flutemetamol imaging demonstrated consistent performance in the visual detection of beta amyloid in the brain when compared with histopathology data. PET scanning with [18F] flutemetamol has the potential to augment the current methods used in the evaluation of patients with symptoms of Alzheimer's disease.”

The accumulation of beta amyloid in the brain is a key pathological characteristic of AD, which is primarily diagnosed following thorough clinical examinations (i.e., medical history, physical,

neurological, psychiatric and neuropsychological exams, laboratory tests and magnetic resonance imaging (MRI) or computed tomography (CT) scans). [18F]Flutemetamol is being studied to determine its potential ability to detect beta amyloid deposition in living humans.

The NDA and MAA submissions are based on data from a series of clinical trials, including phase III brain autopsy and biopsy studies which showed high sensitivity and specificity for visual image reads as well as strong concordance between [18F]flutemetamol PET images and beta amyloid brain pathology. Data from these studies were presented at the Alzheimer's Association International Conference 2012 (AAIC 2012) in Vancouver and the American Academy of Neurology's (AAN) 64th Annual Meeting in New Orleans. The filing also

includes data from a recently completed [18F]flutemetamol PET image reader training validation study, results of which will be presented at a scientific forum in coming months.

“Acceptance of these applications further strengthens GE Healthcare's commitment towards the early and accurate detection of Alzheimer's disease pathology and to improving the quality of life for patients and their caregivers. PET imaging with [18F]flutemetamol has the potential to be part of a larger diagnostic workup that may help doctors rule out Alzheimer's disease by reliably showing the absence of beta amyloid deposits in patients with unexplained loss of cognitive function,” said Jonathan Allis, General Manager, PET, GE Healthcare Medical Diagnostics.

EP News Bureau-Mumbai

Biogen Idec reports top-line results from phase III trial investigating dexpramipexole with ALS EMPOWER trial fails to demonstrate efficacy in primary and key secondary endpoints iogen Idec reported topline results of EMPOWER, a phase-III trial investigating dexpramipexole in people with amyotrophic lateral sclerosis (ALS). The trial did not meet its primary endpoint, a joint rank analysis of function and survival, and no efficacy was seen in the individual components of function or survival. The trial also failed to show efficacy in its key secondary endpoints. Additional analyses of multiple subpopulations failed to demonstrate any efficacy among these groups. Based on these results, Biogen Idec will discontinue development of dexpramipexole in ALS. Douglas E Williams, Executive Vice President of R&D, Biogen Idec said, “We share the disappointment of members of the ALS com-

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munity, who had hoped that dexpramipexole would offer a meaningful new treatment option. Nevertheless, the EMPOWER trial represents a significant contribution to ALS research, and Biogen Idec is committed to advancing ALS science. We continue to work with

researchers around the world to understand the causes of ALS and find potential treatments for people with ALS.” According to a release by Biogen Idec, EMPOWER was a randomised, double-blind, placebo-controlled phase-III trial which enrolled 943 peo-

PATIENTS WERE RANDOMISED ON A ONE-TO-ONE BASIS TO RECEIVE EITHER DEXPRAMIPEXOLE OR PLACEBO.THE PRIMARY ENDPOINT WAS A JOINT RANK ANALYSIS OF FUNCTION AND SURVIVAL, KNOWN AS THE COMBINED ASSESSMENT OF FUNCTION AND SURVIVAL

ple with ALS at 81 sites in 11 countries. Patients were randomised on a one-to-one basis to receive either dexpramipexole or placebo. The primary endpoint was a joint rank analysis of function and survival, known as the Combined Assessment of Function and Survival (CAFS). In addition to CAFS, the trial individually evaluated functional decline, survival and respiratory decline, among other measures.

“As a physician who has treated people with ALS, I hoped with all my heart for a different outcome. While these results were not what we expected, we hope these data will provide a foundation for future ALS research,” said Douglas Kerr, Director, Neurodegeneration Clinical Research at Biogen Idec.

EP News Bureau-Mumbai

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January 16-31, 2013

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RESEARCH UPDATE Addex announces positive data with ADX71441 ADX71441, a novel oral small molecule positive allosteric modulator, on track for Phase I clinical testing in the first half of 2013

ddex Therapeutics, a leading company pioneering allosteric modulation-based drug discovery and development, has achieved a positive proof of concept for its lead GABA-B receptor (GABA-BR) positive allosteric modulator (PAM) compound, ADX71441, in a validated pre-clinical model of Charcot-Marie-Tooth 1A (CMT1A). CMT1A is a rare (1:5,000) hereditary motor and sensory demyelinating peripheral neuropathy (also known as Hereditary Motor and Sensory Neuropathy, HMSN) which is caused by an intrachromosomal duplication and consecutive toxic over expression of the PMP22 gene on chromosome 17.

CMT1A is one of the most common inherited peripheral nerve-related disorders which is passed down through families in an autosomal dominant fashion. CMT1A disease becomes evident in young adulthood and slowly progresses with distally pronounced muscle weakness and numbness. Pain can range from mild to severe.

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The disease can be highly debilitating with wheel chairboundness and is often accompanied by severe cases of neurological pain. There is no known cure for this incapacitating disease.

"We are excited about the promising results obtained with the Addex GABA-BR PAM candidate" said Professor Michael Sereda, Max-Planck Institute of Experimental Medicine, Göttingen, Germany, in whose laboratories the study was performed. “Current CMT1A therapies are primarily symptomatic such as physiotherapy and only focus on the manifestations of the disease, while the data obtained with the Addex compound seem to suggest that positive modulation of GABA-B receptor could lower toxic PMP22 over expression and potentially delay the progression of the disease and offer a unique therapeutic opportunity for CMT1A patients.”

ADX71441 is a potent, selective, orally available small molecule that is brain

penetrant and shows good pharmacokinetic properties for once-daily dosing.

Addex GABA-BR PAM was studied in the transgenic CMT rat model which has 1.6-fold PMP22 over expression (mRNA level) and exhibits clinical abnormalities, such as reduced nerve conduction velocity and lower grip strength that mimic findings in CMT1A patients. Nine week oral therapy of ADX71441 in CMT rats (five weeks every other day at 10 mg/kg followed by 4 weeks at 5 mg/kg every day) down regulated PMP22 mRNA, reduced the amount of hypo-myelinated axons and increased compound muscle action potentials in peripheral nerves when compared to vehicle treated CMT rats.

It also prevented grip strength loss in CMT rats compared to wild type rats.

“These data confirm previous observations obtained using a GABA-BR against and the GABAB1-/- mice (knock-out mice), which identified the importance of

GABA-BR in the inhibition of the proliferation and in the reduction of the synthesis of specific myelin proteins, in particular PMP22,” noted Sonia Poli, VP, Non Clinical Development, Addex.

“These and other data further reinforce the central role of GABA-BR in a broad range of important diseases and conditions, including spasticity, Fragile X, autism, pain, anxiety, obsessivecompulsive disorder, overactive bladder and alcohol binge drinking.”

"We are rapidly advancing ADX71441 into clinical development. phase 1 clinical testing with this compound is planned for the first half of this year, initially for the treatment of spasticity associated with multiple sclerosis (MS),” said Graham Dixon, CSO, Addex. “These data are encouraging as they indicate that the compound may also have a therapeutic benefit in treatment of patients with this debilitating rare disease.”

EP News Bureau-Mumbai

New compound overcomes drug-resistant Staph infection in mice The new compound targets an enzyme not found in human cells but which is essential to bacterial survival

January 16-31, 2013

esearchers have discovered a new compound that restores the health of mice infected with methicillin-resistant Staphylococcus aureus (MRSA), an otherwise dangerous bacterial infection.

The new compound targets an enzyme not found in human cells but which is essential to bacterial survival.

The research team, led by scientists at the University of Illinois and the University of California, San Diego, reports the new findings in the Proceedings of the National Academy of Sciences. The team discovered and developed several compounds that are promising leads for antibacterial drug development, and the most potent was tested in mice infected with MRSA. According to a press release, the rise of antibioticresistant bacterial infections is a global public health problem, said U of I chemistry professor Eric Oldfield, who led the research with UC San Diego professor Andrew

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McCammon.

“There's an urgent need for more antibiotics because of drug resistance,” Oldfield said. "There are, for example, completely drug-resistant strains of tuberculosis. None of the drugs work against these strains of tuberculosis, and so, if you get it, you die.”

Other infections, such as gonorrhea, which once were easily cured with antibiotics, also are becoming resistant to treatment, Oldfield said.

“And Staph itself actually kills more people in the U.S. than does HIV/AIDS.” To begin the study, McCammon and his colleagues at UC San Diego used computer simulations to look for potential chinks in the armor of a bacterial enzyme known as FPPS that aids in bacterial cell wall formation.

The researchers then screened libraries of small molecules to identify some that might target those sites and interrupt the activity of FPPS. Oldfield's team tested some of these www.expresspharmaonline.com

molecules against FPPS, but found that they were not particularly potent inhibitors of the enzyme.

“Then we tested the most promising compound against the next enzyme in the pathway, and we found that it was 20 times more active against that enzyme,” Oldfield said.

That enzyme, called UPPS, “is important because it's involved in bacterial cell wall biosynthesis,” he said.

“And a lot of the antibiotics that we have – drugs like penicillin, methicillin, vancomycin – all target bacterial cell wall biosynthesis.”

Graduate student Wei Zhu and research scientist Yonghui Zhang worked with Oldfield to develop and test new analogs of the compound that worked against UPPS. “And we found one that was about 1,000 times more active than the first hit we had against FPPS,” Oldfield said.

Illinois chemistry and Institute for Genomic Biology

professor Douglas Mitchell tested the new compound against regular and drugresistant S aureus in cell culture and found that it had potent activity against both.

“He also found that it augmented the effects of methicillin" in methicillin-resistant Staph strains, Oldfield said.

In a final test, Dr Victor Nizet at UC San Diego used the new compound to treat mice infected with MRSA. More years of study will be needed to determine whether this compound or others like it will be effective in humans, Oldfield said, but the findings may allow scientists to target multiple enzymes essential to bacterial survival, thus reducing the likelihood that new forms of drug resistance will emerge.

The National Institutes of Health, National Science Foundation and Howard Hughes Medical Institute supported this research.

EP News Bureau-Mumbai EXPRESS PHARMA

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J&J’s new diabetes drug may pose heart risks: FDA Use of the drug canagliflozin could be associated with potential adverse effects on the kidneys new kind of diabetes drug being developed

by Johnson & Johnson raised the level of bad cholesterol in patients during clinical trials and may pose heart risks, US drug reviewers said. J&J is testing canagliflozin to treat type II diabetes, which is often associated with obesity and a lack of exercise. Diabetes affects about 370 million people worldwide, and about 90 per cent of those cases are type II diabetes. The FDA requires companies making treatments for the disorder to prove that their drugs do not increase the risk of heart attacks or other heart problems.

Reviewers with the US Food and Drug Administration also said the use of the drug canagliflozin could be associated with potential adverse effects on the kidneys and increased fungal growth in the perineum and bacterial growth

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in the urinary tract. An independent panel of experts will review and vote on the

drug's safety, efficacy and approval The FDA usually follows the panel’s recom-

mendations. The drug will be sold as Invokana if approved.

Reviewers also said while renal, adrenal, testicular, breast and bladder cancers were carefully evaluated throughout the development of the treatment, available data did not suggest an increased risk of malignancies related to the drug.

Canagliflozin belongs to a new class of diabetes medication, known as SGLT2 inhibitors. These drugs work by blocking reabsorption of glucose by the kidneys and increases glucose excretion in urine to lower blood sugar.

AstraZeneca and BristolMyers Squibb's dapagliflozin, which belongs to the same class, was rejected by the FDA last January over safety concerns, including liver problems. Eli Lilly and Co and Boehringer Ingelheim's empagliflozin, which uses a similar mechanism, is currently in latestage trials.

Reuters

Medicines Co’s anti-clotting drug late-stage study positive Cangrelor, showed statistically significant results, compared to another clotting disorder drug, clopidogrel edicines Co said its experimental anti-clotting drug met the main goal of a late-stage study. The company said the drug, generically called cangrelor, showed statistically significant results, compared to another clotting disorder drug, clopidogrel.

Cangrelor is prescribed to patients who have to undergo a stent-placing surgery or a bypass and prevents formation of clots during such procedures.

Bleeding rates are important for anticoagulants such

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as cangrelor since a high rate could trigger an adverse event. However, Raffat said the bleeding rates during the late-stage study were similar to prior trials. Clopidogrel is marketed by Bristol-Myers Squibb Co and French drugmaker Sanofi under the brand name Plavix, which lost its marketing exclusivity in the US last May. Medicines Co said, it expects to submit data from the late-stage study on cangrelor for regulatory review in the US and European Union in 2013.

Pfizer wins EU approval to expand use of Prevenar to children The vaccine protects against the potentially fatal effects of pneumococcal disease fizer said the European Commission has approved expanding the use of Prevenar 13, its pneumococcal conjugate vaccine, to older children and adolescents six to 17 years old.

The vaccine protects against the potentially fatal effects of pneumococcal dis-

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ease, a group of illnesses caused by the bacterium Streptococcus pneumoniae, also known as pneumococcus. Children in this age group who have not previously received Prevenar 13 may receive a single dose of the vaccine, Pfizer said. The European Commission's deciwww.expresspharmaonline.com

sion to approve this expanded indication followed submission and review of a Phase III trial of Prevenar 13 in 592 healthy children and adolescents, including those with underlying medical conditions such as asthma.

Prevenar 13 was first introduced for use in infants and

young children in December 2009 in Europe and is now approved for such use in more than 120 countries.

It is not indicated for the prevention of pneumococcal pneumonia in the pediatric population in the US. The vaccine is approved for use in adults 50 years of age and older in more than 80 countries.

Reuters January 16-31, 2013

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Lilly, Boehringer diabetes drug meets goals in trials The companies expect to file for regulatory review of the drug in the US, Europe and Japan in 2013 li Lilly and Co and Boehringer Ingelheim said that an experimental treatment for type II diabetes, empagliflozin, met the primary goal of significantly lowering blood sugar levels in four late-stage trials. The companies said they expect to file for regulatory review of the drug in the US, Europe and Japan in 2013 and will present detailed data from the trials this year and next. The trials studied empagliflozin at 10 milligrams and 25 mg alone and in combination with other common diabetes treatments, such as metformin and Takeda Pharmaceutical’s Actos, against a placebo. One of the trials tested the Lilly drug in patients with impaired kidney function.

Empagliflozin belongs to a new class of diabetes treatments called SGLT2 inhibitors that work by blocking reabsorption of

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glucose by the kidney and increases glucose excretion in the urine to lower blood sugar. An advisory panel to the US Food and Drug Administration this week is scheduled to discuss a Johnson & Johnson drug

from the same class called canagliflozin, which is awaiting an approval decision. Dapagliflozin, a drug from AstraZeneca Plc and Bristol-Myers Squibb Co that belongs to the same SGLT2 class, had earlier been

rejected by the FDA over safety concerns, such as liver problems.

Lilly and Boehringer said incidence of adverse side effects was similar for placebo and both doses of empagliflozin.

However, genital infections occurred more often with the treatment than with placebo, as had been seen in earlier studies with the class of drugs. The empagliflozin Phase III programme, including a large heart safety study, involves more that 14,500 patients, the companies said.

Boehringer and Lilly are collaborating on several diabetes drugs. They said, only Lilly would continue with development of one of the treatments, known as LY2605541. About 371 million people worldwide are estimated to have diabetes.

Type II is the most common form of the fast growing disease, accounting for about 90 per cent of all cases.

Reuters

Bayer’s Nexavar meets goal in thyroid cancer trial Nexavar, developed with Onyx Pharmaceuticals, is already approved to treat liver and kidney cancer erman drugmaker Bayer said its cancer treatment Nexavar reached a goal of improving the survival of patients with a certain type of thyroid cancer in a late-stage clinical trial.

The company said that it planned to submit data from

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the trial in the coming months in a bid to win regulatory approval to sell Nexavar as a treatment for radioactive iodine (RAI) refractory differentiated thyroid cancer. It would present a detailed analysis of the study, in which 417 patients took part, at an upcoming medical meeting, it added, without providing details. Nexavar, developed

jointly with Onyx Pharmaceuticals, is already approved to treat liver and kidney cancer in more than a 100 countries, with peak sales seen at $993 million a year.

The drug, which made 725 million euros of sales in 2011, missed its goal in a trial with lung cancer patients last year. There are more than 160,000 new cases of thyroid

cancer each year, and about three times as many women are diagnosed with it as men, making it the sixth most common cancer in women, according to Bayer. RAIrefractory thyroid cancer is more difficult to treat than most types and has a lower survival rate.

Reuters

Vitamin D may not relieve arthritis pain On a 0-to-20 point pain scale, people taking vitamin D saw a 2.3-point decrease during the two years aking daily vitamin D doesn’t keep knee pain from getting worse or slow the loss of cartilage for people with osteoarthritis, according to a US study. Previous research suggested that among people with the joint disorder, those with higher levels of vitamin D in their blood tended to have a slower progression of symptoms.

But whether that meant taking more in supplement form would also have a protective effect was unclear.

“It looked compelling at that point," said lead author Timothy McAlindon, from Tufts Medical Center in

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January 16-31, 2013

Boston. For the new study, published in the Journal of the American Medical Association, he and his colleagues randomly assigned 156 of their patients with knee osteoarthritis to take a daily dose of vitamin D or a vitamin-free placebo for two years. None of the participants knew which type of supplement they were assigned to take. The vitamin D doses started at 2,000 international units (IU) per day and were increased to as high as 8,000 IU daily in some patients. For most adults, the recommended daily allowance of vitamin D is 600 www.expresspharmaonline.com

to 800 IU. The vitamin D group started out slightly worse off than their comparisons on measures of knee pain and function, but the vitamin didn’t seem to offer clear relief.

On a 0-to-20 point pain scale, people taking vitamin D saw a 2.3-point decrease during the two years, compared to a 1.5-point decrease among those taking placebos - a difference that could have been due to chance. Changes in knee cartilage volume - a measure of the progression of osteoarthritis - and knee function were also similar among the two groups during and

after the study period. Robert Heaney, who has studied vitamin D at Creighton University School of Medicine in Omaha, Nebraska, said he wasn't surprised the study didn't find a beneficial effect on knee pain across all patients.

"It's almost certain that vitamin D's effects are different from person to person," said Heaney, who wasn't involved in the new research.

"It's very important for some people, but may not make any difference for others."

That may have to do with genetics or other factors that doctors aren't yet able to test for before the prescribe vitamin D, Heaney said.

Reuters EXPRESS PHARMA

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PACKAGING S P E C I A L W H AT ’ S INSIDE

Goose launches online and offline 2D Bar coding solution PG 40 ACG Pharmapack launches Bio-D, biodegradable PVC film PG 41

'We will invest in Triveni in the years to come to foster growth and quality strategy' PG 42 Ensuring quality in pharma production PG 43 INDIAPACK 2013 to be held at Bombay Exhibition Centre, Mumbai from Jan 28-31 PG 45

PHARMA ALLY 71 PHARMA LIFE 78

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January 16-31, 2013

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After a delay of one year, the Directorate General of Foreign Trade (DGFT)'s mandate on 2D barcoding at the secondary level of packaging came into force from January 1, 2013.

This is part of the DGFT's plan to have track and trace mechanisms at the primary, secondary and tertiary levels of packaging for all export products. The new regulations are aimed at safeguarding India's pharma exports from drug counterfeiters.

India's pharma supply chain has been breached in the past. For example, in November 2011, counterfeit anti-malarial drugs with a 'Made In India' labels but actually originating from China, were seized by Nigerian port authorities.

The loss of reputation resulting from this incident and other similar incidents resulted in the DGFT opting for track and traceability systems like barcodes in the hopes that counterfeiters would find it more difficult to infiltrate the pharma supply chain.

Even though the industry appreciates the rationale behind the DGFT's stance, over the past year, they have asked for and got extensions of the deadlines as smaller

ARCHANA DUBEY MITRA players were finding it difficult to arrange finances to put in place the 2D technology required for the secondary level of packaging.

The initial deadlines for incorporation of track and trace systems was October 1, 2011 for primary packaging, January 1, 2012 for secondary level packaging, and October 1, 2012 for tertiary level packaging.

Over the past year, Pharmexcil has been conveying the viewpoints of its members with the Government and was told to discuss it with Wipro and GS1, as they are also key to the project. Through its latest circular, Dr PV Appaji, Director General, Pharmexcil informs members that the Government of India has decided not to extend the deadline. He mentions that members can familiarise themselves with the system by signing up for the webinars and workshops being organised by GS1 as per schedule given on their website.

Ground realities Many of the larger pharma and biopharma companies have already implemented these systems. Goose Technologies, one of the solution providers, recently introduced Goose ‘Tracker’, a cost effective new generation 2D serialisation bar code for the drug industry with a choice to choose online or an offline solution to secure and protect

Clarifications on certain issues sought by Pharmexcil members a) Are mono cartons primary packing or secondary packaging?

Pharmexcil had informed GS1 that their revised manual had created some confusion regarding status of mono cartons as secondary packing as against primary packing indicated in the previous manual. GSI subsequently revised the manual and clarified that mono cartons would be considered as primary packing and therefore would not require bar coding on mono cartons (as requirement of bar coding from January 1, 2013 relates to secondary packing only). The revised manual of GS1 is uploaded on the Pharmexcil web site b) Status of products manufactured before January, 2013 The Government/DGFT vide policy circular No. 43(RE-2010)2009-14, dt. 25.10.2011 had earlier clarified with respect to bar coding on tertiary packing, that bar coding requirement for pharmaceuticals and drugs would be effective for products manufactured after effective date of implementation of bar coding . Accordingly it is indicated that

January 16-31, 2013

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Vice President-International Marketing, Bal Pharma

DIDIER LACRIOX Senior VP International Sales and Marketing Cognex

The industry is still contemplating the need to implement bar coding on secondary packaging as there is no customer requirement as yet

We feel that the Government should extend its time for applying because of the small-scale players who will face issues for arranging capital to install such machines as well as the costs of running them

both consumers and the pharma companies.

According to product literature, its multi-level authentication features allow tracking of product throughout the distribution channel including warehouse to customer retail chain. The company informs that pharma companies like Strides Arcolab, Indoco Remedies and Macleods Pharmaceuticals have already implemented and adopted Goose Tracker

for to comply with the DGFT's mandate.

The capital expenditure associated with implementing such solutions is still an issue with one section of the industry. As Archana Dubey Mitra, Vice PresidentInternational Marketing, Bal Pharma points out, “There is no standardised software available for capturing all the required data on the barcode. Every programmer develops their own parame-

bar coding on secondary packing would become effective for those products manufactured on or after 1st January 2013 only. c) Bar coding for bulk drugs The Government/DGFT had already clarified vide policy circular No.48(RE-2010)/2009-14, dt. 28.11.2011 that the requirement for bar coding is applicable only to finished pharma products i.e. medical formulations and not bulk drugs/APIs/Intermediates. d) Bar coding for merchant exporters and Ayush products Pharmexcil has requested GS1 to develop appropriate bar coding mechanism for merchant exporters for export of heterogenous drugs produced by various manufacturers. Pharmexcil has also requested the Government to exempt small merchant exporters and Ayush product manufacturers from barcoding. Pharmexcil is awaiting the Government's decision on this. e) Bar coding on drugs meant for Government and physician’s samples Pharmexcil has already taken up this issue with the Government and clarification is awaited. In the absence of clarification, it would be necessary to meet the bar coding requirement.

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P|A|C|K|A|G|I|N|G | S|P|E|C|I|A|L ters to create the programme. The industry is still contemplating the need to implement bar coding on secondary packaging as there is no customer requirement as yet.” The pharma industry is a customer driven industry and manufacturers generally react to customer requirements, is her point.

Moreover, as the industry is well spread at multiple levels, she also points to the practical hurdle of implementing such technology on a mass scale.

As she explains, 'Implementing this at all levels requires capital investments which could be very high making it difficult for all companies to implement at one go. The technology is still not economically priced. Accuracy factors also need to be high while output remains low.”

Mitra suggests that ideal-

THE INITIAL DEADLINES FOR INCORPORATION OF TRACK AND TRACE SYSTEMS WAS OCTOBER 1, 2011 FOR PRIMARY PACKAGING, JANUARY 1, 2012 FOR SECONDARY LEVEL PACKAGING, AND OCTOBER 1, 2012 FOR TERTIARY LEVEL PACKAGING ly the Government should have mandated free software to begin the process of implementation in a phased manner giving time and experience for all to implement.

The Government has meanwhile indicated that it would try to consider reimbursing partial cost to small exporters, provided Pharmexcil furnishes ade-

quate data on this subject.

As the mandate falls into place, things may be looking up on the technology front. Didier Lacriox, Senior VP International Sales and Marketing, Cognex comments, “After the announcement it is seen that many small companies were ready to provide the required 2D bar-coding solutions at reasonable rates. But we feel

that the Government should extend its time for applying because of the small-scale players who will face issues for arranging capital to install such machines as well as the costs of running them. Also for bar coding, exporters will have to register their products with the importing country and take necessary approvals from their regulators and comply with the norms.

Implementation of bar code will require them to make changes in their registration that will involve committing a time line of at least a year.

"He stresses, “The initiative is a positive one and will reduce chances of counterfeit drugs being exported in India.” Here's hoping the all pharma exporters keep this end goal in mind and invest today to reap profits tomorrow. u.sharma@expressindia.com

NEWS Goose launches online and offline 2D bar coding solution ‘Goose Tracker’ is designed to suit pharma industry’s need to meet GS1 Track and Trace requirements oose has launched Goose ‘Tracker’, a cost effective new generation 2D Serialisation Bar Code for the drug industry with a choice to choose online or an offline solution to secure and protect both consumers and the pharma companies.

Goose ‘Tracker’ incorporates several new changes to suit GS1 global traceability guidelines.

Goose ‘Tracker’ creates, manages and tracks unique serial numbers printed on the tertiary, primary and secondary packages. With the introduction of cost effective online and offline functionality options, Goose ‘Tracker’ helps pharma organisations with an alternative product serialisation technology; crucial investment option to minimise per production line serialisation costs.

Leading pharma companies like Strides Arcolab, Indoco Remedies and Macleods Pharmaceuticals, have already implemented and adopted Goose Tracker for Track & Trace solution.

The company expects a rise in demand and surge in

G

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‘Goose Tracker’ customer portfolio as pharma companies get set to implement secondary bar coding which has been made compulsory for pharma exports from January 1, 2013.

“Goose Tracker is a simple and easy to configure Track & Trace solution for achieving bar coding on drug packaging as per the recent Directorate General of Foreign Trade (DGFT) regulation,” said Deb Pattnaik, Founder and CEO, Goose.

He further said, “Our online and offline solution is highly scalable and handles the

track and trace needs for all levels of packaging (up to primary) and e-pedigree easily.”

This powerful solution can be configured to address product-specific integrity challenges and allows seamless scale as an organisation adds new lines, manufacturing plants, etc. “Goose Tracker integrates with existing applications to securely meet data management and printing needs for packaging and shipping labels. We are working with several Government and non-Government entities to include changes as and when they are announced,” Deb added.

LEADING PHARMA COMPANIES LIKE STRIDES ARCOLAB, INDOCO REMEDIES AND MACLEODS PHARMACEUTICALS, HAVE ALREADY IMPLEMENTED AND ADOPTED GOOSE TRACKER FOR TRACK & TRACE SOLUTION. THE COMPANY EXPECTS A RISE IN DEMAND AND SURGE IN ‘GOOSE TRACKER’ www.expresspharmaonline.com

Goose Tracker’s serialisation algorithm generates billions of unique numbers.

It does not store serial numbers in the database for enhanced security and includes a dynamic engine to interact with ERP systems for data retrieval. This solution provides offline application for entities in the supply chain that do not have access to the main database.

Users can also validate the authenticity of the product by using SMS, IVR or website. Validations done on the line such as rejecting wrong carton printings like character missing, wrong character, wrong code, 2D code, datamatrix code, smudging, code line characteristics etc. are stored in the database, that can be used for productivity monitoring and optimisation purposes. This tool helps in providing accurate detection of 2D on carton and Optical Character Verification (OCV) of overprinting details on carton. It supports GS1 data matrix standards and comes with all validation documents required for 21-CFR Part 11 compliance and GxP Critical Validation.

EP News Bureau-Mumbai January 16-31, 2013

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PRODUCT ACG Pharmapack launches Bio-D, biodegradable PVC film The biodegradability of these films has been confirmed using ASTM D5511 testing method and validated by an independent third-party laboratory CG Pharmapack, the company known as a pioneer in introducing high moisture barrier, pharma-grade PVdC coated PVC films in India, has launched a unique bio-degradable calendared PVC film, Bio-D. As compared to normal PVC films, these PVC films render themselves biodegradable at an enhanced rate when they are exposed to active biological landfill environments. The biodegradability of these films has been confirmed using ASTM D5511 testing method and validated by an independent thirdparty laboratory.

Bio-D does not compromise on the intended application and usage condition, and retains the sturdiness, and physical, as well as chemical properties exhibited by normal PVC films. Besides being available in various customisable thicknesses, the biodegradable PVC films have the same shelf life as normal PVC films. These films can be recycled using already established recycled streams, just like normal PVC. ACG’s Bio-D PVC

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January 16-31, 2013

films are also FDA-compliant for direct food contact application and meet with US Federal Trade Commission’s “Green Guidelines.”

Bio degradation of these films may result in methane outgassing, which could be harnessed as an alternative energy source. This landfill gas energy is US EPA recognised renewable energy source.

Bio-D PVC films provide a sustainable packaging option that increases your brand value by being associated with green initiatives. In addition, it reduces the environmental impact, while protecting your product as well as the planet.

These films are aptly supported by a wide range of pharma packaging solutions from ACG including blister-packing and cartoning machines, camera inspection systems, and case packers.

Contact details: Shivprasad HiremathExecutive Corporate Marketing Contact No: +22 3046 2896 Mobile No: 9867509664 EP News Bureau-Mumbai

www.expresspharmaonline.com

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INTERVIEW 'We will invest in Triveni in the years to come to foster growth and quality strategy' Recently, Gerresheimer acquired Triveni Polymer, to enhance its business plans. The company has already made several initiatives to equip the plant at Triveni with access to their know-how and technology. Niels During, Head of Gerresheimer Plastic Packaging discusses how the plant will contribute to the growth of the company in the years to come and about the company's various primary packaging solutions, with Usha Sharma India seems to be a preferred destination for global pharma companies. What does this mean for Gerresheimer?

We expect very good growth opportunities in India, especially with generics and other mass pharma market, which result in high volume demand for primary packaging. After having acquired Neutral Glass last April with a state-of-the-art glass primary packaging production, mainly for parenterals, it is important to have a local production for plastic primary packaging. In addition to that, India plays an increasingly important role as a generics supplier for export in the Western world. India has the highest number of US FDA approved productions. This results in even higher growth rates in India.

Recently, Gerresheimer has acquired Indian plastic packaging company Triveni. What was the rationale for this acquisition?

Triveni is a very fast growing market leader with all necessary national and international approvals and certifications. Triveni has a very broad, well diversified, customer base in the pharma market, a great management team and a state-of-the-art production including clean room technology. Their product portfolio covers plastic containers and closures. We see great opportunities for synergies and to leverage our joint growth.

Which technologies do you plan to bring to the Indian market?

Gerresheimer produces all its products under the same technological and quality aspects and framework worldwide. Therefore, we have already prepared a number of initiatives to make sure that the plant in Triveni will be given access to our know-how and technology as well as our very wide and strong product portfolio to produce according to Gerresheimer standards.

Why did you choose Triveni for this acquisition?

We always look into several opportunities. We decided to sign the agreement with Triveni since the company is a very fast growing market leader with all necessary national and international approvals and certifications as well as a very broad pharma product portfolio and a very good customer base.

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INTERVIEW

the future.

India has a spurious drug market and the Government is trying to implement a standardised strategy in place to counter this. What are your plans to tackle this problem?

We will support any approach which increases product quality and attacks the counterfeiting of drugs.

With the help of the recent acquisition you are exploring emerging markets.

Please tell us about the marketing strategy behind this plan and how will this help to accelerate the company's growth further?

The estimated annual growth rate of the Indian pharma market is 14-17 per cent. With the combined expertise of Triveni and their very good customer relations in India together with the global footprint, strong and broad product offering and technological expertise of Gerrresheimer we plan to increase the current market share and grow fast.

What is the market size of Triveni and how will it further enhance Gerresheimer's capabilities?

Triveni generated annual revenues of approximately ` 1.3 billion (around EUR 20 million) in the financial year 2011-12 and will become a strong platform for realising our customer pipeline in India.

Triveni Polymer is the only company to get an US FDA approval for crucial Drug Master Files (DMF) for plastic containers and closures. Do you think this will enhance the product quality?

Yes definitely, since it proves and shows the high quality standards under which Triveni manufactures. At the same time, it opens export opportunities which we will intensify even further in

ACCORDING TO OUR GROWTH PLANS FOR TRIVENI WE WILL EXPAND AND IMPROVE THE PLATFORM TO MATCH THE GROWTH AND HIRE ADDITIONAL STAFF,WHEN REQUIRED. CONCRETE PLANS WILL BE ANNOUNCED IN DUE COURSE

www.expresspharmaonline.com

What are your plans for the Indian market?

We are confident that the Indian pharma market will grow very strong in the years to come and we want to contribute to this growth with our primary packaging solutions. This can be done either by further acquisitions or by organic growth. We always look into interesting investment opportunities, especially in fast growing countries like India. But there are no concrete projects to be disclosed as of today.

Do you have plans to set up/upgrade facilities in India?

We will invest in Triveni in the quarters and years to come to foster their growth and quality strategy. Concrete investment and enhancement decisions will be announced in due course.

How many employees are you planning to recruit for India operations and how soon?

According to our growth plans for Triveni we will expand and improve the platform to match the growth and hire additional staff, when required. Concrete plans will be announced in due course.

What are the company's plans for the India market in the next two years.

Gerresheimer, together with the local management, will explore further opportunities to broaden the product portfolio and local production as well as broaden the customer base for Triveni. u.sharma@expressindia.com Januaryr 16-31, 2013

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INSIGHT

Ensuring quality in pharma production Didier Lacroix—Senior VP International Sales and Marketing (Cognex) talks about the benefits of implementing machine vision technology in pharma packaging through examples of Cognex In-Sight vision systems roduct safety and packaging integrity is a stringent aspect in the pharma industry. They are “early adopters” in the deployment and use of machine vision technology to stay compliant with regulations and mitigate risks.

P

shipments between manufacturing facilities is record-

ed for further distribution.

Product delivery is recorded

at external supply chain level, allowing for an end-

to-end product verification process.

TURNKEY SOLUTIONS FOR BIOTECH & PHARMA INDUSTRY.

Track and trace Center for Medicine in the Public Interest (CMPI) estimates that more than

WARRINGTON FIRE ASTM BRI POLAND CERTIFIED

CE APPROVED

INTERNAL INFRASTRUCTURE (Modular Panels) 25,000 pharma packaging lines globally require modification to implement effective track and trace technologies. This presents challenges to manufacturers and machine builders.

Track and trace solution requires implementing three levels of functionality: ● print and verify marking numbers on all products ● mark each product with a unique serial number and create a central database ● track, store the location and status of each product as it travels through the supply chain until it is sold to the customer Serialisation data is got from four layers of supply chain operations, from individual medicine to manufacturing and final delivery.

Any hierarchy-level information appearing on packaging such as blisters, folder cartons, bundles, cartons, packages or container also is recorded on production floor. Information is collected at internal supply chain level where product data on January 16-31, 2013

CONTAINMENT SOLUTIONS

CE APPROVED

CE APPROVED

AIR STERILIZATION

CONTAINER STERILIZATION WITH PRE-INSULATED DUCTING

PATENTED TECHNOLOGY PATENT NO. 541/MUM/2010

PLASWALL - OUTER CONSTRUCTION

HVAC & MEP

Head Office : 717, Janki Center, Off. Veera Desai Road, Andheri (W), Mumbai - 400 053, Tel : +91-22-61592900-30 Fax : +91-22-61592855/61592955 e-mail : sales@fabtecheng.com / mails@fabtecheng.com

www.expresspharmaonline.com

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P|A|C|K|A|G|I|N|G | S|P|E|C|I|A|L Counterfeiting WHO estimates that about 15 per cent of medicinal products in the world are counterfeit. CMPI estimates that activities related to counterfeit drugs generate $75 billion annually and expects to grow by 20 per cent annually in coming years.

ready retrieval throughout the records retention period.

Limiting system access to authorised individuals. Use of secure, computer-generated, time-stamped audit trails to independently record operator entries and actions that create, modify or delete electronic records. Use of operational system checks to enforce permit-

inspects the underside of glass vials for cracks. In-Sight Color Vision system checks both vial cap and flip-off-

Defect detection and quality control 21 CFR Part 11 Complying with US Food and Drug administration (FDA) regulations on electronic records/electronic signatures and pharma inspection cooperation schemes has created challenges for pharma manufacturers. It includes fortifying access control measures while providing an electronic trail for all transactions.

FDA suggests that procedures and controls should include: A) Validation of systems

ted sequencing of steps and events, as appropriate.

C) Use of authority checks to ensure that only authorised individual scan use the system. Determine that person who develop, maintain, or use electronic record/electronic signature systems have education, training and experience to perform their assigned tasks.

Establishment of, and adherence to, written policies that hold individuals accountable and responsible for actions initiated under their electronic signatures, in order to deter record and signature falsification.

Machine vision meets the following challenges of the pharma industry: Serialisation and Tracking Advanco serialisation and tracking solutions deployed a traceability solution using Cognex In-Sight ID readers for a manufacturer that produces and distributes 60 million medicine boxes annually. In 1.4 seconds, it decodes all 2-D code sprinted with inkjet onto the surface of each medicine package. An alarm trigger removes defective products ensuring that all shipment packages are traceable and improves production processes.

Defect detection

to ensure accuracy, reliability, consistent intended performance and ability to discern invalid or altered records.

Generate, accurate and complete copies of records in both human readable and electronic form.

B) Protection of records to enable their accurate and

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Product testing company, EISAI Machinery GmbH used two Cognex In-Sight vision systems to inspect delicate glass vials in fraction of a second. It determines the cake height of freeze-dried contents and detects the presence of any foreign objects on their surface and for “splashings” caused by unwanted boiling during the freeze-drying process. In-Sight system www.expresspharmaonline.com

seal, inspecting for parts presence, cover colour and for aluminum caps, correct crimp processing. It ensures that only glass vials with 100 per cent product quality are distributed to clinics, pharmacies, and medical practices.

Process automation Automated Systems of Tacoma, Inc (AST) used Cognex Vision System for developing a single-platform machine to fill vials, syringes and other containers. It eliminates the need to purchase multiple filling machines and can handle all liquid packaging needs.

Code verification Pharma products manufacturer Sanofi-Aventis used Cognex vision systems to implement a print and code verification solution to comply with GS1 codes readability regulations. Designed as a mobile system, it can be adapted for packing lines and installed along the production process. It, with track and trace software, provides information to a PC database to create an audit trail. It reads printed data and verifies against selected information camera at a speed of 300 parts per minute.

Machine vision tools for the pharma industry ● PatMax

uses a set of boundary curves, not tied to a pixel grid, and looks for similar shapes in image without relying on speci?c gray levels. Result is an ability to find objects despite changes in angle, size and shading. ● Test Run delivers quality improvement. If it fails to inspect properly, quality manager can add to Test

Run database and make required modifications. ● OCRMax prevents misreads, handles process variations and provides easy font management. It’s easy to set up and simple to use across all platforms.

Packaging Quality Control Boehringer Ingelheim uses Cognex vision to achieve printing quality inspection on a production line churning out around 300,000 blister packs and 100,000 folding packs every day. Challenge was high speeds at which blister packs move on the production line, variable accuracy of inkjet printing on foils with irregular surfaces and dirt, pressure, and sharp edges. Depending on product type, examination is made of varying details, including lot number, expiry date and pre-printed information. It recognises relevant symbols and letters and on previous parameters and tolerance limits, assesses product quality.

Label verification ArturTheis GmbH has a machine that inspects labels with different identification and information carriers including 1-D codes, genuine lettering and holograms and bollinos. It can affix labels, stickers and bollinosupto200 different types of folding cartons and check their position.

If not aligned, then information such as use-by date, product and lot numbers cannot be applied correctly.

PatMax technology in In-Sight Micro system helps to inspect product variety with different label shapes and colors by orienting itself to geometric features of the cartons. It determines position values without errors—even under variable lighting and position conditions and despite changing angles, sizes, and shading.

January 16-31, 2013

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NEWS INDIAPACK 2013 to be held at Bombay Exhibition Centre, Mumbai from Jan 28-31 International Summit for packaging industry to take place concurrently

I

January 16-31, 2013

their support along with many Packaging & Allied Industries Associations from India and abroad to make

this event a mega show.

Dr Rajat Kumar, IAS, Commissioner-of Industries, Government of Andhra

will be organised to felicitate the winners of the only national awards for the packaging companies in this country.

EP News Bureau-Mumbai

® Trademark of The Lubrizol Corporation © 2011 The Lubrizol Corporation

ndian Institute of Packaging (IIP), an autonomous body working under Ministry of Commerce & Industry, Government of India will organise INDIAPACK 2013 at the Bombay Exhibition Centre, Mumbai from January 28–31, 2013 and International Summit for Packaging Industry (ISPI) from January 29-30, 2013 at Hotel Leela, Mumbai. The Government of Maharashtra is expected to grace this event by extending their support as a ‘Host State’ for INDIAPACK 2013.

The event will see products from some of the largest and eminent industry exhibitors. Many companies from Germany, France, China, Korea, Taiwan, Thailand and many other countries will also be present with latest display of packaging technology. The visitors will see packaging equipment/ machinariesplants on display with live demonstration. The main objective of INDIAPACK 2013 is to provide the Indian packaging industry a unique platform where Indian packaging industry will showcase stateof-the-art packaging technology and machinery, products and services along with international companies providing effective packaging solutions in terms of costs, productivity suitability and quality.

National and internationally renowned experts will present their papers in ISPI to cover prospects of packaging industries, printing technology, converting technology, packaging media, packaging system and machinery, package testing and evaluation, package distribution etc.

The National Awards for Packaging Excellence viz INDIASTAR & PACMACHINE for the year 2012 will be also be given away at a grand function in the evening of January 30, 2013 concurrent with the exhibition.

World Packaging Organization (WPO), Asian Packaging Federation (APF), Sri Lanka Institute of Packaging, Sri Lanka Packaging development Centre have also extended

Pradesh has consented to be the chief guest for the function, while Madan Mohan Reddy, Director, Aurobindo Pharma will be the special guest.

IndiaStar Awards night

Carbopol® polymers are highly efficient gel matrix formers for controlling drug release in solid dosage forms. They offer versatility and flexibility… a winning combination.

Processing Versatility n Ability to choose various manufacturing technologies n Available in both powder and granular forms (Carbopol® 71G NF polymer) Flexibility n In modulating drug release n In formulation - Actives with different properties can be formulated to achieve various extended release profiles

Carbopol® Polymers High Performance Pharmaceutical Ingredients

Efficiency (low total polymer level) n Enables smaller tablet size n Potential formulation cost savings Synergies with other commonly used controlled release excipients

www.expresspharmaonline.com

Lubrizol Advanced Materials India Pvt. Ltd., Application & Business Center, Jaswanti Landmark, 6th & 7th Floor, L.B.S. Marg, Vikhroli (West), Mumbai-400079 Phone: +91-22-66027800 Fax: +91-22-66027888 www.pharma.lubrizol.com

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Express Pharma Business Avenues

January 16-31, 2013

www.expresspharmaonline.com

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Express Pharma Business Avenues

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Silicone Transparent Tubing & Braided Hose Conforms to USP Class VI Requirement & FDA 21 CFR 177.2600 (AVAILABLE IN PLATINUM & PEROXIDE CURED)

Silicone & Viton Rubber O Rings

G Platinum Cured Silicone Transparent Tubes G Platinum Cured Silicone Transparent Braided Hose G Platinum Cured Silicone T/c Gaskets G Silicone Extruded Door Gaskets (Autoclavable)

FBD Inflatable Gasket Conformd to FDA 21 CFR 177.2600

Silicone Extruded Door Gasket

G Silicone Stripss, Cords &sponge Gaskets ISO 14644-1 Certified Clean Room

G Rubber Expansion Joint/Bellows G Viton O-Rings, Cords & Strips G O-Rings (Viton & Silicone)

Quality Management System

Environmental Management System Occupational Health Safety Assessment System

G Tri Clover Gasket

Ami Polymer Pvt. Ltd. (The Sealing Expert in Silicone Rubber)An ISO : 2008 Certified Co.)

G Silicone & Viton Sheets

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January 16-31, 2013

Express Pharma Business Avenues

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For Assured Air Quality ( Sterile Room) & Flexible Cooling Solutions Cutting edge technology in air handling systems HEPA Filters

CONTEC AIR FLOW PROJECTS PVT . LTD. Building No-6 , Gala No - 138, Mittal Industrial Estate, Andheri Kurla Road, Andheri East, Mumbai- 400 059.

Tel - 022- 2859 8231/39 Mob - +91 9320 255 124 Fax- 022 - 2859 8229 Email : mks1_contec@yahoo.co.in. info@contecair.com. Website - www.contecair.com

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January 16-31, 2013

Express Pharma Business Avenues

Quality Through Experience

By Erweka India

GmbH Germany

iHT 100

Multicheck 5.1

GTB Granulate Flow Tester ester

TBH 125 TD

Dissolution Tester Tester

Leak Test Test Apparatus

TBH 425 WTD

TBH 525 WTD

Fully Automatic Disintegration Tester Tester

Media Preparation Unit

Puris Water Water Purification System for HPLC grade Water ater

Torque orque Measurement System for Bottle Cap

Local Contact Erweka India Pvt Ltd. Plot No. 29, Survey No. 415, N. H. No. 8A, Sarkhej-Bavla Road Village-Moraiya, Tal. Sanand, Dist. Ahmedabad-382213 Tele: +91-9228022065 Email : sales@erwekaindia.com www.erwekaindia.com

January 16-31, 2013

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Express Pharma Business Avenues E-mail: alokunipal@alokind.com

Alok Industries Limited (Alok) is the largest diversified and integrated textile manufacturer in India.

Alok's state-of-the art Packaging Division, amongst the largest in the country, has purchased the licence to produce UNIPAL corrugated pallets in India under the brand name, "Alok Unipal". “Alok Unipal" is a modular system to manufacture corrugated pallets. UNIPAL currently operates in more than 10 countries across the world and is known to outperform all other corrugated pallets in the market today.

An "Alok Unipal" Corrugated pallet is a patented, innovative system with flexible construction, high strength characteristics made of water resistant Kraft paper which does not require any fumigation for Export Purposes .By choosing "Alok Unipal" you will be choosing an environmentally friendly way of doing business.

Versatile: Size from 400 mm to

Hygienic: a totally clean solution

1900 mm

Customisable: tailor-made to your

Superior: dynamic loads up to 1 MT

requirements

static loads up to 4.5 MT

Efficient: Save money by assembling on

Light weight: between 6 to 10 Kgs

location

Compliant: in line with international shipping

Flexible: 2- or 4 -way entry

requirements ISPM 15

Safe: Secure handling

Can be assembled at point of use

Recyclable: 100% No fumigation required

Contact Details Plant Address: Survey No. 87/1 & 96/1, Falandi, Umarkui Road, Silvassa -396230 (U.T. of D.N. & H.) Corporate Office: Peninsula Towers, Peninsula Corporate Park, G.K Marg Lower Parel, Mumbai-400013 M.: 898 000 3486, 834 777 0005, 9099012209 | E.: alokunipal@alokind.com | W.: www.alokind.com January 16-31, 2013

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January 16-31, 2013

Express Pharma Business Avenues World Class Bottle Packaging line solution from Countec, Korea New!!! 200 Bottles/minute Tablet-Capsule Bottle Packaging Line

Twice the speed, half the space!!!

New!!!

New!!!

Verification Counting Machine DMC CQ2

New!!!

Bench Top Counter DMC 4

New!!!

Electronic Tablet Counting Model DMC120T/DMC200

High Speed Rotary Screw Capper with Servo Motor Control CT-RC-120/200

Our range of packaging systems include 60BPM, 120BPM & 200BPM container packing line · ·

Mono block unscrambler with air jet cleaner Sachet desiccant inserter

· ·

Case packer Metal detector

·

Canister desiccant inserter

·

Induction sealer

· ·

Electronic tablet counter Tare/Gross check weighing system

· ·

Servo controlled Retorquer Self adhesive labeler

·

Automatic tablet loader

·

Leaflet outserter

· ·

Cap loading system machine Servo controlled Rotary Capping machine

· ·

In feed out feed turn tables Complete line up & Integrations

·

Cotton wool inserting machine

·

Validation support

Manufactured by Countec Ltd, South Korea

Sole Representative in India

Leading world technology today. Driving innovation forward tomorrow.

January 16-31, 2013

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GENETIX BIOTECH ASIA PVT. LTD. 71/1, 1st floor, Shivaji Marg, Najafgarh Road, New Delhi - 110 015 Ph: 011-45027000, Fax: 011-25419631 Email: info@genetixbiotech.com Website: www.genetixbiotech.com

,

Exceptional Handling Advantage, Designed with End User in Mind

Chemical compatibility information is intended as a guide. We recommend that you test bottles for your specific application before use.

CP

LDPE

HDPE

PP

Available in

EZ-Boy

THE NEXT GENERATION CARBOYS

EZ-Boys Carboys TM FlexiCap TM FlexiBarb Spigot Technology

m fro w Ne

EZ-Boys

tix ne e G

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CLEANING, SANITISING EQUIPMENTS CLEAN ROOM ACCESSORIES ASEPTIC PIPING , PW / WFI DISTRIBUTION LOOPS

Floor Drain Traps

Hand Sanitiser

Water Saver Cleaninng Nozzles(self-rotating) Nozzles

Shoe Cover Dispenser

Foot Sanitiser

Split Butterfly Valve

Pendents(Service Shafts) CIP/ SIP MODULE We also design & manufacture # IBC Washing/ Drying Modules # Containers/ Glass Ware Wash Modules # FBD Bag Washing/ Drying Modules # Cannisters Washing Modules # Drums Washing Modules

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Wash Down Hose Station

SIP MODULE

8/B, Surat Singh Est ,SV Rd, Jogeshwari(W), Mumbai-400102 Tel; 022-26797941 Telefax:022-26798066 Cell: 9869231815 email: iewi@mtnl.net.in website : www.iewi.net

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Top Tank / Reactor Sampler

Flush Bottom valve January 16-31, 2013

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January 16-31, 2013

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January 16-31, 2013

PHARMA ALLY WHITE PAPER Resolving challenges in reliable and efficient high containment systems in pharma industry Maurice Pitcher, CEO, Powder Systems considers the reasons why the pharma industry faces challenges in reliable and efficient high containment systems and highlights possible working methods and design considerations to overcome some of the issues faced

rocess equipment are expensive longterm investments, the conundrum for manufacturing is how to address increased safety requirements from ever increasing drug potency.

With current technology, operator exposure levels (OELs) of 10–50 nanogram/m-3 8h Time Weighted Average (TWA) can be readily achieved and should present a reliable outcome. However, over the course of many years, some key failure modes have been observed; including failed OEL measurement during validation, equipment too difficult to work inducing operators to take shortcuts, rapid system deterioration after production use or even lack of budget where there is a need to manufacture high potency compounds without full recognition of the costs.

Fully considering the main influences of the containment failures helps to provide more positive and controlled outcomes.

P

OEL definition and testing The key priorities are operator safety and drug quality. When developing drugs, the risks at the early stages are not always fully understood. An ultra-conservative philosophy has to be applied until there is sufficient established data for the product. It is not untypical for a research level of nanogram/m-3 to be relaxed to 1 microgram/m-3 by the production stage.

A common method to establish OEL performance is to use a placebo such as micronised lactose with a d50 at approximately 20 µg for which accredited laboratories can detect at 2 ng. ISPE guidelines are useful directive to follow when measuring OEL, such as the Risk-MaPP (Risk-based manufacture of pharma products) which provides a scientific risk-based approach. This is based on quality risk management, managing the risk of cross contamination in order to achieve and maintain an appropriate balance between product quality and operator safety. It takes into account background prior to testing and potential weak points around the equipment in addition to passing traffic. It will also allow comparable performance.

There has been a trend in recent years to have bands of OEL for facility performance.

When validating we need to ensure that we test to the lower level. A regular method is to simulate three operations over say a onehour period and utilise this result in a TWA consideration.

Utilising an additional 10:1 safety factor, for example 0.1ug/m-³ rather than 1ug/m-³, is questionable. There is already a considerable January 16-31, 2013

safety factor built into the initial OEL objective and this additional factor has been used due to unreliable system design. This is not a scientific approach as it would suggest a lack of knowledge and understanding resulting in unnecessary cost and complication.

Where does the risk of failure come from?

When you buy a dryer, mill system or capsule filling machine, you expect it to work. A containment provider has to truly understand all relevant manufacturing processes to ensure that practical and safe solutions are provided to address all potential risks.

The risk of breaching the containment: ● It is obvious that isolator designs need to be workable by an operator: when containment equipment is difficult to work with, operators would tend to attempt shortcuts.

Glove boxes and isolators passing an OEL test during site or factory acceptance test (SAT or FAT) will not necessarily perform the same if the defined operating procedure is not strictly followed.

W H AT ’ S INSIDE

SAP hosting services from Netmagic enable Flamingo Pharmaceuticals to save 40 per cent on Capex PG 71 Pharma regulations and their future PG 73 PSL installs high containment filter dryer suite at oncology plant in Bangalore PG 75 AETL receives innovative exporter’s award PG 76 Thermo Scientific Syncronis HPLC Columns available with 3 micron particles PG 77

So what is the solution?

Running through all of the operations with full-scale ergonomic models can prevent this risk. Incorporating oval glove ports for an easier operation and less than 550mm (front to back) for single-sided ridged window access are examples of design features making isolators easier to operate.

Working with full scale mock-ups also helps planning the equipment to its exact requirements and ensures there is sufficient space and installation access to the building. ● Robust designs have to be supported by long-term field operations data. These designs also need to consider construction standards for long-term performance. Will 2mm stainless steel bodies perform as well as 4mm in continuing to seal 10 years later?

Is the reliance of a single thin flexible barrier sufficient if there is a breach? Disposable flexible containment presents a rapid and cost effective solution, but when manufacturing has to address long-term production programmes of highly potent drugs the risk of breach, in regards to longevity, should not be overlooked. ● An assessment of glove permeability should also be considered. When previously working in production with a substance that attacked the cholinesterase in the blood, the product was found to have permeated the initial glove selection. This was picked up by weekly blood sample checks on the operators

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CASE STUDY SAP hosting services from Netmagic enable Flamingo Pharmaceuticals to save 40 per cent on Capex Flamingo Pharma has an ever-growing base of loyal customers in 50 countries across all five continents

l a m i n g o Pharmaceuticals was founded in 1985 as Flamingo Impex. The company has two manufacturing units located in the outskirts of Mumbai, which conform to world-class quality standards.

Flamingo enjoys an evergrowing base of loyal customers in 50 countries across all five continents. The focus of Flamingo’s business revolves around making healthy life not just a privilege but also a right that can be enjoyed by all.

F

Industry Manufacturing– Healthcare Pharmaceuticals

and data centre security and maintenance.

Netmagic’s vision is very clear and over the last three to four years, it has emerged as a strong brand. Netmagic is the best when it comes to outsourcing your IT infrastructure to an external service provider,” says Abdulla Fatiya, GM-IT, Flamingo Pharmaceuticals.

Flamingo Pharmaceuticals wanted to focus their internal resources on expanding and growing their core business rather than setting and managing a data centre to host their SAP ERP application. How did Netmagic Solutions help them achieve their objective?

Business scenario

Key benefits Flamingo Pharmaceuticals realised the following benefits from its partnership with Netmagic Solutions: ◆ Complete technology refresh led to improved application (SAP) performance levels ◆ Hosting SAP application led to increased manageability of internal operations at Flamingo as the company could now focus on more strategic business issues ◆ Savings of 40 per cent in overall cost as compared to setting up a captive data centre to host their SAP application ◆ High availability of the SAP application ensured smooth functioning of business operations ◆ 24x7 monitoring and management of SAP application and faster turnaround time for issue resolution lead to enhanced performance levels ◆ A dedicated team to resolve issues lead to improved service levels and predictability ◆ Flexible utility model for SAP support and operations – the ability to increase or reduce the storage space ondemand, add or reduce users on demand has brought significant cost efficiencies for Flamingo

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Business case With ambitious growth plans for strengthening and expanding their operations and the need for streamlining internal processes to support these plans, Flamingo Pharmaceuticals had implemented SAP ERP. The SAP application was running on HP UNIX and Oracle database.

The company soon realised that supporting and hosting the application internally would involve large capital expenditure for setting up a data centre and recruiting skilled resources to manage it 24x7. Hence, Flamingo decided to avail the services of a managed IT hosting service provider who could provide a highly available and scalable IT environment for hosting and managing the SAP ERP.

Solution Flamingo has availed of complete data centre hosting services for SAP ERP, colocation with operating system (OS) and database support. ● Solution snapshot ● Dedicated server hosting ● Dedicated firewall services ● Bandwidth and connectivity ● Shared SAN storage ● 24x7 OS ● 24x7 database management “On a scale of one to 10, I would rate Netmagic 8 for the expertise of its technical team, service delivery, IT infrastructure environment

Flamingo’s SAP application was running on HP UNIX platform and Oracle database. Hosting and managing the application, Operating System (OS) and Oracle database internally became a challenge for Flamingo and the company did not want to invest in setting up an infrastructure or the resources to manage it.

This led to their decision to look for a managed IT hosting service provider.

Abdulla Fatiya, GM-IT, Flamingo Pharmaceuticals, says, “We wanted to outsource the hosting and management of our SAP ERP application from the very beginning. We are in the pharmaceuticals business so setting up and managing a data centre internally to host this application is not our core competency.

Besides, we would have had to make huge investments for setting up a data centre, right from space, procuring hardware, maintenance, cooling, power and skilled resources to manage it 24x7. So we decided to look for a hosting service provider who could host and manage our SAP ERP application, provide us with the scalability to increase or decrease the number of users on-demand and help us move from a CapEx to an OpEx model.”

Value proposition Fatiya further says, “We www.expresspharmaonline.com

evaluated other service providers also but we found Netmagic to be better when compared with others. The technical expertise of Netmagic’s team was impressive especially their knowledge of various OS and expertise in migration of SAP applications. The commitment of the entire Netmagic team and the fact that they are a pure play hosting and data centre services provider was another reason that made us choose Netmagic as our hosting service provider.

Besides Netmagic is a SAP certified hosting services partner as well.”

Flamingo chose comprehensive data centre hosting services that include dedicated servers with OS and database support. “Our complete SAP application is hosted in Netmagic’s data centre. This includes our production servers, solution development servers and enterprise portal,” says Fatiya.

Working on a pay-as-youuse model, Flamingo has been able to save on costs associated with setting up and managing a data centre on its own. “We wanted a highly available, secure and scalable IT environment for our SAP application. Building that environment and setting up a team with the required skill sets and training was not a viable option as it would have been very capital intensive for us. Netmagic provided us with the option of a pay as you use model, which suited our needs.”

“Our annual maintenance contract (AMC) and license fee for hardware was due for renewal. Instead of going for renewal of the AMC, we wanted to have a fixed cash outflow but within the budget that we already were spending. Netmagic advised us on the sizing of the hardware to host our SAP application, suitability of the operating system, design of the IT environment, what hardware to use, how to combine two instances of development and quality on one single hardware, what would help us save cost and devising a backup strategy for our data.

Following their advice we have now moved to a managed dedicated server hosting where the servers that run SAP application belong to Netmagic. We have also shifted from HP UNIX OS to LINUX OS,” says Fatiya.

He further adds, “The solution suggested by Netmagic has shown us great results in terms of return on investment (ROI). It was customised to our requirements keeping in mind our monthly cash outflows.”

Key takeaways Flamingo Pharmaceuticals is very satisfied with the highly available and scalable IT environment Netmagic has provided for hosting its SAP application. The company has been able to save 40 per cent of the costs that it would have had to incur if it invested in setting up its own data centre and hiring skilled resources to manage it.

Fatiya also says, “We have not faced any downtime for our SAP application till now. 24x7 monitoring and management support at the OS level, as well as, for SAP application ensures that bottlenecks are detected and taken care of before anything happens. Turnaround times (TAT) have improved significantly and a dedicated team ensures that issues (if any) are resolved faster and in real time.”

Flexibility to scale up resources on-demand is another benefit that Flamingo has derived out of its association with Netmagic. “We recently had to add another 500 GB to our existing storage with Netmagic. All that it required was to fill in a requisition form and our storage capacity was increased within a matter of two to three days.

We have recently set up a manufacturing facility at Nanded, which means that we will be adding another 100 users to the existing 125 users using the SAP application. Scalability to provision resources on demand and the speed with which this scalability is being offered to us is impressive.”

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P|H|A|R|M|A| A|L|L|Y Continued from Pg 71 and the glove material was then changed to prevent this occurrence.

The risk of cross-contamination and product exposure: ● Powder handling has to work routinely or be sensibly recovered in a contained fashion. An assessment of powder transfer methods and powder handling characteristics should be carried out as well as an evaluation of materials handling including manual or mechanically assisted requirements. The containment provider has to integrate interconnecting systems – determining powder handling through split valves, airlocks, rapid transfer ports (RTPs) and bag-out ports. ● Sampling can be a very difficult challenge if not considered at the start. If sampling raw materials it may be an opportunity to subdivide at the same time to avoid double handling of the raw material drums.

Process sampling should assess multi-product processes, as different batch levels would limit a fixed posi-

tion sampler. An angled sampler, for example can overcome these height differentials. ● Production facilities can involve numerous machineries, which can put operators at risk of injury when operating the equipment. The containment solution needs to incorporate safety switches to avoid windows being opened or hands being placed inside the gloves whilst any part of the machine is operating.

Gloves guards are installed for safety protection if someone attempts to access the inside of the isolator. ● Cleaning regimes form an integral part of reducing the risk of cross-contamination.

For vessels, reflux cleaning followed by CIP can be very effective reducing levels down to 5ppm or non-detectable.

But for isolators and glove boxes the use wipes to preclean is preferred, as it provides a concentrated solid waste rather than high volumes of liquid waste which are more costly to treat. CIP should be completed following the wiping technique.

Product contact surfaces of

0.4 um Ra are perfectly adequate without electro polishing, which is required for sterile applications. Spraying solvents inside non-pressure vessels, even with purging, is not recommended.

Risk of explosion and solvent ignition ● Where necessary, a modifi-

cation of process equipment can be performed such as the relocation of internal drives to the isolator’s exterior.

Incorporated process equipment such as mills, granulators, blenders or tablet presses requires changes in the control and automation systems to address the ATEX rating. These EU directives describe what equipment and work environment is allowed in an environment with an explosive atmosphere. There is of course a risk of explosion when in the same environment a combustible (gas or dust), a source of ignition (spark or flame) and oxygen meet. ● Safety measures are a critical point to avoid dust explosion or solvent ignition including a nitrogen protection sys-

tem when applicable. Most organic dust will not ignite below 8-9 per cent oxygen.

Aluminium alloys for example will ignite at 2-3 per cent oxygen. Static ignition of solvents in most cases can be prevented below 4 per cent oxygen; however, pyrophoric substances like lithium hydride should be at zero oxygen. ● Laboratory tests can be undertaken on internal and external friction cohesion as well as bulk density (the potential energy to overcome these frictions) in anticipating powder flow. A major installation can fail due to lack of proper powder handling assessment.

Finally a containment provider needs to maintain a long established documentation system with end-users, assuring project efficiency from start to finish. A quality plan and seller document index (listing all documents with a unique reference number and issue status) and a project programme are the documentation part of the qualification and validation of the containment system.

A full documentation

package is provided for review prior to commencing final manufacture, and then final assembly and testing can be performed. SAT and IQ/OQ (installation qualification and operation qualification) would normally be included to certify optimum performance of the containment system.5 Comprehensive training of the operation and maintenance personnel on the equipment ensures knowledge to be transferred to the end user, thus minimising risks of a containment breach as seen previously.

How the equipment will be used and maintained throughout the years has a direct impact on the containment level. OEL testing and ISPE guidelines are essential procedures to ensure that a containment system is delivered and installed according to the industry regulations, but how to guarantee a consistent containment level years after its installation despite robust and ergonomic construction, when the human factor is also involved is a challenge in itself.

Pharma regulations and their future Rajkumar Gupta, Managing Director, Perfect Pharmaceutical Consultant and Director, Global Institute of Regulatory Affairs gives a preview of pharma industry and regulatory affairs in coming two to five years

harmaceutical business has been changing sharply over past few decades. There had been significant changes in FDA regulations, market scenario, business models, the disease pattern and pharma technology. The newer business models are continuously evolving to meet new challenges.

Currently the industry is more vigilant towards blockbuster drugs and formulations. The drug discovery is focused on chirality, polymorphism and genetic engineering. The industry is focusing on automation, productivity, economy and powerful drug molecules. The new treatment models using invasive and noninvasive medical devices are also explored. The pharma industry is now moving towards the low cost highly efficient health solutions.

The changes anticipated in the industry in coming two to five years are as per below:

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R&D models There will be a rapid development in drug designing technology. The new pathways for drug molecules will become available on fast track. Eventually, the drug January 16-31, 2013

molecules will be structured in laboratory the same way as we built-up complex metal structures by welding. New concepts such as chirality and polymorphism within a single molecule will evolve. The talent from other businesses will be researched and customised for pharma manufacturing.

There will be new safe, economical, pollution free routes for the synthesis of APIs. The single pot synthesis will become common. There will be discovery of new drugs which are active in nanograms and picograms against milligrams at the present. HPLC system for assay and impurity profiling of the drug molecules will be replaced by electronic columns. The biotechnical www.expresspharmaonline.com

solutions will be available for almost every major disease.

There will be increased research on pharmacogenomics and pharmacogenetics to limit adverse effects of highly toxic drug molecules.

There will be increased research on humans and animal genetic materials to develop new biological products. The research on personalised medicines will intensify to match with the specific underlying causes.

There will be more focus on diagnostic equipment rather than on the discovery of new drugs. The research on medical devices for replacing/correcting the diseased body parts will intensify.

There will be more collaboration with academia and peers to outsource research intelligence.

Technology models There will be increased use of auto analysers for the analysis of starting materials, in process materials and finished products. Raw materials will be auto sampled, analysed, weighed and issued for batch processing. There will be a substantial reduction in production time

cycle with the automation.

The lesser time will be required. Job of 100 hours will be accomplished in a single hour.

Currently impurity profiling is very tedious and expensive job for marketing authorisation. The available technology is incapable of eliminating all the impurities in the drug products. In future it will be possible to ‘zero impurity drugs’ by super chromatographic technologies.

Business models There will be more focus on return on the built-up but unutilised intellectual capitals.

The expenses incurred to build-up/acquire intellectual property will be encashed by some or other business means. There will be enhanced use of business portals such as B to B, B to C and B to E to reach more and more customers efficiently and economically. The intelligent business modules will be available for comparing prices, delivery and quality of raw materials will evolve.

There will be more collaboration for establishing manufacturing base in emerging marEXPRESS PHARMA

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P|H|A|R|M|A| A|L|L|Y kets. The business in developed market will decline.

However, the business in emerging market will increase. The low cost manufacturing locations such as India and China will become manufacturing hubs. The developed countries will utilise these countries as a base for highly profitable business with underdeveloped countries.

The large pharma companies will try to enhance their drug development pipelines through, mergers, acquisitions and licensing agreements.

There will be a great focus on industry-academia collaboration to develop new drugs.

The developed country will make more money by marketing their talents rather than the products. There will be increased competition for licensing of the biological blockbusters drugs. There will be increased production of raw materials resulting in business through reverse auction.

Pharmaco-economics will emerge as new discipline.

The industry will continue to increase collaborations.

Consequently, the royalty payments will also increase. The specific accreditation system will be available for the recognisation of regulatory consultants and BPO. The litigations on patent issues will keep on increasing. The settlement will be very expensive. There will be greater restrictions on reimbursement of medical bills in developed countries.

Pharma and biotech companies will continue to increase their outsourcing of clinical trials and related drug development. Outsourcing will account for more than 50 per cent of R&D spending in coming years.

Public concerns The health and disease knowledge of the patients will increase. The doctors will be unable to prescribe them promotional drug products or high cost drug products when economical alternatives are available. The public will enjoy increasing health protection and rebates on medicines. The Government will be forced to adopt deficient budget on healthcare. Patients will become more conscious and empowered in making healthcare decisions. The public will be benefited with the new drugs specially focused on short patient population.

Marketing models Social media marketing

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will become a significant part (>10 per cent) of the pharma marketing mix. The next BIG opportunity for targeted marketing to patients and physicians will be mobile apps on ‘smart phones.’ Internetbased drug promotion (including search engine marketing) will overtake TVbased DTC. The role of traditional sales representative will become obsolete.

Training models The clinical researchers will be trained on pharmacokinetics, pharmacodynamic and toxicity of drug molecules using ‘ through technology.’

Training of the trainer/mentorship concept will get momentum.

Regulatory affairs models There will be higher regulatory hurdles leading to greater uncertainty, fewer product approvals, increased regulatory actions and increased product withdrawals. There will be increased bio studies and clinical trial demands all over the world including underdeveloped countries. The postapproval safety requirements and vigilance will increase falsified medicine detective and FDA Friend concept will be utilised to widen regulatory vigilance. There will be enhanced vigilance at sea ports/airports to restrict illegal entry of falsified medicines. FDA will make it compulsory to include Donor section in SOP, BMR, MMF, SOP to built further clarity in GMP Compliance.

The pharma manufacturing bases will become more complicated. FDA control will be further tightened.

Labelling of drug products will become more stringent.

The drug promotion will be sharply curtailed through public news channels. There will be improved information sharing on critical issues such as Pharmacovigilance (PV) and Adverse Drug Reactions (ADR). The posting of ADR will become mandatory on Internet. There will be high demand for CROs for outsourcing clinical studies for introducing the new drugs and exploring new applications for the existing drug molecules. The CRO business in India will take a new turn with active collaborations with foreign CROs. The manufacturer of the drug products will prefer Contract manufacturing organisation (CMO) over their own manufacturing facility. Indian pharma comwww.expresspharmaonline.com

panies will reap full benefit of this trend. The outsourcing of regulatory intelligence will increase. The regulatory filings will be solely handled by RA Consultants and IT organisations. The increasing number of Indian consultants will be employed for drug registrations. The pharma business will become collaborative.

There will be active collaborations for R&D, manufacturing, marketing and regulatory compliance. The penalties on falsified medicines will be tightened. Many of the top companies in India and China will be banned for exports to Europe.

Unified Global Numerical code will be provided to all approved manufacturing units. More drugs will be discovered for rare diseases. There will be more research on underlying causes of disease. The specialised drug molecules will be available for each causative factor.

The treatments will be more customised. Drugs with be targeted on narrow populations unlike vast population now. There will be enhancement in demand for new drugs for Alzheimer’s, cancer, cardiac and other complex diseases for which drug development takes many years. There will be increased manufacturing of generic drugs eclipsing high cost patented drugs. However, the consumer psychology and brand loyalty will continue to have upper hand on generic production on patent expiration. There will be increased shift of thinking from disease treatment to disease prevention. Further, the pharma industry will get merged with the fast evolving healthcare industry. The CMS (Content Management Systems) for SOP, CTD/ANDA/NDA/SPL, CDM (Clinical Data Management), GxP, and electronic submissions will increase The drug development will involve more integrated plan to develop new drug molecules. The review time by FDA will increase.

There will be more research on biomarking, pharmacogenomics and individualised medicines.

There will be increment in focus on South America, India, China and Russia as legitimate drug markets. See through education and training system will be in place for pharmacokinetic and pharmacodynamic aspects of drug molecules. The manufacturing, QC and QA functions will be automatically documented to meet FDA expecta-

tions. The periodical product review such as APR will be computed automatically from production and QC records.

The periodical certification will be compulsory for regulatory, manufacturing and QC/QA to establish credibility on new regulations. The clinical/toxicological trials will be conducted on robotic system simulated to human body and physiology. The regulatory mentors and consultants will command high value. The regulatory authorities will introduce special certification scheme for them. The stability testing will get automated. The stability chambers will be connected with auto samplers and HPLC system for sampling, analysing and computing stability of the drug products.

Summary The drug industry will expand and specialise into new therapeutic areas rapidly in coming two to five years time.

There will be rapid improvements in discovery of new drug molecules and dosage forms. The industry will get fully automated. The drugs will become more specific and side effects will be reduced to a great extent. The vigilance by heath authorities will multiply and falsification will be prevented. Nonresearch and unregulated companies will be side tracked and/or hammered down by FDA. The consumers and patients will become wise and will resist the medical profession for any negligence or malpractices. There will be more stress on keeping healthy.

The heath authorities will be forced to ensure essential drugs at affordable prices to the public.

References www.news.pharma-mkting.com www.biodeutschland.org http://blogs.hbr.org/hbsfaculty/2010/04/pharmas-futuredepends-on-thes.html www.kpmg.com www.siliconrepublic.com Rajkumar M. Gupta ©Copyright Perfect Pharmaceutical Consultants Pvt. Limited, December 2012 www.manufacturingexecutive.com www.fiercepharma.com www.bluefocusmarketing.com www.cognizant.com www.management-engineers.de www.medreps.com www.medicalnewstoday.com www.pharmaphorum.com January 16-31, 2013

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VENDOR NEWS: New data shows value of morphologically directed Raman spectroscopy for bioequivalence studies Morphologi G3-ID enables the determination of component-specific particle size distributions new application note on the Malvern Instruments website describes the use of morphologically directed Raman microscopy in assessing the bioequivalence of a generic and innovator drug with a dual active pharmaceutical ingredient (API). The work was carried out using the Morphologi G3-ID, which combines automated image analysis with Raman spectroscopy. The Morphologi G3-ID enables the determination of component-specific particle size distributions, which in this study were important because of the effects of particle size on tablet disintegration and subsequent bioavailability.

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In order to show that a generic drug is bioequivalent to an innovator it must display comparable bioavailability when studied under similar experimental conditions.

Bioavailability is the rate and extent to which the active

ingredient is absorbed from a drug product and becomes available at the site of drug action. Bioequivalence refers to equivalent release of the same drug substance from two or more drug products or formulations.

Morphologically directed Raman microscopy enables independent characterisation of individual components present within a blend or mixture. As well as its application in bioequivalence studies, it can be used to gain better product understanding across many areas of the pharma industry from regulatory to troubleshooting. In delivering this capability, the fully automated Morphologi G3-ID is designed to allow both particle characterisation scientists with limited spectroscopy experience and more experienced spectroscopists to get an in-depth understanding of their particulate samples.

EP News Bureau-Mumbai

PSL installs high containment filter dryer suite at oncology plant in Bangalore Has provided a suite of filter dryers for both small and large-scale production of potent APIs owder Systems Limited (PSL) supplied a full suite of contained filtration and drying solutions to India's leading drug manufacturer for their new oncology plant in Bangalore.

The new plant includes several production lines and PSL has provided a suite of filter dryers for both small and large-scale production of potent APIs. The suite provided incorporates contained discharge to achieve a proven OEL (occupational exposure limit) of less than 1µg.m-³ during the sampling period.

The high containment filtration and drying suite consists of four filter dryers with integrated high containment discharge isolators for assured operator and product protection. One of the small scale agitated nutsche filter dryers for Kilo Lab production is in PSL's revolutionary GFD FilterBox. This stainless steel isolator comprises a glass filter dryer, both

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January 16-31, 2013

designed and integrated by PSL. The number one Indian pharma company opted for a full high containment scale-up solution to repeat their process while handling small to large quantities of highly potent compounds. The contained product offloading can be done either inside the filter box or through the discharge isolators mounted on the side of the 0.125m², 0.3m² or 0.6m² filter dryers.

Scale-up from chemical development in small-scale batches to industrial volume is a complex and time intensive process requiring considered technology risks, equipment design and process constraints. The commercial application of a technology developed at an early stage requires scalability of the equipment used throughout the whole process.

“The new oncology plant needed to transfer from the kilo-lab scale for oncologic chemical development to www.expresspharmaonline.com

obtain larger volumes of highly potent APIs. The contained filtration suite provided by PSL is an ideal solution. The highly active batch production will be carried over to the scaled-up industrial yield and they will obtain kilograms of dry and homogeneous HAPIs in a shorter time-to-commercialisation,” explains Rémy Wattiaux, Managing Director, PSL. Before starting the manufacturing of the 15 different anti-cancer products, the manufacturer and PSL proceeded to the SAT (Site Acceptance Test) last month at the oncology plant based in Bangalore. It is primordial that all the containment systems complied with the targeted OEL level prior commencing production. Independent OEL tests were carried out during surrogate (lactose) handling trials in the PSL’s Filter Dryer Discharge Isolators and the Kilo-Lab GFD FilterBox. The target con-

tainment limits for personal exposures of less than 1 µg.m-³ averaged over the task duration and less than 0.3 µg.m-³ as an eight-hour time weighted average (8h TWA) were achieved. It was also desirable to prove control personal exposures to less than 25 per cent of these values i.e. < 0.25µg.m-³, over the task duration and < 0.075 µg.m³, 8h TWA. PSL has been established for 23 years and is an original pioneer of high containment systems such as isolators and glove boxes.

We have significant experience designing and engineering advanced containment processes for highly potent and valuable products including sterile, oncology, hormone and many other pharmaceutical compounds. PSL provides a full range of filtration, drying and contained isolator products for small scale production to full process systems.

EP News Bureau-Mumbai EXPRESS PHARMA

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New, revised standards for Omega-3s, natural sweeteners proposed for Food Chemicals Codex USP seeks comments on proposals from food manufacturers, ingredient suppliers and other interested stakeholders

n order to help ensure the quality of popular food ingredients increasingly being incorporated into products sold in the US and worldwide, standards for omega 3-rich krill oil and natural, low-calorie stevia sweeteners are among the latest proposed revisions to the Food Chemicals Codex (FCC). FCC is an internationally recognised compendium of food ingredient quality standards published by the US Pharmacopeial Convention (USP).

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“Ensuring the quality of the food ingredients that make up so much of our global food supply is not only part of responsible business practice, but is critical to the health of consumers,” said V Srini Srinivasan, Executive Vice President, Global Science and Standards, USP. Srinivasan said, “Public standards defining the identity, quality and purity of ingredients incorporated into finished products can be an important resource for man-

ufacturers as they source ingredients from suppliers around the world, offering some assurance that they are receiving the ingredients they expect by providing public specifications to which they can be compared. While important for all ingredients, it is especially crucial for high-value ingredients, including those linked to health benefits such as krill oil and so-called natural ingredients such as stevia, which manufacturers and consumers pay a premi-

um for and are in high public demand. We invite comment on the new proposals to allow us to develop robust public standards that are valuable to all parties.”

Manufacturers and other parties are encouraged to comment on these proposals, which are contained in the most recent FCC Forum (www.usp.org/fcc/fccForum .html) —the free, online vehicle for public review and comment on draft FCC standards.

EP News Bureau-Mumbai

BASF’s world tour ‘We create chemistry’ arrives in India Innovations include organic solar cells, modern insulation materials, electro-mobility solutions, and sustainable concrete technologies

nnovative ideas to solve global challenges are the focus of the ‘Marketplace of Innovations’ in BASF’s ‘We create chemistry’ world tour, which is making its South Asia debut at Mumbai’s NESCO grounds, Bombay Exhibition Centre. The tour, which kicked off in Mannheim, Germany, in January 2012 and will continue until mid-2013, is designed to help the company’s stakeholders experience some of the company’s leading inno-

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vations for a sustainable future.

The interactive exhibition features 20 world-class BASF innovations, ranging from organic solar cells to electromobility solutions to modern insulation materials and sustainable concrete technologies.

“Through the Marketplace of Innovations, BASF is showcasing solutions from the world of chemistry for the challenges of a growing world population. The exposition’s examples of BASF’s

innovations in sustainability tangibly demonstrate how economic success, social responsibility and protecting the environment are interconnected as key elements of our strategy,” remarked Prasad Chandran, Chairman, BASF Companies in India & Head South Asia.

The ‘We create chemistry’ world tour offers stakeholders a panoramic view of the latest innovations from BASF. Prior to Mumbai, the ‘Marketplace of Innovations’

has made numerous stops – Shanghai in China, as well as Detroit, Florham Park, Charlotte, Houston, Mexico City, Toronto and Sao Paulo in North and South America. In Asia, after Mumbai, the tour will travel to Tokyo in February and Seoul in May 2013.

“At the tour, we prove with proof-points that innovation is the key to solving global challenges,” said Chandran.

EP News Bureau-Mumbai

AWARD Neelikon Food Dyes & Chemicals bags Best Manufacturer-Exporter (Small) award eelikon Food Dyes & Chemicals has received the Best Manufacturer-Exporter (Small) award at the ECGC – D&B Indian Exporters’ Excellence Awards 2012.

Mukund Turakhia. Managing Director, Neelikon Food Dyes & Chemicals, received the award.

Dun & Bradstreet, a leading provider of global business information, in association with Export Credit Guarantee Corporation of India (ECGC), India’s leading provider of export credit insurance, announced the ‘ECGC – D&B

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Indian Exporters’ Excellence Awards 2012’ to recognise the contribution of the Exporters to the Indian economy.

The ECGC-D&B Indian Exporters Excellence Awards were introduced to recognise the growing contribution of export to the Indian economy.

The awards event was closely tied to the publication, ‘India’s Leading Exporters 2012’ that features the award winners and other leading exporters of the country.

AETL receives innovative exporter’s award dvance Enzymes Technologies Limited (AETL) has received most innovative exporter’s award at at the ‘ECGC - D&B Indian Exporters’ Excellence Awards 2012’ organised by Dun & Bradstreet Information Services India.

Sandeep Bijamwar, Business Head- API, AETL received the award on behalf of AETL. CL Rathi, Managing Director,

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AETL, said, “A proud moment for all of us at Advanced Enzymes since the company is being honoured with such a prestigious award for Export category. This award truly recognises AETL’s great contribution in the field of Indian exports and reaching customers with customised solutions.”

EP News Bureau-Mumbai

EP News Bureau-Mumbai

www.expresspharmaonline.com

January 16-31, 2013

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PRODUCTS AX/VX series tunnels by Venera Biotech Systems enera Biotech Systems has manufactured AX/VX series tunnels. The features of AX/VX series tunnels are:

container sizes

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● Programmed cycles for auto/manual

operation, shutdown and temperature mapping

Sterlising tunnel AX/VX series tunnels are specially designed for ampoules and vials with various capacities. The tunnels are energy efficient and suitable for online production in conjunction with washing and filling machines. The receptacles are treated with sterile air through entire travel for thermal treatment.

Control system: The PLC along with the MMI controls various process parameters including sterilising temperature, residential time and to select different container recipes.

Data recording: A data logging printer is interfaced with PLC which records hard copy data including temperature inside various zones within the tunnel and residential time as well.

Optional ● Sleep mode during non-productive

hours ● Cool zone sterilisation before start-

up ● Separate cooling module for cooling

zone air re-circulation Infeed/Outfeed chutes: To facilitate integration of the tunnel with washing and filling machines, along with material and overload sensing devices ensuring seamless operation of complete line.

Tunnel operation ● Sterilisation

and depyrogenation based on 3 log reduction cycle @ 296.40.C ● Menu driven operation for different

Contact details: Venera Biotech Systems C-110, Ram Girdhar Industrial Estate, Station Road, Vithalwadi (W), Dist-Thane - 421 003. (M.S) - India.

Telefax: 91 251 2569 695 / 2559 695 Phone: 91 251 2552 993 e-mail:sales@venera.in, venera@vsnl.com Website: www.venera.in

TEMPO Instruments introduces new range of glass door lab refrigerators empo Instruments have launched its new range of glass door lab refrigerators suitable for scientific, medical and pharmaceutical applications. The refrigerators offer cold storage in the temperature range of 20.C. to 80.C. Tempo range of lab refrigerators come with high density insulation for effective heat rejection and energy saving. Suitable air circulation is provided inside the chamber to maintain uniform temperature.

The

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equipment are available in standard and GMP models

with additional features like PLC-based control, Standby refrigeration systems, PC and printer connectivity, data logger for storage of temperature readings etc.

Software for data aquisition is also made available.

Besides the main door the equipment is provided with an additional inner door to ensure secure sealing of the chamber. A port hole of 50 mm diametre is provided for validation purpose. The equipment is offered in

excellent quality with precise control, quiet low vibration, effective energy saving and environmentfriendly model.

Contact details TEMPO Instruments 10-11, Prospect Chamber Annex, 317-21, Dr.D.N.Road, Fort, Mumbai – 400 001. (INDIA) Cell. +91 9820464003 E-mail : tempo@vsnl.com Web: www.tempoinstruments.com

Inflatable gaskets and sanitary ‘O’ ring by Shree Gaurav Rubber Products hree Gaurav Rubber Products, silicone cord manufacturer and exporters, has launched inflatable gaskets, which are manufactured from MOC like food grade white neoprene rubber as well as food pharma grade transparent silicone rubber. These gaskets operate like a cycle tube that can be inflated to accommodate a variable sealing gap. These gaskets are inflated by 14mm when 2 kg pressure is applied.

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Three gaskets are normally used in fluid bed dryer as inflatable gaskets. They are product container top and retarding chamber i.e. PC Top gasket (40mm x 22mm); product container lifting i.e. PC Bottom gasket (40mm x 22mm) and finger bag sealing gasket (50mm x 20mm).

These gaskets for alliance model for GMP 60 kg, GMP 120 kg, GMP 200 kg, GMP 250 kg and GMP 500 kg are readily available.

The company also manufactures and supplies moulded elastomer gaskets and 'O' rings in sanitary design, for all applications, in all sizes. The materials used meet the FDA standards for non toxicity, and range from Neoprene, Nitrile, Silicone, EPDM, VITON etc, to Teflon. It also offer rubber gaskets for triclover clamps, DIN gaskets, SMS gaskets, butterfly/Iris valve gaskets (sizes from 1”dia to 20”dia) shifter gaskets etc.

Contact details: Shree Gaurav Rubber Products 112/B, Marudhar Indl. Estate, Opp. Old Syndicate Bank,Goddev Road, Bhayandar(E) Thane401 105 Tele-Fax: 022 2819 7355 ?

Mobile: 98924 14152 / 98204 69764 E-mail: sari@mtnl.net.in / gaurav_rubber@rediffmail. com Website: www.gauravrubbers.net

Thermo Scientific Syncronis HPLC Columns available with 3 micron particles hermo Fisher Scientific announced that Thermo Scientific Syncronis HPLC columns are now available with 3 mm particle size. This new particle size complements the existing 1.7 and 5

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µm particle sizes. Syncronis columns are built on a backbone of highly pure, high surface area silica. Dense bonding and double end-capping minimise variation due to silanol activity. Enhanced www.expresspharmaonline.com

automated column packing methods drive consistency even further, and each column is individually tested.

Contact details Chromatography

Social Media Contact Information, Sonya Pelia 1214 Oakmead Parkway Sunnyvale, CA 94085 USA Phone: +1 408 481 4172 sonya.pelia@thermofisher.com EXPRESS PHARMA

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A Global Manager: Made in India INSIGHT

Mohan Joshi, Strategic Advisor, SCHOTT, a German MNC, provides an outlook about the need for good global managers and how Germany and India can create magic by simply putting together their best management practices

“We must head for India, too!”

These could be the wise words of a 21st century German head honcho who has recognised the signs of the times. But these words were spoken by Jakob Fugger, the famous Augsburg merchant who saw major opportunities coming from India in the 16th century-opportunities that many German entrepreneurs after him also seized successfully.

Deutschland and India have cultures that are poles apart; likewise, business and management practices that are vastly different from one another. Then how are so many Indo-German alliances making it successfully to the altar and living happily-ever-after in the cutthroat world of international business?

The answer is simple – by putting together the best minds and best management practices to work!

The best of both worlds – The best of German and Indian management practices Germany and India can create magic by simply putting together their best management practices. What the Germans have, Indian managers can learn and what the Indians have, the German managers can imbibe; creating a win-win global alliance.

Qualities German managers possess ● Sense of the future and a

view of the long-run ● A clear purpose of estab-

lishing excellence in their products and services ● Total product orientation and complete confidence that a good product will sell itself ● Structured approach, follow up on action points with an eagle’s eye on timelines and schedules ● Every single person in the plant works with a focus on improving quality, productivity and reducing costs

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Strengths Indian managers possess: ● Ability and willingness to

put in long working hours ● Requisite skills to absorb

technology ● Ease of communication in

English and also communication with diverse sets of people ● Building and sustaining relationships

The making of a global manager—Made in India By focusing on the following areas, Indian managers can well become successful global managers and leave their footprints on the international business map.

Good is the enemy of the great. Kill it!

Indian managers need to shift gears from ‘being good’ to ‘becoming great’! The casual approach to excellence usually becomes the nemesis of Indian managers in the international arena, where managers from around the world practice excellence as a habit. Instead, they should adopt the German attitude to ensure that the outcome of whatever they undertake must be of the best quality; which will make all the difference in the final outcome.

Get rid of the fire-fighting syndrome Indian managers tend to look at problems from a short-term point of view and then resort to fire fighting for the moment. A more complete approach would be to think long term and anticipate the issues likely to emerge and ways to address them. A good example from our daily life can be found in the automobile industry. In manufacturing parlance, a global managers needs to go for ‘preventive maintenance’ and not ‘reactive maintenance’.

Don’t lose sight of the time- frame Indian managers are focused on the activity at hand and tend to lose the time-frame. They shy away from commitment to plans www.expresspharmaonline.com

and schedules. For a successful global manager, while building an activity plan, cannot forget that along with the activity plan, equally important is to identify time lines of achievement and monitoring them.

Practice ‘active listening’ Most of our solutions can be found easily if we listen attentively to the problems and issues being discussed and understand what the customer requires. Therefore, building listening skills is imperative to figure out important information that will be crucial in developing the relevant plan and to build the correct strategy in addressing his needs.

Understand that information-sharing is a strength Indian managers do not share complete information on any given situation or problem. There is an inherent tendency to withhold crucial data and to protect information; the fear here is for ‘loss of job’ for divulging information. This attitude might protect one in the short term but will only fan one’s insecurity in the long term which is detrimental not only to the individual, but also to the team’s and the company’s well being.

Be not democratic, but be conscientious Being

too

democratic

does not add or create any additional value; in fact is can only add to the nuisance value. A good example is about email communication and whom to copy on a particular mail. Instead of copying the whole department, one must be judicious in judging who must be kept informed and to what purpose.

Communication systems must be kept lean and simple that will not only simplify the process but also help achieve the desired action in a shorter time.

The world is getting flatter by the day and the need for good global managers is on the fast track. In Germany alone, business opportunities abound for Indian companies and managers. Many German companies are growing much faster in India than globally.

Both countries share a rich business history that spans more than 500 years. In 2011, bilateral diplomatic relations between the countries completed 60 years. In 2013, euro 20 billion of trade between India and Germany is targeted. Every fourth acquisition in Germany is from India.

It’s the writing on the wall. We need a fast-growing tribe of Global Managers – Made in India!

The author can be contacted at mohan.joshi@globalalliances.in January 16-31, 2013

REGD.WITH RNI NO.MAHENG/2005/21398 REGD.NO.MH/MR/SOUTH-77/2013-15, PUBLISHED ON 5TH & 20TH EVERY FORTNIGHLY & POSTED 6-7-8 & 21-22-23 OF EVERY FORTNIGHLY. AT IND.EXP.PSO.