Pharma Bio World November 2108

VOL 17 | ISSUE 4 | NOVEMBER 2018 | MUMBAI | TOTAL PAGES 60 | ` 150

www.pharmabioworld.com PHARMA BIO WORLD VOL 17 ISSUE 4

Genomic Medicine

A new frontier of the 21st century NOVEMBER 2018 MUMBAI TOTAL PAGES 60 ` 150 BioPharma World Expo 2019 20-23, February 2019 Venue: Bombay Exhibition Centre, Goregaon (East), Mumbai, India

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4 ◄ November 2018

Pharma Bio World

INTERVIEW 8

“Unsolved Chronic Wounds Increasing Rapidly In India ” Mr. K. S. Dharshan, CEO – Dermozone

FEATURES 10

Only About 5% Of Rare Diseases Have Treatments

14

Pharma Logistics: The Top Overlooked Factors

INSIGHTS

08

20

Indian Pharma: Leapfrogging Beyond Generics

24

Driving Radical Growth To Make India A Pharma Superpower RESEARCH

29

Genomic Medicine: A New Frontier Of Medicine In The Twenty First Century Dhavendra Kumar

34

Polymers In Pharmaceutical Drug Delivery System: A Review Krushnakumar J Gandhi, Subhash V Deshmane& Kailash R Biyani

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PRODUCT TRENDS BACKYARD

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Ad Index

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interview

“Unsolved chronic wounds increasing rapidly in India…” +dalethyne, a path breaking molecule, only one of its kind in the world, invented after 18 years of untiring research since 2000 by K.S. Dharshan, the Founder and Chairman of Indonesia based Dermozone , is all set to revolutionize the wound care market in India. +dalethyne would be the key ingredient of the new Dermozone range of wound care products soon to be launched in India.

Mr. K.S. Dharshan, CEO – Dermozone gives us more details in this brief interview with PharmaBio World.

What is the main constituent of +dalethyne? +dalethyne is a clinically tested compound obtained from artificial segregation of naturally abundant fatty acids in virgin olive oil.

What are the targets of this pathbreaking molecule? +dalethyne, a breakthrough in medicinal science, would be the key ingredient of the soon to be launched Dermozone range of wound care products that would be a new hope for unsolved chronic, acute, cancer radiotherapy and burn wounds, which are now increasing rapidly in India.

Is +dalethyne a life-saving compound?

A) In many cases our wound care products (the key ingredient being +dalethyne) have been lifesaving and have also prevented near certain amputations of patients suffering from diabetic related wounds.

What is the USP of +dalethyne?

It has proven effect of anti-microbial, fungicidal and antiviral quality with deep skin-penetrable quality. Investigations have revealed that +dalethyne reduces inflammation and accelerates wound healing.

What is the patent grade value of this compound? +dalethynehas been patented in several countries and this patent is certified as a Novel Innovation Patent in Geneva. The compound 8 ◄ November 2018

has been ranked as 10 out of 10 in Geneva and is treated as a novel finding in IP/patents.

Are your products available in India?

After more than 3 years of extensive market study and research in India we are all set to launch our +dalethyne based Dermozone wound care range of products for the treatment of chronic and acute wounds. The Wound Care range would be launched first closely followed by the Dalenix range and subsequently the Derma range. The three Dermozone wound care products to be launched are- 'Dermozone Antiseptic Wash' for chronic wounds, 'Dermozone Antiseptic Burn Gel' for burns and 'Dermozone Antiseptic Wax' for those with metabolic disorder wounds especially cancer and diabetic patients.

What has been the response to your product samples?

Our wound care products have received overwhelming initial response from hospitals and doctors. It may be noted that our wound care range of products would be initially available only for use in hospitals and clinics on recommendation by doctors.

Could you list out a few of your brands?

Dermozone range of 9 Products are soon to be Launched in India (the key ingredient of all these products being '+ dalethyne') under the 3 key brands of Dermozone - Wound Care, Derma and Dalenix

You are based out of Indonesia.

Is this your company’s first foray outside Indonesia?

Yes, this is my first company outside Indonesia.

What is the state of the Indonesian pharmaceutical industry and how would you compare it with the Indian pharmaceutical industry?

The state of Indian pharma Industry is wider and larger in all aspects compared to Indonesian pharma industry. India has its own technologies and expertise which is being widely acknowledged in SE Asia.

How big is the Indian wound care segment in terms of market size?

The wound care market in India has seen a huge upsurge in recent years due to growing incidences of untreated chronic, acute, cancer radiotherapy and burn wounds coupled with the largely ineffective traditional methods of treating them. Rising prevalence of diabetes and cancer, attempts to lower the duration of hospital stay in order to reduce the healthcare expenses and the growing inclination towards products that enhance therapeutic outcomes are also driving the demand for advanced wound care products.

What are the major and latest innovations in wound care?

I am not seeing any major new technologies or innovations in wound care in recent times.

Traditional methods of wound treatment are still being mostly followed.

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Only about 5% of rare diseases have treatments

O

rphan drugs, those medications that are typically produced in small quantities for limited patient populations, are growing in importance worldwide. Once largely considered too costly to produce, given the limited number of patients affected by a particular disease, new technology and new breakthroughs in biopharma have changed the landscape, allowing more orphan drugs to be produced than ever before, thus saving countless lives that would otherwise be lost.

But bringing an orphan drug to market has its own unique set of challenges and considerations that must be overcome, many due to the narrow scope of use for which the drug is intended. Overcoming those challenges while endeavoring to produce a needed drug as quickly as possible requires the cooperation of clinical trial investigators, drug manufacturers, local and national governments, and more.

Where to start?

Typically, the need for an orphan drug is recognized by a doctor needing a specific drug in order to treat a rare disease. At this point, the doctor may apply for a research grant through one of many funding services, including the National Institute for Health (NIH), various philanthropic concerns, or private industry.

Alternatively, the need may be raised by a disease advocacy group, spotlighting a certain ailment that needs attention This was the case, for example, with the Muscular Dystrophy Association (MDA), who began advocating for cures for various neuromuscular diseases in 1950. Since its founding, MDA has funded research and clinical trials for a number of rare diseases, including Emery-Dreifuss muscular dystrophy (EDMD), ZASP-related myopathy, and Walker-Warburg syndrome (WWS).

10 ◄ November 2018

The next step in the process is finding a drug manufacturer interested in producing the needed drug. Due to their limited audience and small production runs, orphan drugs can be very expensive to produce, and there is a very real possibility that the manufacturer may never break even on their investment. In the case of life-saving drugs, it is not uncommon for manufacturers to provide the approved medications through charitable access, or patient assistance programs, often at no charge for those that need it. On the other hand, the cost of clinical trials can be significantly lower than those investigating better known diseases, as the study samples are necessarily smaller and there is a lack of competing medications.

The health vs. economic benefits must be weighed when one contemplates taking on a treatment for a rare disease. These treatments can be very expensive, and the ramifications of such an investment must be considered. Someone somewhere has to make an objective decision about whether or not to move forward. Sadly, we live in a world in which there are very real restrictions. Consequently, we may have the ability, but not the resources, to cure everyone.

Second life

Of course, there is always the possibility that a drug intended to treat a rare disease may be found to have a secondary, more profitable use, as in the case of Botox. Derived from botulinium toxin, it was originally developed to treat spasms and dystonias due to its ability to weaken muscle function. More recently, it has been used in cosmetic treatments by paralyzing muscles and preventing the development of wrinkles. In 2012, more than 6 million Botox injections were administered in the United States at an average cost of $570 each, for a total cost of more than $3.42 billion. Of course, when a drug is found

to have a second purpose, it must still go through trials for efficacy, even though safety has already been proven.

Trials and tribulations

The next step in the process is the holding of clinical trials. Like all clinical trials, the main purpose here is to prove the safety and efficacy of the drug in question although, due to the small patient sample size, some compromises must be made.

While clinical trials for a drug to treat diabetes, for example, might require a sample size of several hundred, or even several thousand, patients, the required sample size for a drug to treat a rare disease might, by necessity, number fewer than 20. In some instances, historical consults – case histories of patients suffering from the disease – are used to supplement the actual live patient sample.”

The key question that is asked in some of the orphan drug clinical trials conducted to prove the drug’s efficacy is, simply, whether or not the sample population made it to their first birthday. Being such a particular niche market with such a small number of patients in the study population, there’s much more personal interaction with doctors, nurses, researchers, and subjects.

This means that the researchers really get to know the people in their study, and losing one through the failure to come up with an effective treatment can be devastating.

Ethical and Practical considerations

Another consideration unique to studies of rare, life threatening diseases is whether or not it’s ethical to give certain patients a placebo, as is regularly done in ordinary drug trials. That’s a hard question to answer when you’re trying to determine how much good a drug actually does. By providing certain patients with a placebo, are you sentencing them to death? And do you, Pharma Bio World

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amount of time, as after the trial is over, the licensing process starts.

Although orphan and non-orphan drugs go through the same licensing process, those in the pipeline clearly recognize the need for life-saving drugs and go the extra mile to make things happen quickly and efficiently. This greatly streamlines the process wherever possible; meaning that the drug can be released faster than it would otherwise.

as a researcher, have a right to do that in service of a greater good? That’s a terrible question to answer.

In cases like these, lower safety standards may actually apply. Again, due to the small sample sizes, studies may accept a higher degree of toxicity in the study drug as doctors are more able to treat the results of the toxicity than they are the effects of the underlying disease. One has to consider the risk/benefit ratio, especially in the case of life-threatening diseases.

Another difference between trials of orphan and non- orphan drugs is the amount of follow-up that is done. In a typical non-orphan situation, follow-ups are usually part of the trial, examining the effects of the drug after a certain period of time. With orphan drugs, or with drugs that need to be moved to market quickly, additional surveillance of patients is allowed to be done after the trial, to facilitate getting the drugs out there in a timely fashion.

The Last Mile

Aside from the challenges that occur due to the small number of patients suffering from a rare disease, logistics can also be an issue. Particularly in the early stages of development many rare disease, or orphan, 12 ◄ November 2018

drugs tend to require cold chain logistics of one form or another, especially when going through regions in which temperature control can be a challenge. When dealing with drugs produced in such small quantities, any degree of damage or spoilage can be a major issue. In the case of life-saving drugs, the consequences may be severe. These days, some researchers might choose to have a quantity of study medications stored at the patient’s home, to reduce the risk of damage in transit and to make administering the drugs easier. Practical solutions are available, for example, an RFID refrigerator that monitors when the unit is open, what drugs are removed or replaced, and even keeps track of expiration dates. Even with all that, however, it’s critically important to have a shipper that intimately understands cold-chain and temperature-controlled logistics, otherwise all the efforts may be for naught.

There’s an enormous pressure to get everything right in doing this kind of work.

The difference between 95% right, which may be the case in non-orphan trials, and 99.5% right, in the case of rare disease trials, is enormous. This is why having good systems in place, and solid contingency plans as well, is absolutely critical. In many cases, paperwork can take an enormous

Once the licensing portion of the journey is complete, the drug is taken to market.

It’s common in the case of rare diseases for key opinion leaders and patient advocacy groups to spread the word about a new treatment, supplementing the manufacturer’s own marketing plan. At that point, the drug is out in the world, working to both improve, and save, lives. Whilst many of these drugs are expensive, it is not unknown for drug companies to have charitable programs in place, where the drug can be made available to patients without charge or at substantially reduced cost.

(Source: AB Group Market Research) Pharma Bio World

Pharma Logistics: The Top Overlooked Factors

T

here is risk inherent to global pharmaceutical logistics. When designing a logistics strategy any pharmaceutical company or shipper should make certain they consider the following risk factors: •

Temperature control

•

Speed of service

•

Transport handling

•

Customs clearance

However, within these broad factors, there are many aspects that could be overlooked. These include: Road and air transportation of the packaging Organizations can misjudge the difficulty of executing transport. Significant preparatory work is required to ensure that the physical movement of the shipment is handled smoothly, including planning the route, selecting an airline and the type of temperature-controlled packaging. Equally important is providing proper instructions to airlines and ground handlers, and ensuring that all documentation meets custom requirements to safeguard against any delays in clearance.

Customs clearance The complexity of custom clearances in areas such as Southeast Asia, Latin America and Africa can be underestimated. It’s widely assumed that the shipment will be available within hours anywhere in the world, but that is not the case. Conducting due diligence on the customs requirements for documents to avoid clearance delays is essential. Companies must implement procedures in collaboration with their specialty logistics partner for all shipments requiring customs clearance, verifying all relevant paperwork is comprehensively available and correct ahead of the actual transport to ensure smooth customs clearance and avoid delays.

14 ◄ November 2018

Preparing and handling of temperature controlled packaging The design of new temperature controlled units simplifies preparation and handling.

Such packaging improves the security of the product but does not negate the risk of improper handling; a risk some companies may underestimate. The emphasis is now on ensuring that all the preparatory work is done correctly. Companies need to develop processes including training, testing of equipment and labelling.

Underestimation of environment during pickup and delivery Critically, with temperature-controlled shipments, a significant number of issues occur during loading of the product into the packaging or unloading the goods at the final destination. Proper preconditioning of the packaging system requires professional equipment and training of the handling staff. The packing process should occur in a temperature-controlled environment to avoid temperature excursions at the earliest and final stages of the transport chain. At the point of delivery, they should unload wherever possible in a temperature controlled environment, and provide instructions to ensure proper storage conditions at the final consignee site.

The risk of using consignee brokers There are frequent reports of incidents of temperature deviations which occurred due to improper handling by consignee brokers. To avoid these scenarios, the brokers and the pharmaceutical company’s logistics partner need to collaborate closely to ensure compliance with the handling instructions. Ideally, the logistics partner should have direct access to the shipment.

logistics strategy requires consistent and precise language and communications skills. Introducing interpretation into communications ranging from work instructions, regulatory paperwork, meetings and telephone conversations increases the risk of miscommunication. All parties must be able to communicate in the local language and understand the unique vernacular and cultural variances of an area to ensure all instructions are fully understood and followed.

Integrity of the business partner All key stakeholders of the pharmaceutical supply chain must commit to the highest ethical standards and recognize the importance of all applicable laws. In addition to compliance with GDP guidelines, vendors must avoid violations of international anti-bribery laws, including the US Foreign Corrupt Practices Act (FCPA) and the UK Bribery Act. Proper due diligence processes as well as a sophisticated vendor management program should be part of company policy to mitigate the risk of non-compliance as well to ensure that all business dealings are conducted with the highest level of business ethics, honesty and integrity.

Pharmaceutical companies must focus on developing a robust risk management strategy in the mobile supply chain, ensuring that effective controls and procedures are in place to proactively mitigate the potential risks.

Language barriers Cultural complexities are a reality of global logistics. Ensuring the success of a

(Source: World Courier) Pharma Bio World

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insights

Indian Pharma: Leapfrogging Beyond Generics The past decade will be earmarked as a transition period in Indian pharma industry, where the idea of going beyond generics has been seeded into many established companies and at the same time, there is slow, yet a steady upswing in the number of aspiring ventures attempting to crack the code in novel drug discovery and development. The innovation ecosystem has evolved and has been nurtured from several ends. Some of the notable developments are briefly discussed below.

Ease of access created for seed and early risk funding As a fore-runner in innovation funding, Technology Development Board (TDB) under DST has been providing financial assistance up to 50% of project cost in the form of soft loans. Additional extramural funding that was introduced by DBT through BIRAC since 2012 has proven to be a strong pillar of financial support for R&D ventures in the country, especially for early stage funding. BIRAC alone, through its several vectors has supported 617 projects that have filed closed to 150 patents as of September 2017. BIRAC’s flagship scheme (Biotechnology Ignition Grant) has supported more than 140 entrepreneurial ideas at pre-proof of concept stage. Given the various non-dilutive funding platforms created, most biotech entrepreneurs can today access seed capital without any hindrance and can often leverage such funding platforms for early support to the range of USD 100 thousand to USD 1 million. This has empowered ventures to pursue ideas and advance to in-vitro proof of concept stage with Government support.

Several other evolving newer initiatives such as Start-Up India and BIRAC’s i3 program further nurture the path of innovation and provide additional boost to the innovation ecosystem in the country.

Several of these funding programs also serve as technology de-risking funding that larger companies can access and thus have the potential to catalyze greater corporate investment in innovation led portfolio development.

16 ◄ November 2018

BIRAC i3 Program Birac’s i3 is a USD 250 million corpus created as part of Biopharma Mission to fund biotech startups and accelerate innovation in the areas of vaccines, bio-therapeutics and medical devices. With USD 125 million from the World Bank and an equal contribution from Government of India, the program will fund companies to advance assets and other capacity building efforts Incubation infrastructure and nurturing of innovation hubs There is significant global evidence that life science innovation is fostered more effectively in clusters. There has been both a natural evolution as well as a concerted effort to support various thriving geographic hubs in the country. The nucleus continues to be Hyderabad, Bangalore and Pune but there is considerable level of investment an engagement in other locations such as Delhi and Chennai and emerging engagement in nascent hubs such as Bhubaneshwar and Trivandrum. This has been supported by creation of required incubation infrastructure through various Government programs funded by DST, DBT and even NITI Aayog.

Access to shared labs and bench equipment for initial proof of concept research is no more change for life science ventures.

Combined with the expansion of early stage funding platforms, this has supported the spurt of innovation led ventures across the breadth of the country.

Regulations and Fiscal Incentives The ecosystem has been supported by a supportive regulatory framework and a forthcoming approach from regulators to pro-actively work with industry to create an

enabling environment. Examples of proactive regulatory change include the Medical Device Rules 2017 and the revised guidelines for Biosimilars issued in 2016. With the draft guideline for gene editing expected to be put in the public domain for comments soon, the anticipated of continued proactive approach from the regulatory system provides great impetus for the young innovation ecosystem.

While tax benefits on R&D investments are been gradually phased out, the country has introduced taxation on royalty income at a concessional rate of 10%, down from corporate tax rate of around 30%.

Need for International Benchmarking The transition from a large generics base to an innovation led era is complex due to the significant step up in risk level and nature of investments needed. Given the rapidly evolving global context where several economics around the world are trying to catapult into higher margin innovation led growth, it is very essential that India can leapfrog level of engagement. While there is no single recipe to do so, it would be myopic to assess areas that call for attention without benchmarking with quantum and nature of efforts being driven by economies that have made similar transitions or are doing so. As a precursor to a discussion on the way ahead for India to advance to the next realm, we present below a brief summary of notable global initiatives: International Benchmarks for Innovation Benchmarks discussed below have been strategically chosen for their relevance.

Israel stands out as the one of the most prolific innovation hubs globally, including in the area of biopharmaceuticals. The country Pharma Bio World

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insights has been extended to include the start-up community of incubatees of the Hong Kong Science and Technology Parks Corporation (HKSTPC) and Cyberport. Additionally, to encourage the spirit of innovation in the startup community, the Government subsidizes these parks to recruit up to 2 graduates from local universities as interns with a monthly allowance of up to $ 16,500.

South Korea: South Korea is a highly pertinent global Public Sector Trial Scheme and Internship Programme: Hong Kong’s Public Sector Scheme reference given the Trial commendable provides funding support for production of prototypes/samples and conducting of trial schemes transformation of the country from a in the public sector to facilitate commercialization of R&D results focused under public projects.

As partto a domestically generics industry of the budget 2017-18, the scope of this funding strong has been extendedforce to include the start-up innovation in pharmaceuticals, community of incubatees of the Hong Kong Science with and Technology (HKSTPC) USFDA andParks EMACorporation approved drugs today.

and Cyberport. Additionally, to encourage the spirit of innovation in the start-up community, the Government subsidizes these parks to recruit up to 2Korea graduatesDrug from local universities as interns Development Fund with a monthly allowance of up to $ 16,500.

(KDDF): KDDF has been a strong driving

has delivered several blockbusters to the world, including small molecule oncology drugs such as Doxil and more recently, the one of the first few CAR-T cell therapies to be approved by USFDA (Kite Pharma). South Korea attempted the transition from small molecules generics to biologics in parallel with India and now boasts of an active pipeline. Lastly, Hong Kong has gained great relevance in the recent past, especially for initiatives around access to capital for innovation led ventures.

Hong-Kong: Hong Kong is undeniably one of the thriving global hot spot today, teeming with innovation. Although it is more popular as a FinTech hub, the government thrust on innovation and makes it a good global case study with significant recent measures taken towards fostering transformative growth of innovation-led start-up ecosystem.

force behind the evolution of South Korea as South Korea: companies, and allowing companies valued a strong powerhouse intransformation global pharmaofindustry South Korea is a highly pertinent global reference given the commendable the over HK$10 billion, already listed in other stock country from a domestically focused generics industry strong force in today. A $to1.5abillion fundinnovation from the Government, exchanges, a secondary listing in Hong Kong, pharmaceuticals, with USFDA and EMA approved drugs today.

KDDF specifically provide grants for drug to name a few. Considering the high criticality

development companies, lofty target Korea Drug toDevelopment Fund (KDDF): KDDF has been a strong driving with forcethebehind the of of access capital for late stage validation creating 10 blockbuster drugs by year 2020.

A evolution of South Korea as a strong powerhouse in global pharma industry today.

A $ 1.5 billion and market entry of young ventures, this is a to its success, it has fund from the Government, KDDF specifically grantsprogram for drugen-route development companies, favorable move that deserves emulation provide in powerful a robust pipeline program of novel drugs in the with lofty target of creatingto 10 rapidly blockbuster drugsfostered by year 2020.

A powerful en-route othertheemerging economies, propel toinnovation its success, it has a robust pipeline of novel drugs in as theshown country today, country today, below . as shown from labsfostered to market. below2.

25 •Leads

43 •Candidates

25 •NonClinical

20 •Phase I

14 •Phase II

0 •Phase III

HK Benefits $ 2 Billion Fund: Acquisition: In September Fiscal for Technology Tax credits and benefits to Fiscal Benefihave ts been for introduced Technology 2017, the Innovation Technology encourage technology and IPand acquisitions.

Corporate tax on income by benefi SMEs ts and Acquisition: Taxgenerated credits and have Commission (ITC) of companies Hong Kong launched specified medium-scale from the transfer of patents to a Korean national is reduced been introduced to encourage technology an50%. innovative HK$ 2 are billion whereby VC activities by Tax incentives alsofund provided for M&A that furthers innovation of and IP acquisitions.

Corporate potential tax on income funds from When within aasdomestic well as Korean outsidefirm Hong the country. merges with a technology-led SME the merger generated by SMEs and specified mediumKong can co-invest with thetaxgovernment company is eligible to avail a 10% credit on the payment made, up to the value of the acquired scale companies from the transfer of patents in local technology-led start-ups. The technology.

Government and the eligible Fund will invest

to a Korean national is reduced by 50%.

Robust Stock Exchange: Korea is home to a robust NASDAQ like stock exchange favoring Overhaul of listing policies: With in an approximate 1: 2 ratio on each venture. Tax incentives are also provided for M&A innovation-led ventures, allowing them a pre-revenue listing based on a technology assessment. activities that furthers innovation potential of

the stock exchanges of New York, Shanghai, This is an innovative measure is expected to trigger VC interest in local startups and the country. When a domestic Korean firm London and Singapore leading as IPO hubs for Israel: merges with a technology-led SMEand theismerger Over the pastinnovations few decades, has cemented its reputation as the "Start-up Nation" the to Israel markets. raising equity capital for young ventures, Hong accelerate second most innovative nation in the world, according to the World Economic Forum’s Global company is eligible to avail a 10% tax credit Kong had until recently stayed out of the race, Public Sector Trial Scheme and on the payment made, up to the value of the content with most listed companies being large industrial or financial ventures. The city repealed Internship Programme: Hong Kong’s acquired technology.

Sector Trial Scheme provides funding its listing policies in December 2017 that are 2 Public KDDF website set to be effective in mid-2018, in an attempt support for production of prototypes/samples Robust Stock Exchange: Korea to attract younger ventures. The new rules and conducting of trial schemes in the public is home to a robust NASDAQ like stock have brought in significant changes favoring sector to facilitate commercialization of R&D exchange favoring innovation-led ventures, technology-led companies, such as waiving results under public projects. As part of the allowing them a pre-revenue listing based on revenue track record in the city for lower valued budget 2017-18, the scope of this funding a technology assessment.

18 ◄ November 2018

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insights Israel: Over the past few decades, Israel has cemented its reputation as the “Start-up Nation” and is the second most innovative nation in the world, according to the World Economic Forum’s Global Competitiveness Report 2016-2017. Between 1999 and 2014, Israelis started 10,185 companies, with half of them still in operation and 2.6% having annual revenues of over $100 million.

Growing trend of incubation spaces and co-working spaces: The Israeli government founded the Technology Incubator program in the early 1990s with over 25 incubators now been privatized. The incubators also offer government funding of up to 85% of early stage project costs for two years. Israel also has a number of city-funded co-working spaces which have been growing rapidly over the last few years.

Incentives for supporting foreign R&D centers of MNCs in Israel: The number of multinational corporation (MNC) R&D centers in Israel is among the world’s highest, and is the highest per capita. There are more than 320 global companies having R&D labs in Israel today, with 80 of them being Fortune 500 companies.

Israel has entered more than 40 bilateral industrial R&D support programs all over the world Israel Innovation Authority: The Israel R&D fund facilitates the operations of the IIA which provides a variety of support programs, on an annual budget of about USD 400 million . The main program is the R&D Fund that offers R&D grants of up to 40% of the approved R&D program cost.

IIA also offers bi-national funds (joint R&D programs with foreign counterpart such as China, Canada, USA, etc.), which are entitled to financial assistance of 50% of the Israeli company’s R&D costs. IIA also manages the grant programs as part of the tax benefit approval for eligible companies.

Funding efforts to nurture startups: Israeli government has set up special purpose vehicles to give $600,000 riskfree loans to promising starts ups with no requirements to payback on failure and 3% royalty for successful companies. The government also provides employment grants for R&D centers and large enterprises with a 4-year grant scheme covering on average 25% of the employer’s cost of salaries for each new employee. The R&D fund of Israel 20 ◄ November 2018

also provides financial grants of 20%-50% of approved R&D programs. In geographical areas designated as National Priority Areas (NPAs) the benefit can reach 60%.

Tax benefits: Israeli tax and investment laws have played an enabling role in enhancing the innovation ecosystem in the country. The Israeli Income Tax Ordinance enables companies to deduct their R&D expenses from their current income in the year they were paid. The Israeli Investment Law also enables foreign companies to benefit from a reduced company tax rate and investment grants. The Angel Law in Israel also provides tax benefits to single investors who invest in Israeli companies in their initial R&D stage (seed) to facilitate more financing sources for early stage investments.

Catalyzing Transition to the Next Realm of Growth It is clearly evident that the Indian pharma industry is more than ready to leapfrog from its currents status of a global generics hotspot to become emerge as a notable innovation hub in the global arena. Many companies are advancing towards their next leg of growth, have novel drug discovery programs in place, with active pipelines.

There is also a vibrant start-up ecosystem with a handful of companies aspiring to crack the code in indigenous drug development.

However, success doesn’t come easily in this long drawn and capital intensive stream of business. Many large companies that have attempted to test the waters have fallen back, curbing their discovery programs altogether and stands testament to the high level of binary risk and other challenges obstructing the path to success. The issues involved are complex and cover different aspects of research and development, funding and market access. It is imperative that such challenges are addressed and the path to market streamlined in order make novel drug discovery a success in the Indian context.

Critical challenges and key recommendations for catalyzing this transition to innovation led growth are summarized below.

A. Scale-Up Funding and Tech Access Mechanisms Initiatives and innovative programs from DBT and DST has ensured that India today has a strong foundation of funding for early seed and proof of concept validation. Complemented by

international grants, philanthropic funding and state government resources, there is a robust umbrella of risk capital for entrepreneurial aspirants. Unfortunately, the current funding mechanisms do not differentiate the level of funding based on level of risks of business segment or disparity in time to markets. The field of novel drug discovery differs from other sectors of life sciences in many ways: Significantly Longer Time to Market: While products such as medical devices and diagnostics have relatively shorter paths to market, the early seed funding tides ventures over by a large measure. On the other hand, novel drug discovery is a much more capital intensive business segment with a much extended time to market. New drugs and vaccines in particular can take between 8 to 10 years to develop and progressively need increasing amounts of capital as the asset is advanced through stages of pre-clinical and clinical validation.

Binary Risk: The threat of binary risk in late stages of the product development lifecycle in terms of regulatory approvals adds an extra layer of complexity in conducting business in novel drugs.

Low Risk Appetite in Large Companies: Indian pharma industry is traditionally entrenched in low risk market segments and thus even deep-pocketed large pharma firms have low risk appetite and are apprehensive about expanding investments in their discovery programs. Past failures of peers or from first-hand experience demotivate greater momentum or funding allocation for high risk portfolio development.

Thus, there is an urgent need to enhance the level of match funding for large corporates by a large measure to catalyze higher level of initial investments in portfolio development until a stage of initial commercial reward that can then ensure continued corporate investment.

High Venture Mortality: There is a much higher level of venture mortality in this field as smaller venture do not have the financial muscle Ventures are at a much more difficult situation. With expanded extramural funding possibilities, an active innovation ecosystem has been seeded and overall more than 500 life sciences ventures have been created in the country. However, access to Pharma Bio World

insights capital beyond the initial half a million remains a challenge. There are several pipeline ventures in the country that have advanced to the in-vitro stage but are stagnated due to the challenge of access to equity capital that has appetite for binary product development risk in biopharmaceuticals. Fruits of all the efforts invested in creating this impressive pipeline of startups will only be realized if this challenge of access to equity is declogged and a net of VC funds with appetite for technology risk are seeded with interest in the segment. It is disheartening to note that there has been negligible allocation to biotech ventures early stage funding even by Funds that have been funded by the Rs. 10,000 crore Fund of Funds created under the Startup India Program. To avert venture mortality and fleet of Indian ventures to domiciles where capital is available, it is critical that we quickly address this challenge of access to equity captial.

Based on the current pipeline in India and continued venture creation, we estimate that aggregate investment required for developing assets until stage of commercialization is USD 6.2 Billion Technology access is another gap in the country’s innovation ecosystem today. While several large pharma companies remain apprehensive in triggering indigenous R&D for novel drug discovery from the ground up, an easier mechanism would be to access technologies and in-license candidates from other parts of the world. While there is little evidence of success from such a strategy yet, with exceptional examples such as Sun Pharma’s ILUMYA, which was acquired as a late stage asset from Merck, it is important to trigger the thinking in that direction through directed initiatives.

To support companies in nurturing a risk balanced portfolio of early to late stage assets, it would be ideal to incentive technology access through fiscal and financial incentives.

There are global benchmarks where countries have supported access to both upstream and downstream technology as a critical step in nurturing their own ecosystems. This will be most impact in supporting larger companies in their quest for this transition into a higher risk segment.

Pharma Bio World

Recommendations • Given the high dearth of scale up funding for aiding R&D in novel drugs, it is essential to increase the quantum of funding under existing programs for ventures and newer initiatives enhance the level of engagement in risk mitigation especially for smaller ventures.

• Match funding for large corporates need to be enhanced multifold for supporting innovation-led R&D in big pharma • There is a high need for incentivizing technology access initiatives as a derisking mechanism to actualize Indian made novel drugs. South Korea could serve as a comparable benchmark, where the corporate tax on income generated by SMEs and specified medium-scale companies from the transfer of patents to a Korean national is reduced by 50%. Such schemes provide impetus to the industry for inlicensing technologies and are worth emulating.

B. Nurturing a Convergent Ecosystem for Innovation Indian ventures have a large skill pool to develop deep-science based products and technologies. But the country lacks a strong foundation for nurturing ideas and translating from labs to global markets. While there is evident momentum in the medical devices space with initiation of programs such as National Biodesign Alliance, a parallel in the pharmaceutical sector remains absent.

Therefore, there is a very small subset of ventures that pursue high complexity areas of innovation such as novel drug discovery, next generation regenerative therapies, genomics and novel biomarker discovery, with very little activity in institutional research in these areas.

Protection of IP remains a long and hard battle for most entities in the Indian ecosystem. IP related challenges loom over the industry as a whole, affecting research across institutes, young ventures and larger companies. Indian institutes usually fall short in well-formulated mechanisms to reward inventors for IP creation.

In cases where institutional research facilities support incubation of novel ideas, they lack adequate engagement with the market and adequate capacity in technology transfer to

third parties. This results in either research with low translational market potential, or worse, high potential research with inaccessible market channels. Resultantly, there are very few institutional spin-offs in the pharma sector.

The handful of ventures which reach the next stage of business cycle often get stuck in limbo because of dearth of equity funding.

To add fuel to the fire, India has long dealt with global perception of poor IP policy & enforcement. Although, the perception is often harbored without awareness of details of either legal cases or circumstantial context, it prevents global companies from promoting and absorbing Indian innovation. In the case of start-ups as well as established pharma companies exploring novel drug discovery, their entire value-creation potential pivots on the IP value of their innovation and thus this issue has a huge bearing on nurturing global relationships and asset-partnerships. The select few ventures that attract interest of global investors on the strength of their innovation are often required to engage in IP inversion and redomicile their IP assets in a different geography.

Even established pharma companies that enjoy reputed market presence in regulated markets today often tread a harder path than their global peers do to partner their assets.

Conclusively, the high level of risk and investment involved, currently lower level of institutional spin-out creation, and dearth of entrepreneurs experienced in global context of drug discovery and development tend to be significant deterrents that need to be addressed.

As India progressively begins to make its mark on global platform for sophisticated and upstream technological advancements, there is an urgent need to sustain and intensify the momentum by designing catalytic solutions to address these specific challenges C. Need for Globally Benchmarkable Fiscal Incentives To anchor a well-rounded innovation ecosystem, fiscal benefits need to evolve further to reward continued innovation momentum, and be globally comparable.

Tax regimes on royalty incomes and inhouse R&D expenditure reflects the fiscal benefits provided for innovative ventures.

The Indian 2016 budget received a mixed response from the life sciences community, one of the main industries entrenched in innovation. On one hand, it introduced November 2018 ► 21

insights Recommendations • Regulatory processes needs to be streamlined especially for clinical trials, and time to markets for novel drugs accelerated multifold • With a handful of Indian ventures engaged in therapeutics for rare diseases, next generation solutions such as gene therapy and emerging areas of regenerative medicine, it is critical that the policy frameworks evolve accordingly to support the evolution in science in the country.

• The high out of pocket market in India hinders ease of implementation of any value based healthcare pricing approach.

However, alternative solutions such as cross-subsidization are great models to consider in the Indian context. This model has also witnessed proven success in the Indian vaccines industry, where affordable access through public channel is compensated for higher pricing allowance in private markets. It is imperative that the fear of value realization in companies pursuing innovation is alleviated and rightful reward for innovation is considered. the special ‘royalty tax’ that provides tax rebates on royalty income earned from out-licensing technologies. The discounted royalty tax is 10% against the standard rate of 30% after deducting expenses, which is definitely a positive step towards incentivizing indigenous innovation.

However, this was also accompanied by a lower tax benefit on overall in-house R&D expenditure. The tax deductions of 200% offered on in-house R&D expenditure was reduced to 150% for 2017-2020 and 100% thereafter. Such a decrease in tax benefit on in-house R&D expenditure is very discouraging, especially for the pharma sector in the country that is just formulating its initial steps in innovation and is already facing several funding related tailwinds.

Additionally, the royalty incentive should also be broader to truly catalyze innovation led growth – it needs to cover royalty on inlicensed assets and global patents which are currently not included in the provision as well as sale of IP or other mechanisms for monetization.

Several superior global benchmarks exist today that support R&D activities with 22 ◄ November 2018

better tax regimes, indirectly incentivizing innovation. Some such benchmarks are highlighted below.

Singapore • A base level of 100% deduction is given which is followed by additional 50%.

• Additionally, a 250% (for Singapore-based R&D) or 300% (for non-Singapore based R&D) enhanced deduction is given Switzerland • Differential tax schemes for companies based on size • 130% tax exemption on R&D expenditure for large companies and 230% for SMEs Malaysia • 200% super deduction is given and an Investment tax allowance of 100 % on qualified capital expense for R &D Services. The above incentive applies to R&D conducted outside Malaysia as well.

Ireland • Besides having one of the lowest corporate tax rates of 12.5%, a 25% volume based credit is given on the expenditure on infrastructure, with the option of carrying forward unused credits indefinitely to reduce any preceding tax liability.

• IP Tool Box scheme also provides incentives for innovations in products and processes.

Recommendations When benchmarked with global ecosystems that are encouraging greater biopharmaceutical R&D engagement, our fiscal incentives fall behind. Considering the pharma industry in India is at the cusp of its next big growth avenue in novel drug development, the path to success needs streamlining and calls for globally comparable fiscal incentives as well as strategic initiatives that will encourage greater investments in new product development.

D. Furthering Market Openness and Rightful Reward for Innovation As all the above described building blocks for a robust innovation ecosystem are geared in place, the most crucial component in actualizing innovation success, the right environment for commercialization, also needs to be nurtured in order to ensure smooth bench-to-bedside transition of promising drug candidates. The lure of

regulated markets is already high for pharmaceutical companies due to better value realization potential. Thus, only if existing commercialization challenges in the country are alleviated, there is scope for Indian innovations to benefit the domestic ecosystem.

Today, much of the commercialization related challenges persist in either sailing through regulatory hurdles or because of the lack of rightful reward for innovation.

Augmenting better Precision in Policy and Regulations: Indian drug approval regulations need better streamlining in order to accelerate time to markets for innovative drug pursuits. Delay in clinical trial approvals is a significant concern in India, which is often pushing even CROs to consider alternate trial sites in other emerging econ. Although India is home to 15% of global population, and is a popular destination for cost minimization in any industry, less than 2% of global clinical trials are today conducted in India.

Thus, it is time to undertake measures to ease the uncertainty and ambiguity in regulatory frameworks and chart a clearer pathway for companies pursuing novel drugs. Additionally, India lags behind global standards in certain policy frameworks in newer drug avenues such as biosimilars and regenerative medicine.

Rethinking Price Capping as means for Affordable Access: India has long-battled with price capping as a means to ensuring affordable access of key medicines which has demotivated even large pharma companies from across the world to launch revolutionary drugs in India. Thus, price capping has many a times proven to be counter-intuitive and caused a much delayed access of innovative drugs to Indian patients. With several innovative ventures in the country making in-roads into novel drug discovery and development, the timing can’t be more perfect for rethinking drug pricing and access to ensure that pursuit of novelty doesn’t becomes an exercise in vain for pharma companies, which is a no-win situation that will come back to affect the patients involved.

Pharma Bio World

insights Recommendations • Strengthening the institutional backbone: There is a high need for fostering multidisciplinary training and leapfrogging the level of institutional engagement in industry-relevant translational research in pharmaceutical drug development with targets that are globally benchmarkable.

• Industry-academia collaboration: Platforms for industry-academia engagement need to be multipliedeline. This is and global translational researchhighly critical collaborations need to be enhancedfor nurturing multi-fold. A stronger collaboration will necessitate dedicated technology transfer cells, and more market-relevant research.

• Change IP related perception: EXPAND In addition ADVERTISE to constructing TO stronger your reach mechanism to create, commercializethrough and monetize IP, India needs to urgently change the perception around unreliability and inadequacy of the IPR policy, and create awareness around the quality of innovation pipeline. This is highly critical for nurturing globally translatable drug development and enhanced value creation for Indian-made assets.

(Source: Sathguru Management Consultants)

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November 2018 ► 23

insights

Driving Radical Growth To Make India A Pharma Superpower The Indian pharma industry ranks 3rd in volume and 13th in terms of value. It is the 2nd largest supplier of generic medicines to the US indicating the ability to produce quality products. We are highly fragmented both in manufacturing with more than 10,000 facilities and in the domestic market the largest company has just about 7 – 8% market share. However, several challenges exists that put the brakes on the industry growth including trust deficit on product quality and integrity of data, sub-scale operations in API manufacturing limiting cost competitiveness, investment crunch to fund R&D in NCE, unfavourable and at times unpredictable policies, and inadequacies in the drug regulatory infrastructure, to name a few.

The Path to Growth Among the enablers of growth of the domestic market, expansion of healthcare reach to the rural areas aided by increased healthcare spend by the government is being seen as a key factor. E-Commerce is considered as one way to reach out to the larger populace. However, without having the right ecosystem and infrastructure this is not going to be as helpful in improving reach. A need to strengthen our primary care centres, the district hospitals, community centres is necessary.

Additionally, increasing the medical profession base through more medical colleges is seen as vital. Other enablers include insurance penetration, maybe even making it compulsory. An implementation of Jan Aushadhi on the lines of the Aadhaar Card may turn out to be a possible game changer. Mega tenders for medicines are expected from the government, however, these may have a mixed impact on growth – increasing the volume, but not moving the needle radically from a value perspective. It is considered vital to address the patient factor by improving the journey from diagnosis of the disease to management of the disease and focus on wellness and prevention.

24 ◄ November 2018

Cost of transaction is seen to be high with retailer and distributor margins contributing to 30% of the cost to the patient and bringing in efficiencies here is necessary. For exports, tapping into opportunities in markets like Japan, Australia, New Zealand, Korea, Thailand, whole of South-East Asia, Latin America, GCC is the new imperative. Among these, Japan is seen as a key target as it is the third largest pharmaceutical market and are opening up to generics at favourable pricing levels and above all, it is open to sourcing from India. Focus on generic plus incremental innovation, complex generics, 505(b)2 play; emphasis on investing and leveraging technology are all necessary along with diversification, backward/ forward integration, foray into OTC, nutraceuticals, and entry to services based offerings as potential growth drivers.

Skill upgradation and development is also a key enabler of growth. There is a view that we are limiting our focus on skills that are already in existence, for example, we know chemical technology well and hence we should additionally be focusing on biopharmaceuticals; our skills in biology have to be reinforced through a partnership or collaboration.

A revamp of education to make it more technically relevant, and help it serve enhanced management needs of export oriented manufacturing and globalization is a dire need. Increased collaboration with academia is important and mutually beneficial and mechanisms for this to happen need to be functionalised – if required through policy push by the government.

The overall theme is to excel in quality and the vision is to be the global benchmark of quality. The focus is not just on compliance, but also includes the drug regulatory infrastructure and overall quality excellence. It is suggested that India should consider becoming part of IGDRP (International Generic Drug Regulatory Programme) as this would enable India to influence the decision making at this level purely based on science. The industry has been working with the government to make a statement to abide by the UN high level panel’s report and provide a stable TRIPs compliant – no TRIPs minus or TRIPs plus - IPR regime.

Perceived threats to growth include challenge on the formulation front from China on the same scale as for APIs. A word of caution is also to be noted regarding cyber security.

Pharma Bio World

insights

As a trend, one can expect increase in demand for APIs as several countries are encouraging domestic production of formulations to support 100% coverage of medication under insurance, for instance, countries in Latin America, SE Asia, and South Korea. This could be an additional growth driver. Biosimilars and the entire biotechnology domain are considered as high growth areas with a lot of work being done in genomics, rare diseases and Oncology.

APIs We import close to about, $8bn worth of APIs, from China, and on the other hand we export $6bn to regulated markets. The paradigm is one where the volume difference is significant; what we export is low volume, high value; imports into India are very high volume and with low pricing.

Additionally, the domestic industry is vulnerably dependent on Chinese APIs – to the extent of 90% of the supply.

The threat of any political, geopolitical, economic issues disrupting supply looms large. Recently, 50 – 60% of the manufacturing in China was curtailed because they wanted to control the pollution, consequently, there was a crisis in the Indian formulation industry, because Indian manufacturers of API had abandoned vanilla APIs. Pharma Bio World

A word of caution being sounded is that if we do not protect our ground on APIs we could be in a real threat from China, impacting not just domestic sales, but also sales to semi-regulated markets.

Current trends do not portend well. As per Pharmexcil, exports of APIs have shown a decline. A contrarian view is that dependence on China is for commodity APIs such as Paracetamol, Metformin and similar products. For products going off patent where Indian companies want to be first-to-file, Indian firms are conducting inhouse development. It is argued that the industry has continued to grow in spite of this dependence on China, especially the 20 odd companies that contribute to 80% of exports, so is this really a problem?

There are two issues here, supply for the domestic / semi-regulated markets and the regulated markets. The former is under threat. Several factors are being cited for the dependence on API, including the impact of reservation of certain molecules for small scale industries and license raj limiting capacity growth; also for pricing purposes API from China was used as a benchmark rendering several entities sick. The pertinent question is: why is it that China is able to make intermediates at about 20 – 50 % of our cost? The main concern is that the variable cost of manufacturing of an API in India is higher

than the selling pricing of Chinese APIs. This is mainly due to indirect subsidies.

Based on cases successfully fought at the WTO against the Chinese manufacturers a few Indian companies were able to prove this point and introduce anti-dumping duty for Ceftriaxone from China.

While it is considered necessary to build scale, and increase investment on API to reduce dependence on China, the onus of action lies with the government and also on the industry. Proponents of the view of need for support from the government feel that if the government is looking to contain drug prices for essential medicines, it would be necessary for it to support API manufacturing. Additionally, the remit of the government should be limited to creating a level playing field for both Indian and foreign manufacturers. The government should also probe into the reasons for the low cost APIs from China and address these appropriately.

Fermentation has been identified as a critical area where support from the government was sought in the form of some kind of an EMI, on zero discharge, due to the high capital outgo. Similar support is being proposed to enable creation of scale – a must have in the API industry to remain cost competitive.

Some possible mechanisms for the same November 2018 ► 25

insights political ramifications.

The measure of how standards are implemented is found to be different.

One approach is determination of quality by testing the product for its identity, strength and purity. Regulated markets on the other hand consider the manner in which the product is manufactured, for instance, non-compliance with the good manufacturing practices requirements leads to the product being declared as adulterated. The distinction between quality and compliance is also to be noted.

The key point being highlighted here is that implementation of the standards determines the extent of compliance.

are capital subsidies, facilitation of a low rate of interest: LIBOR + 3%, and subsidy on utilities – since it is the single biggest cost in API manufacturing contributing 20 - 25% of the total cost. Also, the need for land not too far away from current technology hubs has been expressed strongly by the industry.

key starting materials such as Benzene or commoditized APIs as the margins are slim. So the required expansion will have to come from either new entrants or Small/ Medium Enterprises. It is obvious that unless the industry received a reasonable return on investment it will be difficult to sustain investment in commoditized APIs.

A solution considered more pragmatic is the waiver of charges on power supply to API units provided through a captive power plant within the SEZ; co-location of the API complex to petrochemicals complex to enable availability of solventson-tap, removing the need to transport and store solvents, and similarly, collection of solvent again by a pipeline. It is suggested that states with high API player concentration should take a lead in setting up such SEZs. At the same time, it is also being suggested that subsidies from the government as misplaced in light of the perceived high profitability of the pharma industry and potential for other industries to demand similar subsidies. Moreover, it is felt that in cases of anti-dumping duties, the onus of proof has to be on the industry.

Additionally, in the API space, it was opined that one cannot expect large pharma firms to backward integrate into manufacturing

Regulations and their adherence Regulatory standards across the world are the same and the difference lies in enforcement of those standards. It has been accepted that dual standards of implementation prevail for products supplied for regulated markets versus those for semi-regulated markets.

Dedicated high class facilities are being used for regulated markets while facilities for the domestic market are found to be sub-standard and located in distant parts of the country. The MSME sector currently is largely non-compliant with regulatory standards. It is being questioned as to why dual standards of implementation are being permitted by the Government of India. It is acknowledged, however, that the strict enforcement of Schedule M for this sector could lead to potential closure of these units and associated unemployment – with

26 ◄ November 2018

Standards are the same but if their implementation is poor, it essentially translates into lower standards. The lower quality standard for products for the domestic market is mainly because the defaulters are not penalized for noncompliance with standards, whereas one has higher standards for regulated markets because there is a high penalty for non-compliance. The inadequate level of compensation from the domestic market is also being cited as a reason.

The issue of lack of harmonization in standards of implementation across various state regulatory authorities and differences from those of the centre is also to be noted. A need for a central drug authority which governs what products can be launched has also been felt by the authorities. In terms of division of State/ Centre roles, it has been proposed that states can have a role to play in regulation by issuing and monitoring chemist / druggist licenses, and conducting manufacturing inspections. Another point to be noted is the lack of clarity on who will audit manufacturing facilities as the Centre is hiring auditors for this purpose, and this impinges on the boundaries of the State – an issue that needs resolution. It is proposed that the creation of centres of excellence in SEZs, could help address Pharma Bio World

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the issue around environment, supply chain, etc since the state and centre both benefit. There is no duality or conflicts around SEZs as the sharing mechanism is designed so in that policy. The need for a more proactive policy to regulations is a priority especially for clinical trials as the decline of the clinical trials industry was due to a reactive policy. Currently, the e-pharmacies domain needs regulation; additionally a policy to encourage academia to collaborate with the industry is also sorely missing. It is recognized that we need to be clear about what it is that we are trying to do and then align our view on ethics.

If India has to become a global player and a force to be reckoned with, then we need to recognize that domestic patients are not different from global patients and act accordingly from a regulatory compliance standpoint. The image of India’s drug regulator will be key to driving growth of India’s export industry. India should consider joining the PIC/S (Pharmaceutical Inspection Co-operation Scheme). Joining PIC/S would establish a pathway of how the Indian drug regulator would develop, Pharma Bio World

and it would take at least 5 years, if not 7 to reach the level to qualify to become a member of the PICS. The pathway would also define the reforms that would take place between centre and state.

Now, increasingly global regulators are working together and any quality issue with a particular regulatory agency may trigger action by various regulatory agencies.

A cabinet position for the Ministry of Pharmaceuticals would drive efficiencies in interface with the Centre. It seems that the efforts of the centre in improving quality compliance are bearing fruits.

The CDSCO has shortlisted companies for inspection based on number of samples from the market that are found to be ‘Not of Standard Quality’ – NSQ; companies which had maximum incidence of NSQ, were chosen for inspection first.

Frequent quality lapses have widened the trust deficit between the industry and government.

There are a large number of industrial clusters where the centralized approach of a common effluent treatment system is not working. Reasons cited for this are

that permission given by the regulator was only specific to a particular set of APIs. If the manufacturer wanted to change the APIs produced, permission needed to be sought again and this is not an easy process apart from being time consuming.

Resultantly, some manufacturers actually produced different products than what have been approved and the effluent treatment plant simply could not keep track of what is being manufactured.

A decentralized approach may be the solution whereby the approach has to be changed from a license monitoring regime to a self-regulation regime on environmental aspects. Post the enactment of the Environmental Act, Indian companies have taken more than a decade to effectively manage waste and this has led to a capacity gap. It is felt that the government should leave it to the industry to self-regulate this aspect.

One neglected aspect regarding compliance is the use of vernacular language in manufacturing facilities. The use of vernacular languages has the potential to improve compliance by 30 – 40%. Also, IT can be leveraged to ensure more compliance and productivity.

Innovation As a percentage of GDP spent on R&D, India spent a mere 0.9%, versus 1.9% by China and companies are not taking a long term vision on this aspect. India needs to show some commitment to innovation, and that again will come not just by the industry but also by research collaborations with academia. In some quarters, India is not seen as a market which either respects innovation, or is even willing to invest in that; and there is need for a cultural change. The necessity for a body similar to the NIH in the US, whether public or private has been felt for quite some time.

A contrarian view has been put forth that it is not that Indian companies have not done work on NCEs as many Indian firms have patents on NCEs, but what is needed is November 2018 ► 27

insights government gives a matching grant on the amount spent on research.

an Indian company to introduce an NCE in regulated markets. It takes 70% more effort to take the product to regulated markets and the issue is of funding and skillset.

Additionally, big companies now require proof-of-concept before collaborating and it is becoming a big challenge today for small-scale companies since only 1/3rd of the total amount of product development investment is required till PoC. This, in the Indian context could be INR 200cr to INR 250cr, and Indian companies are capable of managing development on their own till this stage. Funding is only required for work beyond Phase 2.

NCE development is a risky proposition with a very high rate of failure: 99%, and even if one is able to develop a product till Phase 2, this translates into a large investment considering the failure rates.

Some experts feel that if we expect Indian companies to invest billions of dollars and wait for an NCE, it is not going to happen, and instead we should aim for the low hanging fruits that incremental innovation may yield with relatively less funding. In this regard, it is suggested that the government should recognize incremental innovation and companies should be allowed to benefit from it through a provision of exclusivity period.

To address the issue of funding, Indian companies may want to look at partnering with smaller innovator companies as done 28 â—„ November 2018

by the IT industry but the Indian pharma industry needs to market itself well as these small startups may have very little knowledge about India.

One area to consider may be precision medicine, as it is considered as the next era of innovation with a lower likelihood of failure. Another option is to collaborate with big pharma/ academia/ financial institutions or a combination thereof. In the US, it is already happening, for example, smaller players in Boston have tied up with the big pharma and with academic institutions.

There are now companies that are being formed which are LLCs and separate from the parent company. There are actually established models for this type of collaborations, including how the royalties are split and how the patents are treated. IPR need not be an issue as commonly perceived since there are several instances of collaborations between Indian and global players. In fact, there is the opportunity for Indian players to do global registrations in such cases. It is generally agreed that the industry needs to convey the key issues in pharma innovation to the government, especially regarding long gestation, high risk of failure, and funding like other developed countries, where the

Summary In summary, the key takeaways for the industry are: growth through market 1. Drive expansion, move up the value ladder, incremental innovation and rural outreach 2. Drive indigenisation of commodity API manufacturing 3. Push for self-regulation and incremental innovation 4. Investing in NCEs R&D and working closely with government research institutes On the other hand the government is urged to: 1. Enhance investment in healthcare infrastructure by increasing spend from 1% to 2% of GDP. 2. Create a level playing field for the API industry by subsidizing capital and operating cost for building mass scale API units 3. Setting up API zones next to petrochemical plants 4. Levying anti-dumping duties on Chinese API 5. Foster collaboration and innovation

(Source: CPhI Report on The Indian Pharma Industry) Pharma Bio World

research

Genomic Medicine: A New Frontier Of Medicine In The Twenty First Century Although the concept of heredity has been in existence since ancient times, the science of genetics began to evolve only around 150 years ago. The Darwinian theory of evolution by natural selection made clear reference to hereditary factors that reflect at least some of the present-day concepts of the genetic basis of life. Mendel’s laws of inheritance, and successive discoveries in various aspects of genetics, laid the foundation for a number of disciplines covering different areas within the modern science of genetics.

The emergence of human genetics was no exception.

I

t has taken seven decades since the recognition of DNA as the carrier of hereditary information to arrive at our present state in the science of genetics.

The future now appears bright, opening up many new and challenging opportunities.

During the last four decades, medical genetics has established itself covering clinical and laboratory diagnostic applications. The basis of medical genetics is grounded in a sound knowledge and understanding of principles governing ‘human genetics’. Clinical genetics is now a recognized medical specialty among several disciplines comprising the current spectrum of modern medicine.

Fifty years after the discovery of the doublehelical structure of the deoxyribonucleic acid [DNA] molecule (Watson and Crick 1953), the characterization of the virtually complete sequence and organization of the human genome was successfully accomplished (Lander et al. 2001; Venter et al. 2001). This major scientific achievement laid the foundation of ‘human genomics’; that section of the biological sciences which studies variations, mutations and functions of genes and controlling regions, and their implications for human variation, health and disease.

This is strengthened by developments in the other areas of genomics relating to microorganisms, animals and plants.

The identification of all human genes

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and their regulatory regions provides the essential framework for understanding the molecular basis of disease.

This advance has also provided a firm foundation for the future development of genomic technologies that can be applied to medical science. Rapid developments in global gene analysis, gene product analysis, medical bioinformatics, and targeted molecular genetic testing are destined to change the practice of medicine.

However, many practicing clinicians perceive developments in genomics as primarily confined to the research arena with little clinical applicability. DNA / RNAbased methods of disease susceptibility screening, molecular-based disease diagnosis and prognosis, and genomicsbased therapeutic choices and prediction of treatment outcome are some of the key areas that are likely to influence the practice of modern clinical medicine.

Undoubtedly, the science of genomics has tremendous potential for improving human health. The World Health Organization [WHO] had made several recommendations for the scope and application of genomics on global health (WHO 2002). It is acknowledged that the information generated by genomics will provide major benefits in the prevention, diagnosis and management of communicable and genetic diseases as well as other common medical diseases, including cardiovascular diseases, cancer, diabetes and mental illnesses (Cardon

and Bell 2001). Together these constitute a major health burden, as reflected in chronic ill-health and mortality. In addition, a number of infectious diseases are associated with genomic mutations manifesting in the form of increased susceptibility, clinical severity, favorable and unfavorable response to anti-microbial therapy and in conferring protection. It is possible that the protective effect of a microbial vaccine might be influenced by genomic variation.

The sequencing of the entire human genome completed over a decade ago was a mammoth project since each person carries a distinct sequence. The variation among all humans is reflected in sequence polymorphisms scattered across the whole genome. The genomic variation between individuals together with environmental factors probably determines disease sus-ceptibility and protection, and is important in drug efficacy and side effects (Holden 2000; Chakravati 2000). The key to genomic variation lies in deciphering single nucleotide polymorphisms [SNPs] and copy number variations [CNVs] and their use in studying disease mechanisms (Stephens et al. 2001). The mapping of the disease sus-ceptibility loci depends upon the successful application of haplotype associations. This is strengthened by valuable data gathered from the International Haplotype Mapping [HapMap] and the Human Variome projects.

This is likely to be promising in conducting November 2018 ► 29

research glycomics, toxicogenomics, and many more. Whatever the basis of distinction might be, the driver of all these specialist fields is GENOMICS - the study of genomes in their entirety.

clinical studies to find individuals in whom a drug is likely to be efficacious. The use of SNPs and CNVs in pharmacogenetics and pharmacogenomics is currently restricted to studying genes encoding drug-metabolizing enzymes, such as P450s, and variation in genes that encode drug receptor target proteins.

The newly emerging dynamic field of pharmacogenomics is an exciting application of genomic variation in drug discovery and drug development.

and Bell 2001). Some of the impressive genetic studies of this kind include susceptibility to infectious disease, for example an association between chemokine receptors (CCR5) and HIV susceptibility, and between the bacterial transporter protein Nramp and resistance to macrophage- infecting bacteria such as Mycobacterium tuberculosis. Similarly, various alleles at the G6PD locus determine malaria susceptibility (Tishkoff et al. 2001).

Developments in human genomics or, to be precise, in medical genomics, will have a powerful impact on our understanding of pathogenesis and management of common medical diseases of complex etiology. The recent identification of a number of susceptibility genes for multifactorial diseases is encouraging.

Examples include the identification of NOD2 as a susceptibility gene for Crohn’s disease, an inflammatory bowel disease [IBD] (Hugot et al. 2001 and Ogura et al. 2001). This is a major development in understanding the pathophysiology of IBD. Similar studies are likely to unravel the genetic mechanisms in other complex medical diseases. A comprehensive SNP map will allow the cloning of other susceptibility alleles. However, this will depend upon the population sample size, the method employed, linkage disequilibrium or association studies rather than the technology used (Cardon

These kind of studies and the clinical applications of the resulting outcomes are not without ethical concerns. Some of the questions and concerns are related to ownership of the genes and freedom to use collected DNA for such studies. These are complex and emotional issues, especially when dealing with populations who may have been exploited or perceived to have been exploited. These issues should always be dealt with carefully under the statutory requirements and rules.

30 ◄ November 2018

There has been a tremendous surge in various sub-specialties and technologies with names ending in -omics. We are rapidly moving into the ‘omics’ era.

In addition to genomics, several new specialist fields with an ‘omics’ suffix have recently appeared, for example, pharmacogenomics, nutrigenomics, metabonomics, metabolomics, transcriptomics, proteomics, micribiomics,

Genomics is not just about genome sequencing. Apart from full-length cDNAs and their sequences, copies of mRNAs that encode different proteins are probably equally important. The study of proteins thus derived falls within the broad field of proteomics which encompasses functional genomics. It is likely that eventually proteomics will have more practical applications in clinical medicine. This is rapidly moving ahead with the completion of the Hap-Map project (Nature 2005) and the future ‘functional-variant database’, a natural outcome of the HapMap project (Gibbs 2005).

It is vital that existing gaps in our knowledge about various ‘omics’ disciplines are filled to ensure efficient use of the valuable information emerging from research. It is also important that the gap between ‘genetic professionals’ and the ‘primarycare community, as well as the ‘public health community’, is narrowed (Khoury et al. 2003). Integration of this knowledge in the medical education curriculum and in continued professional education programs is urgently required to ensure applications of genomics in the provision of healthcare.

During the last two decades, the practice of medical genetics or clinical genetics, has found its niche within the broad horizon of clinical medicine (Collins and Guttmacher 2001). Genetic services now constitute a small, but important, component of modern medical practice and public health. Currently, genetic services focus on providing information on chromosomal and singlegene diseases with limited contribution to multifactorial/polygenic diseases. How would this then be different from genomics?

Already there is tremendous enthusiasm for the term, ‘genomic medicine’. In a primer on genomic medicine, Guttmacher and Collins (2002) viewed genetics ‘‘as the study of single genes and their effects’’ and genomics as ‘‘the study not just of single genes, but of the functions Pharma Bio World

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and interactions of all the genes in the genome.’’ In simple terms, there is a quantitative difference between the two fields - the study of multiple genes as opposed to one gene. Few would argue for genetics to be part of genomics. This distinction is not yet fully understood and accepted. However, there is a qualitative dif- ference between genetics and genomics in medical and health applications ranging from the concept of disease in genetics to the concept of information in genomics (Khoury et al.

2003).

The practice of medical genetics has traditionally focused on those conditions that result from specific alterations or mutations in single genes (e.g., inborn errors of metabolism, Duchenne muscular dystrophy and Huntington’s disease), abnormal chromosomal constitution involving whole or part of chromosomes (e.g., trisomy 21 in Down syndrome and multiple malformation syndromes associated with a chromosomal microdeletion or microduplication) and a wide

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range of conditions resulting from genetic and environmental interactions such as single or multiple congenital malformations and developmental disabilities. The existing model of medical genetic services for these conditions includes laboratory diagnosis, genetic counseling and management. This is supported by public health measures to ensure delivery of genetic services and genetic screening (e.g., newborn screening or screening high-risk population groups).

On the other hand, the practice of genomics in medicine and public health will focus on information resulting from variation at one or multiple loci and strong interactions with environmental factors, for example diet, drugs, infectious agents, chemicals, physical agents, and behavioural factors (Khoury et al. 2003).

Many medical and public health applications were expected following the completion of the human genome sequence in 2003. But, the catch is to use the human genome data to tackle the 95% of human diseases that do not fall under the rubric

of genetic disorders. These are some of the likely challenges related to genomic medicine. Medical and public health professionals urgently need to make the changes necessary to accommodate rapid identification and characterization of the numerous genomic variants at multiple loci which increase or decrease the risks for various diseases, singly or in combination with other genes, and with various chemical, physical, infectious, pharmacologic, and social factors (Khoury 1999). This genetic and genomic information is crucial in assessing disease susceptibility among healthy individuals, and in personalized primary and secondary prevention planning. Collins and McKusick (2001) stated that ‘‘It is expected that predictive genetic tests will be available in the future for as many as a dozen common conditions, allowing individuals who wish to know this information to learn their risks for which interventions are or will be available. Such interventions could take the form of medical surveillance, lifestyle modifications, diet, or drug therapy.

Identification of persons at highest risk for colon cancer, for example, could lead to targeted efforts to provide colonoscopic screening to those individuals, with likelihood of preventing many premature deaths.’’

One of the major areas of clinical medicine is pharmacotherapy. It has been argued and largely agreed in principle that individual genetic variation could play a significant role in drug response.

Arno Motulsky put forward the term ‘pharmacogenetics’ in the 1950s which essentially refers to the role of genetic variation influencing the drug response or adverse drug reactions (Motulsky 1957; Weinshilbourm 2003). Several monogenic disorders are now linked to drug response variation or alternatively drug response being dependent upon possessing a specific allele affecting drug metabolism.

Examples include pri- maquine-induced hemolytic anaemia in G6PD deficiency and prolonged muscle relaxation and apnea following administration of succinylcholine during general anesthesia. Variation to drug response was also observed in twin November 2018 ► 31

research deciphering genetic and genomic variation. The potential of personalized medicine is enormous. However, other powerful factors should not be ignored.

Powerful factors that also influence health and wellbeing include personal choice, economic and political constraints, lifestyle, diet, misuse and abuse of toxic substances and alcohol, environmental pollution and the impact of natural climate change. Perhaps more importantly, the potential for misuse of genetic and genomic information and outright discrimination are legitimate concerns (Collins and Watson 2003).

studies comparing the drug response in identical (monozygotic, MZ) and nonidentical (dizygotic, DZ) twins (Vesell and Page 1968). However, despite such a promising and encouraging beginning, the progress in pharmacogenetics has been very slow. This was largely due to technological limitations and difficulties in conducting family studies due to lack of appropriately matched controls.

With the completion of the Human Genome Project, our ability to understand and analyze individual genomic variation has vastly improved with the prospect of massive improvements in the future. This has opened doors to an entirely new approach to drug discovery, drug development and studying drug response based on specific genomic make up. This field is appropriately called pharmacogenomics. In a real sense this promises to be the basis of personalized medicine in the future. Apart from dealing with drug discovery and drug development, similar techniques could also be applied in studying an individual’s response to various environmental agents (ecogenomics) including foreign biological material (xenobiotics) and toxic agents (toxicogenomics). Undoubtedly, this approach would attract attention of public health professionals and health care managers. Several examples of personalized pharmacotherapy are 32 ◄ November 2018

now available. This is good evidence that modern clinical medicine is rapidly adopting and assimilating developments resulting from the Human Genome Project. A notable example includes fatal myelosupression following the administration of thiopurine medications (azathioprine, 6-mercaptopurine and thioguanine) linked to relative differences in the activity of the enzyme thioprine S-methyltransferase (TPMT) which is completely absent in about 1 in 300 white Caucasians and partially deficient activity in about 10% of the same population. This is related to genetic polymorphisms influencing TPMT enzyme activity. A simple assay to measure TPMT enzyme activity will allow the clinician to modify the drug dose in patients with low enzyme activity and thus minimize the risk of the fatal complication of myelosupression.

The TPMT polymorphism is probably an excellent model for translational genomics in guiding the patient therapeutics or in other words supporting the concept of personalized medicine (McLeod and Siva 2002).

The age of personalized medicine has begun. Clinicians will be able to tailor treatment and to understand response to treatment better than ever before (Thrall 2004). The power of personalized medicine lies in understanding and

Personalized medicine will encompass not only common medical diseases, but as well as a broad range of preventable diseases [www.genovations.com]. In future, testing for disease susceptibility using multiple genomic variants will be possible and affordable with the application of ‘high throughput’ genome-based (for example, arraycomparative genome hybridization and array - CGH) genetic testing.

A wealth of information on genomics is rapidly being acquired with the potential for a major impact on human health.

However, these data are scattered through multiple scientific journals, reviews and state-sponsored reports and bulletins. A clinician or health professional often has difficulty in accessing and assimilating this information for application in medical and public health practice. More importantly, an inability to assimilate and interpret leads to frustration and avoidance of potentially useful information.

In view of the above developments and the rapidly increasing gulf in the available literature resource, there is a need for more dedicated journals on genomic medicine. It is anticipated that the articles and original papers being published in such bio-medical journals will facilitate the acquisition of factual information on genomics, developing concepts on the genomic basis of human disease, and in providing a practical basis to enable an interested clinician and health professional to develop an understanding Pharma Bio World

research for clinical pharmacogenomics. Pharmacogenomics 3:89–98 Motulsky AG (1957) Drug reactions, enzymes and biochemical genetics. JAMA 165:835–837 Nature (2005) A haplotype map of the human genome-report from the International HapMap Consortium. Nature 437:1299–1320 Ogura Y et al (2001) A frameshift in NOD2 associated with susceptibility to Crohn’s disease. Nature 411:603–606 Stephens C et al (2001) Haplotype variation and linkage disequilib- rium in 313 human genes. Science 293:489–493 Thrall JH (2004) Personalized medicine.

Radiology 231:613–616

of applications of genomics in clinical medicine and health. The purpose of these journals is to provide a suitable platform and resource to a wide-range of genetic scientists, genetic clinicians, clinicians in both primary and specialist practice and a broad range of health professionals. The success of these journals will be judged by the quality of the published material covering a broad remit in applied or translational genomics research in clinical diagnosis, therapeutics and teaching and training in medicine and health.

Finally, the practice of medicine is an art based on sound scientific principles.

It would be appropriate to quote Sir William Osler’s remarks, ‘‘If there were no individual variability, medicine would have been science not an art.’’ Genomics in this context provides the basis of individual variability and the modern genomic era clinician will need to ensure that this is applied as an art.

References Cardon LR, Bell JI (2001) Association study designs for complex diseases. Nat RevGenet 2:91–99 Chakravati A (2000) To a future of genetic medicine. Nature409:822–823 Collins FS, Guttmacher AE (2001) Genetics moves into medical mainstream. JAMA 286:2322–2324 Collins FS, McKusick VA (2001) Implications Pharma Bio World

of the Human Genome Project for medical science. JAMA 285:540–544 Collins FS, Watson JD (2003) Genetic discrimination: time to act.Science 302:745– 746

Tishkoff SA et al (2001) Haplotype diversity and linkage disequilib- rium at the human G6PDH: recent origin of alleles that confer malarial resistance. Science 293:455–461 Venter JC et al (2001) The sequence of the human genome. Science 291:1304–1351

Genovations - the advent of truly personalized healthcare. http:// www genovations.com

Vesell ES, Page JG (1968) Genetic control of drug level in man: phenylbutazone. Science 159:1479–1480

Gibbs R (2005) Deeper into the genome.

Nature 437:1233–1234

Watson JD, Crick FHC (1953) Molecular structure of nucleic acids. Nature 171:737–738

Guttmacher AE, Collins FS (2002) Genomic medicine: a primer. N Engl J Med 347:1512– 1520

Weinshilbourm R (2003) Inheritance and drug response. N Engl J Med 348:529–537

Holden AL (2000) The SNP consortium: a case study in large pharmaceutical company research and development collabora- tion. J Com Biotech 6:320–324

World Health Organization (2002) Genomics and World Health-report from the Advisory Committee on health research. WHO, Geneva

Hugot JP et al (2001) Association of NOD2 leucine-rich variants with susceptibility to Crohn’s disease. Nature 411:599–603 Khoury MJ (1999) Human genome epidemiology: translating advances in human genetics into population-based data for medicine and public health. Genet Med 1:71–73 Khoury MJ, NcCabe LL, McCabe ER (2003) Population screening in the age of genomic medicine. N Engl J Med 348:50–58 Lander ES et al (2001) Initial sequencing and analysis of the human genome. International human genome sequencing consortium.

Nature 409:860–921 McLeod HL, Siva C (2002) The thrioprine S-methyltransferase gene locus: implications

(Dhavendra Kumar Institute of Medical Genetics, University Hospital of Wales, Cardiff University, UK) November 2018 ► 33

research

Polymers In Pharmaceutical Drug Delivery System: A Review The current review article focuses on polymers in pharmaceutical drug delivery of therapeutic agents. These dosage forms include tablets, patches, tapes, films, semisolids and powders.

Polymers are the backbone of a pharmaceutical drug delivery system as they control the release of the drug from the device. Biodegradable polymers attracts the attention of its use as they can be degraded to non-toxic monomers and most important, a constant rate of drug release can be achieved from a biodegradable polymer based controlled release device.

Natural polymers can be used as the means of achieving predetermined rates of drug delivery and their physico-chemical characteristics with the ease of availability provide a platform to use it as a polymer for drug delivery systems. Biodegradable polymers have been widely used in biomedical applications because of their known biocompatibility and biodegradability. In the biomedical area, polymers are generally used as implants and are expected to perform long term service. These improvements contribute to make medical treatment more efficient and to minimises side effects and other types of inconvenience to patients. The main role of polymer is to protect the drug from physiological environment and prolong the release of drug to improve its stability. The drug is released from polymer by diffusion, degradation and swelling. This review also presents characteristics and behaviours of plant derived and mucoadhesive polymers which are currently used in drug delivery.

O

ver the past decades research at the level of molecular biology has unveiled the molecular basis for many diseases. New important technologies and concepts such as recombinant DNA and gene therapy have provided tools for the creation of pharmaceuticals and methods designed to specifically address such diseases.

However progress towards the application of these medicines outside of the laboratory has been considerably slow principally due to the lack of effective drug delivery systems that is mechanisms that allow the release of the drug into the appropriate body compartment for the appropriate amount of time without seriously disrupting the rest of the organism functionality. The application of 34 â—„ November 2018

the polymeric materials for medical purposes is growing fast. Polymers have found applications in diverse biomedical fields such as drug delivering systems, developing scaffolds in tissue engineering, implantation of medical devices and artificial organs, prosthesis, ophthalmology, dentistry, bone repair, and many other medical fields. 1 Polymers have been used as a main tool to control the drug release rate from the formulations.

Extensive applications of polymers in drug delivery have been realized because polymers offer unique properties which have not been attained by any other materials. Advances in polymer science have led to the development of several novel drug delivery systems.

A proper consideration of surface and

bulk properties can aid in the designing of polymers for various drug delivery applications. 2 These newer technological development include drug modification by chemical means, carrier based drug delivery and drug entrapment in polymeric matrices or within pumps that are placed in desired compartments. These technical developments in drug delivery/targeting approaches improve the efficacy of drug therapy thereby improve human health. 3 Polymer chemists, chemical engineers and pharmaceutical scientists are engaged in bringing out design predictable, controlled delivery of bioactive agents. 4 Extensive biodegradable polymers have been widely used in biomedical applications because of their known biocompatibility and biodegradability.

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research In the biomedical area polymers are generally used as implants and are expected to perform long term service.

These improvements contribute to make medical treatment more efficient and to minimize side effects and other types of inconveniences for patients .5 The pharmaceutical applications of polymers range from their use as binders in tablets to viscosity and flow controlling agents in liquids, suspensions and emulsions. Polymers can be used as film coatings to disguise/mask the unpleasant taste of a drug, to enhance drug stability and to modify drug release characteristics. Pharmaceutical polymers are widely used to achieve taste masking; controlled release (e.g. extended, pulsatile and targeted), enhanced stability and improved bioavailability. Monolithic delivery devices are systems in which a drug is dispersed within a polymer matrix and released by diffusion. The rate of the drug release from a matrix product depends on the initial drug concentration and relaxation of the polymer chains which overall displays a sustained release characteristic. 6, 7 Simple manipulation of the water solubility of polymers, by increasing their chain length through cross-linking or by hydrophobising or hydrophilizing them with copolymers and other groups yields a wealth of materials with a wide spectrum of possible application.

The resulting materials are capable of a variety of drug-enhancing functions. 8 Polymers are able to: • Prolong drug availability if medicines are formulated as hydrogels 9 or microparticles. 10 • Favourably alter bio distribution, if formulated into dense nanoparticles.

• Enable hydrophobic drug administration if formulated as micelles.

•

Transport a drug to its usually inaccessible site of action if formulated as gene medicines.

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• Make drugs available in response to stimuli.

History The use of polymers in the medical field is not a novelty, natural polymers have been used as components of herbal remedies for centuries. When it comes to synthetic polymers, however the situation is very different. Because polymer science is a relatively recent area of research, synthetic watersoluble polymers as macromolecular drugs or as part of drug delivery systems related to inoculation can be considered a modern achievement. The first polymer drug conjugates appeared around 1955, being mescaline-N-vinylpyrolidine conjugate one of the first.

About ten years later Frank Davis and Abraham Abuchowski were able to foresee the potential of conjugating poly(ethylene glycol) (PEG) to proteins causing the birth of a technique called PEGylation.

PEGylation consists in the covalent bond of poly(ethylene glycol) polymer chains to another molecule usually a drug or a protein with therapeutic effects.

In 1994, the first synthetic polymerdrug conjugate (as shown in figure 1b) designed to treat cancer was clinically tested. It consisted on an HPMA (N-(2-hydroxypropyl) methacrylamide) copolymer conjugate of doxorubicin.

Targeted release of anticancer agents can also be made using block copolymer micelles which have the ability to entrap the drug or to covalently link to it.

In the 2000s, two polymer-protein conjugates,(as shown in figure 1a) PEGinterferonα (an antiviral drug intended to treat chronic hepatitis C and hepatitis B) and PEGGCSF (PEG granulocyte colonystimulating factor) were placed in the market and five years later the first therapeutic nanoparticles (albuminentrapped paclitaxel) was approved as a treatment for metastatic breast cancer. All the above achievements and researches were the core element that

led to the development of polymer based pharmaceuticals namely polymeric drugs, polymer drug conjugates and polymerprotein conjugates. The clinical trials of these new technologies eventually lead to the resolution of many other unexpected challenges that quickly appeared, such as the manufacturing of the polymers at an industrial scale and the quick and total solubilization of the pharmaceuticals for safe inoculation. The optimization of these clinical tests (in terms of dosage and frequency) is still being evaluated today for a large variety of products. 11

Figure 1: The families of polymer constructs called polymer therapeutics.

Role Of Polymer In Pharmaceutical Drug Delivery8 • Immediate release dosage forms Tablets Polymers have been used for many years as excipients in conventional immediate-release oral dosage forms, either to aid in the manufacturing process or to protect the drug from degradation upon storage. Microcrystalline cellulose is often used as an alternative to carbohydrates as diluents in tablet formulations of highly potent low-dose drugs. Starch and cellulose are used as disintegrants in tablet formulations, which swell on contact with water, resulting in the tablet “bursting,” increasing the exposed surface area of the drug and improving the dissolution characteristics of a formulation.

Polymers including polyvinyl-pyrrolidone and hydroxypropyl methylcellulose (HPMC) also find uses as binders that aid the formation of granules that improve the flow and compaction properties of tablet formulations prior to November 2018 ► 35

research tableting. Occasionally, dosage forms must be coated with a ‘non-functional’ polymeric film coating in order to protect a drug from degradation, mask the taste of an unpalatable drug or excipients, or improve the visual elegance of the formulation without affecting the drug release rate. 12 Capsules Capsules are used as an alternative to tablets, for poorly compressible materials, to mask the bitter taste of certain drugs, or sometimes to increase bioavailability. Many of the polymeric excipients used to ‘bulk out’ capsule fills are the same as those used in immediate-release tablets. Gelatine has been used almost exclusively as a shell material for hard (two-piece) and soft (one-piece) capsules. HPMC has recently been developed and accepted as an alternative material for the manufacture of hard (two-piece) capsules.

• Modified-release dosage forms It is now generally accepted that for many therapeutic agents, drug delivery using immediate release dosage forms results in suboptimal therapy and/or systemic side effects. Pharmaceutical scientists have attempted to overcome the limitations of conventional oral dosage forms by developing modified release dosage forms.

• Extended release dosage forms The therapeutic effect of drugs that have a short biological halflife may be enhanced by formulating them as extended or sustained release dosage forms.

Extended and sustained release dosage forms prolong the time that systemic drug levels are within the therapeutic range and thus reduce the number of doses the a patient must take to maintain therapeutic effect thereby increasing compliance. The most commonly used water-insoluble polymers for extendedrelease applications are the ammonium ethacrylate copolymers (Eudragit RS and RL), cellulose derivatives ethylcellulose, 36 ◄ November 2018

cellulose acetate, and polyvinyl derivative, polyvinyl acetate. Eudragit RS and RL differ in the proportion of quaternary ammonium groups, rendering Eudragit RS less permeable to water, whereas ethylcellulose is available in a number of different grades of different viscosity, with higher-viscosity grades forming stronger and more durable films.

• Gastroretentive Dosage Forms Gastroretentive dosage forms offer an alternative strategy for achieving extended release profile, in which the formulation will remain in the stomach for prolonged periods, releasing the drug in situ, which will then dissolve in the liquid contents and slowly pass into the small intestine. Unlike a conventional extended release dosage form, which gradually releases the drug during transit along the gastrointestinal tract, such a delivery system would overcome the problems of drugs that are absorbed preferentially from specific sites within the gastrointestinal tract (for example, many drugs are absorbed poorly from the distal gut, where an extended-release dosage form may spend the majority of its time), producing nonuniform plasma time profile delivery systems do not relay on polymers present, to achieve gastroretention mucoadhesive 13-17 and low-density 18,19 polymers have been evaluated, with little success so far, for their ability to extend gastric residence time by bonding to the mucus lining of the stomach and floating on top of the gastric contents respectively.

Types Of Polymer Drug Delivery System8 Polymers for Drug Delivery in Tissue Engineering Several strategies have been developed in order to regenerate functional tissue, the majority of which involve the use of polymer scaffolds specifically designed to direct tissue growth. The cell transplantation method is one of the most commonly used in cartilage and bone formation. 20 Polymer matrices both

natural and synthetic can play a vital role in the delivery of protein growth factors and cytokines to aid angiogenesis and tissue reconstruction procedures. These molecules are essential to tissue growth as they control a number of vital cellular processes including proliferation and differentiation. It has been shown that by careful selection of the polymer and the processing method, controlled-release matrices, incorporating proteins and growth factors that induce and enhance tissue growth can be produced. The future use of gene therapy as a way of regenerating tissue is an exciting area, and despite still being in its infancy, it may yet provide a solution to the challenge of delivering drugs and proteins more effectively in all areas of medicine.

Poly (lactic-co-glycolic acid) Microspheres The term microsphere refers to a small sphere with a porous inner matrix and variable surface from smooth and porous to irregular and nonporous. The drug when encapsulated is dispersed throughout the inner matrix. The size range of microspheres is typically 1 to 500 µm in diameter. Poly (lacticco-glycolic acid) microspheres have increasingly become the focus of research efforts in the scientific community and pharmaceutical industry. Their application as drug delivery vehicles has risen in line with the expanding biotechnology sector and the promise of new drugs discovered in the wake of the human genome project and proteomics.

Polymeric Nanoparticles as Drug Carriers Certain chemical entities are either rapidly degraded and/or metabolized after administration (peptides, proteins, and nucleic acids). This is the reason the idea that nanotechnologies may be employed to modify or even to control the drug distribution at the tissue, cellular, or sub cellular levels has emerged. Among the technologies utilized for drug targeting are polymer-based nanoparticles, which have been developed since the early 1980s, when progress in polymer chemistry Pharma Bio World

research allowed the design of biodegradable and biocompatible materials. Nanoparticles may be defined as being submicron (<1 µm) colloidal systems generally composed of polymers. Thus, nanoparticles are colloidal systems with a size 7 to 70 times smaller than the red cells. They may be administered intravenously without any risk of embolization. Depending on the method used in the preparation of nanoparticles, either nanospheres or nanocapsules can be obtained. Nanospheres are matrix systems in which the drug is dispersed within the polymer throughout the particle.

On the contrary, nanocapsules are vesicular systems, which are formed by a drug-containing liquid core (aqueous or lipophilic) surrounded by a single polymeric membrane.

Polymeric Micelles as Pharmaceutical Carriers Polymeric micelles demonstrate many attractive properties as pharmaceutical carriers. They are stable both in vitro and in vivo, can be loaded with a wide variety of poorly soluble pharmaceutical agents, effectively accumulate in pathological body areas with compromised vasculature (infarcts, tumors), and can be targeted by attaching various specific ligands to their surface.

Both therapeutic and diagnostic micelles can be easily produced in substantial quantities. It appears that micellar carriers have a promising future.

Polymeric Vesicles Polymeric vesicles may be fabricated from a variety of macromolecular amphiphile architectures, which include: block copolymers, random graft copolymers, and polymers bearing hydrophobic lowmolecular-weight pendant or terminal groups. These tough particles, which reside in the nanometre and micrometer size domains, may be used for drug targeting, the preparation of responsive release systems, and other drug delivery applications.

Polymer Drug Conjugates Current research in the field of polymer anticancer drug conjugates is directed Pharma Bio World

towards the identification of the mechanism of action of free and polymer-bound drugs at the cellular and subcellular levels.

Newer applications for polymer–drug conjugates are also being explored 21.

Inflammatory diseases are characterized by an increase in the vascular permeability (similar to tumors).

Though there may be lesser amounts of retention as the lymphatics are not blocked, there may be a therapeutic advantage offered by the conjugation of drugs to polymer backbones. These represent new and exciting avenues of research for polymeric drug delivery scientists.

Polymers Used for the Delivery of Genes in Gene Therapy A number of polymers by virtue of possessing a cationic charge at physiological pH have been found to be suitable candidates for the transfer of genes across the various biological barriers outlined in the preceding text. An ideal gene delivery system has to be able to shuttle the gene safely to the nuclei of its target tissue with the travelling gene having limited encounters with degradative influences.

Polymers In Pharmaceutical Applications 22 24 Water-Soluble Synthetic Polymers • Poly (acrylic acid) Cosmetic, pharmaceuticals, immobilization of cationic drugs, base for Carbopol polymers.

• Poly (ethylene oxide) Coagulant, flocculent, very high molecular-weight up to a few millions, swelling agent.

• Poly (ethylene glycol) - Mw <10,000; liquid (Mw <1000) and wax (Mw >1000), plasticizer, base for suppositories.

• Poly (vinyl pyrrolidone) - Used to make betadine (iodine complex of PVP) with less toxicity than iodine, plasma replacement, tablet granulation.

• Poly (vinyl alcohol) - Water-soluble packaging, tablet binder, tablet coating.

Cellulose-Based Polymers • Ethyl cellulose - Insoluble but dispersible in water, aqueous coating system for sustained release applications.

• Carboxymethyl cellulose - Super disintegrant, emulsion stabilizer. and hydroxypropyl • Hydroxyethyl celluloses - Soluble in water and in alcohol for tablet coating.

• Hydroxypropyl methyl cellulose - Binder for tablet matrix and tablet coating, gelatin alternative as capsule material.

• Cellulose acetate phthalate - Enteric coating.

Hydrocolloids • Alginic acid - Oral and topical pharmaceutical products; thickening and suspending agent in a variety of pastes, creams, and gels, as well as a stabilizing agent for oil-in-water emulsions; binder and disintegrants.

• Carrageenan - Modified release, viscosifier.

• Chitosan - Cosmetics and controlled drug delivery applications, mucoadhesive dosage forms, rapid release dosage forms.

Water-Insoluble Biodegradable Polymers • (Lactide-co-glycolide) polymers Microparticle–nanoparticle for protein delivery.

Starch-Based Polymers • Starch Glidant - a diluent in tablets and capsules, a disintegrant in tablets and capsules, a tablet binder.

• Sodium starch glycolate super disintegrant for tablets and capsules in oral delivery.

Plastics and Rubbers • Polyurethane - Transdermal patch backing, blood pump, artificial heart, and vascular grafts, foam in biomedical and industrial products.

• Polyisobutylene - Pressure sensitive adhesives for transdermal delivery.

• Polycyanoacrylate - Biodegradable tissue adhesives in surgery, a drug carrier in nano and microparticles.

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research • Poly (vinyl acetate) - Binder for chewing gum.

• Poly (vinyl chloride) - Blood bag, and tubing.

• Polyethylene - Transdermal patch backing for drug in adhesive design, wrap, packaging, containers.

• Poly (methyl methacrylate) - Hard contact lenses.

• Poly (hydroxyethyl methacrylate) Soft contact lenses Classification of Polymers

• It should be compatible with biological environment.

• It should be biodegradable.

• It should provide good drug polymer linkage.

the aqueous solvent content within the formulation as well as the polymer mesh size, enabling the drug to diffuse through the swollen network into the external environment. 27

General mechanism of drug release from polymers There are three primary mechanisms by which active agents can be released from a delivery system namely:

Polymers In Pharmaceutical Drug Delivery System

Based on interaction with water • Non-biodegradable hydrophobic Polymers:- E.g.Polyvinyl chloride, • Soluble Polymers:- E.g. HPMC, PEG • Hydro gels:- E.g. Polyvinyl pyrrolidine

Diffusion Diffusion occurs when a drug or other active agent passes through the polymer that forms the controlled-release device.

Diffusion occurs when the drug passes from the polymer matrix into the external environment. As the release continues its rate normally decreases with this type of system since the active agent has a progressively longer distance to travel and therefore requires a longer diffusion time to release. In these systems, the combinations of polymer matrices and bioactive agents chosen must allow for the drug to diffuse through the pores or macromolecular structure of the polymer upon introduction of the delivery system into the biological environment without inducing any change in the polymer itself.25

Based on polymerisation method • Addition Polymers:- E.g. Alkane Polymers • Condensation polymers:-E.g. Polysterene and Polyamide Based on polymerization mechanism • Chain Polymerization • Step growth Polymerization Based on chemical structure • Activated C-C Polymer • Inorganic polymers • Natural polymers Based on occurrence • Natural polymers:- E.g. 1. Proteinscollagen, keratin, albumin, cellulose • Synthetic polymers:- E.g. Polyesters, polyamides Based on bio-stability • Bio-degradable • Non Bio-degradable Characteristics of an ideal polymer • It should be versatile and possess a wide range of mechanical, physical, chemical properties.

• It should be non-toxic and have good mechanical strength and should be easily administered.

• It should be inexpensive and easy to fabricate.

• It should be inert to host tissue and compatible with environment.

Criteria followed in polymer selection • The polymer should be soluble and easy to synthesise.

• It should have finite molecular weight.

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Degradation Biodegradable polymer degrades within the body as a result of natural biological processes, eliminating the need to remove a drug delivery system after release of the active agent has been completed. Most biodegradable polymers are designed to degrade as a result of hydrolysis of the polymer chains into biologically acceptable and progressively smaller compounds. 26 For some degradable polymers, most notably the polyanhydrides and polyorthoesters, the degradation occurs only at the surface of the polymer, resulting in a release rate that is proportional to the surface area of the drug delivery system Swelling They are initially dry and when placed in the body will absorb water or other body fluids and swell. The swelling increases

Rosin Rosin, a film-forming biopolymer and its derivatives have been extensively evaluated pharmaceutically as filmcoating and microencapsulating materials to achieve sustained drug release. They are also used in cosmetics, chewing gums, and dental varnishes. Rosin has been used to prepared spherical microcapsules by a method based on phase separation by solvent evaporation. Rosin combination with polyvinyl pyrrolidone and dibutyl phthalate (30 % w/w) produces smooth film with improved elongation and tensile strength. 28-30 Chitin and Chitosan Chitin, a naturally abundant muco polysaccharide and consist of 2-acetamido-2- deoxy-b-D-glucose. Chitin can be degraded by chitinase. Chitosan is a linear polysaccharide composed of randomly distributed β-(1-4)-linked D-glucosamine (deacetylated unit) and N-acetyl D glucosamine (acetylated unit).

The most important property of chitosan with regards to drug delivery is its positive charge under acidic conditions. This positive charge comes from protonation of its free amino groups. Lack of a positive charge means chitosan is insoluble in neutral and basic environments. 27 Zein Zein, an alcohol-soluble protein contained in the endosperm tissue of Zeamais, occurs as a by-product of corn processing.

Zein has been employed as an edible coating for foods and pharmaceuticals for decades. Zein is an inexpensive and most effective substitute for the fast disintegrating synthetic and semi synthetic film coatings currently used for the formulation of substrates that allow extrusion coating. 31 Pharma Bio World

research Collagen Collagen is the most widely found protein in mammals and is the major provider of strength to tissue. It has not only been explored for use in various types of surgery, cosmetics and drug delivery, but in bioprosthetic implants and tissue engineering of multiple organs.

Starches It is the principal form of carbohydrate reserve in green plants and especially present in seeds and underground organs. Starch occurs in the form of granules (starch grains), the shape and size of which are characteristic of the species, as is also the ratio of the content of the principal constituents, amylose and amylopectin. A number of starches are recognized for pharmaceutical use. These include maize (Zea mays), rice (Oryza sativa), wheat (Triticum aestivum), and potato (olanum tuberosum). To deliver proteins or peptidic drugs orally, microcapsules containing a protein and a proteinase inhibitor were prepared.

Starch/bovine serum albumin mixed-walled microcapsules were prepared using interfacial cross-linking with terephthaloyl chloride. The microcapsules were loaded with native or aminoprotected aprotinin by incorporating protease inhibitors nin the aqueous phase during the cross-linking process. The protective effect of microcapsules with aprotinin for bovine serum albumin was revealed in vitro.

Polycaprolactone Polycaprolactone (PCL) is biodegradable polyester with a low melting point of around 60°C and a glass transition temperature of about −60°C. PCL is prepared by ring opening polymerization of ε-caprolactone using a catalyst such as stannous octanoate. The most common use of polycaprolactone is in the manufacture of speciality polyurethanes. Polycaprolactones impart good water, oil, solvent and chlorine resistance to the polyurethane produced.

Polyorthoesters These materials have gone through several generations of synthetic improvements to yield materials that can be polymerized at room temperature without production of condensation by-products. These materials are hydrophobic with hydrolytic linkages that are acidsensitive, but stable to base. They Pharma Bio World

degrade by surface erosion and degradation rates may be controlled by incorporation of acidic or basic excipients.

Polymeric Plant-Derived Excipients In Drug Delivery System32 Polymers have been successfully employed in the formulation of solid, liquid and semisolid dosage forms and are specifically useful in the design of modified release drug delivery systems. Both synthetic and natural polymers have been investigated extensively for this purpose but the use of natural polymers for pharmaceutical applications is attractive because they are economical, readily available, non-toxic, capable of chemical modifications, potentially biodegradable and with few exceptions also biocompatible.

Cellulose The polysaccharides of the plant cell wall consist mainly of cellulose, hemicelluloses and pectin used in pharmaceutical applications such as filler in tablets, it is microcrystalline cellulose that represents a novel and more useful cellulose powder.33 Microcrystalline cellulose is mainly used in the pharmaceutical industry as a diluent/binder in tablets for both the granulation and direct compression processes.32 Microcrystalline cellulose is partially depolymerised cellulose prepared by treating high quality cellulose with hydrochloric acid to produce free flowing non-fibrous particles. It was further found that the hydroxypropylmethyl cellulose matrix systems have a stronger gel structure than those made of polyethylene oxide, which may provide superior in vivo performance in terms of matrix resistance to the destructive forces within the gastrointestinal tract.34

Figure 2: Chemical structure of a) powdered cellulose (n ≈ 500) or microcrystalline Cellulose (n ≈ 220) and b) hydroxyl propyl methyl cellulose.

Pectin Pectin is a family of complex polysaccharides present in the walls that surround growing and dividing plant cells.

It is also present in the junctional zone between cells within secondary cell walls including xylem and fiber cells in woody tissue. 35, 36 Pectin has been investigated as an excipient in many different types of dosage forms such as film coating of colon-specific drug delivery systems when mixed with ethyl cellulose, microparticulate delivery systems for ophthalmic preparations and matrix type transdermal patches. The composition of pectin can vary based on the botanical source, for example pectin from citrus contains less neutral sugars and has a smaller molecular size compared to pectin obtained from apples. 37-39

Figure 3: Chemical structure of pectin.

Inulin Inulin is resistant to digestion in the upper gastrointestinal tract, but is degraded by colonic microflora. Inulin with a high degree of polymerisation was used to prepare biodegradable colon-specific films in combination with Eudragit® RS that could withstand break down by the gastric and intestinal fluids. It was shown in another study where different Eudragits® were formulated into films with inulin that when a combination of Eudragit® RS and Eudragit® RL was mixed with inulin it exhibited better swelling and permeation properties in colonic medium rather than other gastrointestinal media. 40, 41 November 2018 ► 39

research beads. The carrageenan parts of the hydrogel pronouncedly enhanced the thermostability of the polymeric network.

These beads were introduced as novel carriers for controlled drug delivery systems. 46

Figure 4: Chemical structure of inulin.

Alginates Alginates have been used and investigated as stabilizers in emulsions, suspending agents, tablet binders and tablet disintegrants. 42 The gelling properties of alginate’s guluronic residues with polyvalent ions such as calcium or aluminium allow cross-linking with subsequent formation of gels that can be employed to prepare matrices, films, beads, pellets, microparticles and nanoparticles. 43, 44

Figure 5: Chemical structure of alginates Carrageenans Carrageenans is the generic name for a family of high molecular weight sulphated polysaccharides obtained from certain species of red seaweeds belonging to the class Rhodophyceae, especially Chondrus crispus, Euchema spp, Gigartina stellata and Iridaea spp. Carrageenan extracted from seaweed is not assimilated by the human body and provides only bulk but no nutrition. There are three basic types of carrageenan: kappa (κ), iota (ι) and lambda (λ). The λ-type carrageenan results in viscous solutions but is nongelling, while the κ-type carrageenan forms a brittle gel. The ι-type carrageenan produces elastic gels. 45 Hydrogel beads were prepared from a mixture of crosslinked κ-carrageenan with potassium and cross-linked alginate with calcium and they exhibited a smoother surface morphology thanthat of the one-polysaccharide network 40 ◄ November 2018

Figure 6: Chemical structure of a) λ-carrageenan, b) ι-carrageenan and c) κ-carrageenan Guar gum Guar gum has recently been highlighted as an inexpensive and flexible carrier for oral extended release drug delivery. 47 Guar gum is particularly useful for colon delivery because it can be degraded by specific enzymes in this region of the gastrointestinal tract. It is also used as thickener for lotions and creams, as a tablet binder and as an emulsion stabilizer. 48

Figure 7: Chemical structure of guar gum.

Novel Mucoadhesive Polymers 49 Bioadhesion can be defined as a phenomenon of interfacial molecular attractive forces amongst the surfaces of the biological substrate and the natural or synthetic polymers, which allows the polymer to adhere to the biological surface for an extended period of time. 50 The

focus of pharmaceutical research is being steadily shifted from the development of new chemical entities to the development of novel drug delivery systems (NDDS) of existing drug molecules to maximize their effectiveness in terms of therapeutic action and patent protection. The development of NDDS has been made possible by the various compatible polymers to modify the release pattern of drug. The use of acrylate polymers for the development of mucoadhesive formulations have increased manifold, various authors have investigated the mucoadhesive properties of different polymers with varying molecular architecture. 51 The use of a mucoadhesive polymer that attach to related tissue or to the surface coating of the tissue for targeting various absorptive mucosa such as ocular, nasal, pulmonary, buccal, vaginal ,etc. This system of drug delivery is called as mucoadhesive drug delivery system. The various mucoadhesive polymers used for the development of buccal delivery systems include cyanoacrylates, polyacrylic acid, sodium carboxymethylcellulose, hyaluronic acid, hydroxypropylcellulose, polycarbophil, chitosan and gellan. 52, 53 Lectins Lectins are proteins which have the ability to reversibly bind with specific sugar / carbohydrate residues and are found in both animal and plant kingdom in addition to various microorganisms. 54-56 Lectins extracted from legumes have been widely explored for targeted delivery systems. The various lectins which have shown specific binding to the mucosa include lectins extracted from Ulex europaeus I, soybean, peanut and Lens culinarius. 57 The use of wheat germ agglutinin has been on the rise due to its least immunogenic reactions, amongst available lectins, in addition to its capability to bind to the intestinal and alveolar epithelium and hence could be used to design oral and aerosol delivery systems. 58 Pharma Bio World

research Thiolated polymers These are the special class of multifunctional polymers called thiomers which are modified existing polymers by the addition of thiol group. These are hydrophilic macromolecules exhibiting free thiol groups on the polymeric backbone. Thiomers are capable of forming intra and interchain disulphide bonds within the polymeric network leading to strongly improved cohesive properties and stability of drug delivery systems such as matrix tablets. Due to the formation of strong covalent bonds with mucus glycoproteins, thiomers show the strongest mucoadhesive properties of all so far tested polymeric excipients via thioldisulphide exchange reaction and an oxidation process. Various thiolated polymers include chitosan–iminothiolane, poly(acrylic acid)–cysteine, poly(acrylic acid)–homocysteine, chitosan–thioglycolic acid, chitosan–thioethylamidine, alginate cysteine, poly(methacrylic acid)–cysteine and sodium carboxymethylcellulose– cysteine. 59 Poloxomer Poloxomer gels have been investigated as they are reported to show phase transitions from liquids to mucoadhesive gels at body temperature and will therefore allow insitu gelation at the site of interest.

Mechanisms Of Mucoadhesion 60 The mucoadhesive must spread over the substrate to initiate close contact and increase surface contact, promoting the diffusion of its chains within the mucus . Attraction and repulsion forces arise and, for a mucoadhesive to be successful, the attraction forces must dominate. The mechanism of mucoadhesion is generally divided in two steps, the contact stage and the consolidation stage (shown in figure 8) Future Trends Despite the excessive use of synthetic polymers the need for natural biodegradable polymers to deliver drugs continues to be an area of active research. Natural polymer has numerous Pharma Bio World

Figure 8: The two steps of the mucoadhesion process advantages over synthetic ones as being readily available, relatively inexpensive, natural products of living organisms and possibilities of chemical modifications. The most exciting opportunities in polymer drug delivery lie in the arena of responsive delivery systems, with which it will be possible to deliver in response to a measured blood level or to deliver a drug precisely to a targeted site. Much of the development of novel materials in controlled drug delivery is focusing on the preparation and use of these responsive polymers with specifically designed macroscopic and microscopic structural and chemical features.

Such systems include: • Copolymers with desirable hydrophilic/ hydrophobic interactions.

• Complexation networks responding via hydrogen or ionic bonding.

• Polymers as nanoparticles for immobilization of enzymes, drugs, peptides, or other biological agents.

• New biodegradable polymers.

• New blends of hydrocolloids and carbohydrate based polymers.

Design and synthesis of novel combinations of polymers will expand the scope of new drug delivery systems in the future. This will obviously require assimilation of a great deal of emerging information about the chemical nature and physical structure of these new materials.

There is an increasing movement of scientists and engineers who are dedicated to minimizing the environmental impact of polymer composite production.

Life cycle assessment is of paramount importance at every stage of a product’s life, from initial synthesis through to final disposal as a sustainable society needs environmentally safe materials and processing methods. 61, 62 Conclusion Polymer-based pharmaceuticals are starting to be seen as key elements to treat many lethal diseases that affect a great number of individuals such as cancer or hepatitis. Although excipients have traditionally been included in formulations as inert substances to mainly make up volume and assist in the manufacturing process, they are increasingly included in dosage forms to fulfil specialized functions for improved drug delivery because many new drugs have unfavourable physicochemical and pharmacokinetic properties. The synthetic polymers can be designed or modified as per requirement of the formulation by altering polymer characteristics and on the other hand natural pharmaceutical excipients are biocompatible, non toxic, environment friendly and economical. Several polymers have been successfully used and others are being investigated as excipients in the design of dosage forms for effective drug delivery.

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40. Vervoort, L.; Van den Mooter, G.; Augustijns, P.; Kinget, R. Inulin hydrogels. I. Dynamic and equilibrium swelling properties. Int. J. Pharm. 172, 1998, 127-135.

50. Smart J D, Kellaway I W and Worthington H E C. An in vitro investigation of mucosa adhesive materials for use in controlled drug delivery. J. Pharm.

Pharmacol., 36, 1984, pp. 295-299.

41. Sudhakar, Y.; Kuotsu, K.; Bandyopadhyay, A.K. Buccal bioadhesive drug delivery – A promising option for orally less efficient drugs. J. Control. Release 114, 2006, 15-40.

51. 51. Andrew G P, Laverty T P and Jones D S. Mucoadhesive polymers for controlled drug delivery. European Journal of Pharmaceutics and Biopharmaceutics, 71 (3), 2009, 505-518.

42. Sarmento, B.; Ribeiro, A.; Veiga, F.; Sampaio, P.; Neufeld, R.; Ferreira, D. Alginate/Chitosan nanoparticles are effective for oral insulin delivery.

Pharm. Res. 24,2007, 2198-2206.

52. Remuñán-López C, Portero A, VilaJato J L, Alonso M J., Design and evaluation of chitosan/ethylcellulose mucoadhesive bilayered devices for buccal drug delivery. Journal of Controlled Release. 55 (2-3), 1998, pp.

143-152.

43. Ching, A.L.; Liew, C.V.; Heng, P.W.S.; Chan, L.W. Impact of cross-linker on alginate matrix integrity and drug release. Int. J. Pharm. 355, 2008, 259-268.

44. Nerurkar, J.; Jun, H.W.; Price, J.C.; Park, M.O. Controlled release matrix tablets of ibuprofen using cellulose ethers and carrageenans: effect of formulation factors on dissolution rates. Eur. J. Pharm. Biopharm. 61, 2005, 56-68.

45. Mohamadnia, Z.; Zohuriaan-Mehr, M.J.; Kabiri, K.; Jamshidi, A.; Mobedi, H. Ionically cross-linked carrageenanalginate hydrogel beads. J. Biomater.

Sci. Polymer Edn. 19, 2008, 47-59.

Pharma Bio World

56. Hietanen J and Salo O P. Binding of four lectins to normal human oral mucosa.

European Journal of Oral Sciences, 92 (5), 2007, pp. 443 – 447.

60. Raj Kumar Poddar, Pankaj Rakha, SK Singh and DN Mishra, Bioadhesive Polymers as a Platform for Drug Delivery: Possibilities and Future Trends, Research J on Pharmaceutical Dosage Form and Technology, 2,1, 2010,40-54.

61. Ebihara., Controlled release formulations to increase the bioadhesive properties, Drug Res, 33,1983, 163.

53. Lehr C M., Lectin-mediated drug delivery: the second generation of bioadhesives. J. Control. Release, 65, 2000, pp. 19– 29.

54. Haltner E, Easson J H and Lehr C M. Lectins and bacterial invasion factors for controlling endo and transcytosis of bioadhesive drug carrier system.

Euro. J. Pharm. Biopharm, 44, 1997, pp. 3-13.

55. Smart J D., Lectin-mediated drug delivery in the oral cavity. Advanced Drug Delivery Reviews. 56 (4), 2004, pp. 481-489.

(Krushnakumar J. Gandhi, Subhash V. Deshmane & Kailash R. Biyani Department of Pharmaceutics, Anuradha College of Pharmacy, Maharashtra, India) November 2018 ► 43

marketing initiatives

Metal Detectable Silicone Rubber - A unique solution to multiple industries .

Scope of metal detectable silicone Traditional silicone sealing solution: Product quality is matter of bigger concern rubber in pharmaceutical, food and drink industry. To assure that the products are Major processing steps involve the dynamic contamination free, the idea of metal movement of silicone rubber parts. Silicone detectable silicone arose. As the name is most preferred choice for sealing suggests, metal detectable silicone rubber application in food and pharma industry. is a unique solution to avoid contamination There was a risk in the pharmaceutical, food in production line. Metal detector devices and drink industry of silicone rubber particles can detect silicone-based products made approved metalsilicone detectable siliconeand rubber applications and its applications ed FDA metal detectable rubber accidentally falling into the productsits during from this unique formulation. the production process, due to natural wear During mass production if device generates and tear. This kind of contamination can any signal of metal presence in product due Food contact applications: cause serious quality silicone problems during theand FDA approved metal detectable rubber and its applications FDA approved metal detectable silicone rubber its applications to failure of seal or abrasion of gaskets, the act applications: production and it may affect the reputation production line can be stopped immediately. of company.

brush

Food contact applications: Food contact applications:

FDA approved metal detectable silicone rubber and its applications

Silicone brush

Silicone brush

Silicone brush brush Silicone

Silicone anti-slip conveyor Silicone anti-slip conveyor Silicone anti-slip conveyor Silicone anti-slip conveyor

Silicone anti-slip conveyor

Silicone seal

Silicone seal

Silicone seal seal Silicone

Silicone seal

Silicone conveyor for food industry

Pharma applications:

Food contact applications Pharma applications: Silicone conveyor for food industry

Pharma applications: Silicone conveyor for food Silicone conveyor forindustry food industry

Silicone conveyor for food industry

Silicone bellow

Pharma applications

Silicone bellow Silicone bellow Silicone bellow 44 ◄ November 2018

Silicone sieve

Silicone sheet

Silicone sieve sheet Silicone Silicone Silicone sievesieve Silicone Silicone sheet sheet

FRENCH PHARMACOPOEIA

Due to this safe and cost effective solution, metal detectable silicone rubber products are quickly become best solution for the pharmaceutical, food and drink industry.

FDA approved metal detectable silicone rubber Designing formulation as per food and pharma regulatory compliances is a really challenging task for rubber formulators. To maintain the rubber properties along with the metal detectable feature is a matter of expertise, which is required to balance both the properties. There are only a few silicone products which are used in food and pharma product contact applications due to compliance issues.

Pharma products like bellows, sieves, sheets, etc made from detectable silicone can be traced through x-ray devices. Any small segment of rubber contaminating the drug product can be traced through devices and defective products can be separated due to this innovation.

The market of metal detectable silicone is growing and many industries are waiting to taste fruits of this development.

Polymer industries are developing multiple applications of this innovative material and it is expected that conventional silicones will be soon replaced with metal detectable silicones.

   Nikunj Thakkar (Asst. Manager – R & D) Ami Polymer Pvt. Ltd. Tel: +91 82389 22236 Email: research@amipolymer.com Website: www. amipolymer.com Pharma Bio World

marketing initiatives

Launch of Romaco’s new blister line Romaco Noack NBL 400 blister line Romaco’s new Noack NBL 400 blister line was specifically designed to meet the needs of the Asian pharmaceutical markets. With an output of 400 blisters and up to 300 cartons per minute, this durable line is ideal for medium batch sizes. An integrated solution comprised of a blister machine with rotary sealing and a continuous motion cartoner, it is very easy to use. Machine operators require no specialist technical know-

solid products. What’s more, nearly all format parts of the Noack 921 blister machine, which is firmly established in the market, are also compatible with Romaco’s new Noack NBL 400 blister line. Here, too, the new blister technology convinces with outstanding versatility and excellent value for money.

Regarding product feeding, the Noack NBL 400 allows very flexible configurations. Tablets and capsules

processing any standard thermoformable laminate and can also be employed in the manufacture of aluminium-aluminium blisters. Romaco trusts in BlisterMagic, its innovative software solution, to design the cavity geometries and develop individual packaging layouts. This innovative tool provides a very quick and easy route to customise blister packaging. Users of the Noack NBL 400 blister packaging line also profit from Romaco’s expert support when it comes to packaging designs.

Romaco Noack NBL 400 blister line

how to work on the blister packaging line and carry out product and format changes. That is why the robust Noack NBL 400 is also recommended as an entry level model for contract packers and pharmaceutical manufacturers seeking to expand their business with

with different specifications can be placed in the blister cavities either individually or using a brush-box feeder. The products can also be fed manually, which is mainly an advantage with sample packs or with very small or clinical batches. The NBL 400 from Romaco Noack is capable of

Romaco Macofar MicroMaxX 18 microdosing machine Pharma Bio World

Romaco Macofar MicroMaxX 18 microdosing machine The Romaco Macofar MicroMaxX 18 microdosing machine processes pharmaceutical powders with different flow properties as well as freeze-dried products and sterile liquids. The system is equipped with a dual dosing disc which allows multiple dosing into the same vial; alternatively, the product can be filled in two separate process steps. Furthermore, even very small product quantities right down to 25 mg can be dosed precisely.

Thanks to an innovative in-line weighing system, one hundred percent weight control is now possible for the first time.

The machine achieves a maximum filling speed of 12,000 vials per hour. Up to 18,000 vials an hour are possible in the version with statistical weight control.

The Romaco Macofar MicroMaxX 18 can be supplied in different containment designs. Automated processes ensure November 2018 ► 45

marketing initiatives

Romaco Kilian K 720 double-sided rotary press

Romaco Kilian KTP 590X single-sided rotary press for bi-layer and effervescent tablets

reliable operation and meet the high cGMP requirements for dosing sterile powders and liquids.

scrapers, which are in constant contact with the die table surface due to magnetic force.

Romaco Kilian K 720 double-sided rotary press The tablet presses in the Romaco Kilian K series are specially tailored to the needs of the Asian market and impress with their excellent value for money. The K 720 double-sided rotary press was configured by Romaco Kilian for the production of mono and bi-layer tablets and can be switched flexibly between the two operating modes. This high speed press has a maximum output of 1,000,000 tablets per hour. The technology is used both in the pharmaceutical industry and in the non-pharmaceutical sector, and is particularly suited for compressing effervescent tablets, nutraceuticals and drugstore items. The systematic reduction of product loss was a top priority when Romaco Kilian developed the K series. Amongst other features, this is achieved by means of product

Single-sided rotary press for bi-layer and effervescent tablets: Romaco Kilian KTP 590X The KTP 590X, a model in the successful KTP-X series from Romaco Kilian. The KTP 590X is an extremely versatile single-sided rotary press which can be used to manufacture both mono-layer and bi-layer tablet formats. Bi-layer tablets can be compressed at any time on the version with three compression rollers. The tablet press is equipped for this purpose with two standard fill shoe modules, which distribute the powder uniformly in the die. Thanks to the optimised paddle design, even poorly flowing or sticky powders can be processed efficiently and compressed homogeneously. With its three separate compression stations, the Kilian KTP 590X is equally suited for manufacturing effervescent tablets. The powder is tamped initially to prevent air pockets

46 â&#x2014;&#x201E; November 2018

and capping. It is then pre-compressed and finally converted into finished tablets in the main compression unit. The dwell time is significantly longer owing to the use of Kilian 28/41 tooling, meaning harder tablets can be made. All in all, the Romaco Kilian KTP 590X single-sided rotary press boasts a maximum output of up to 510,000 tablets per hour, even in bi-layer mode.

Romaco Kilian STYLâ&#x20AC;&#x2122;ONE Evolution tableting robot The Romaco Kilian STYLâ&#x20AC;&#x2122;ONE Evolution single-stroke press is the ideal solution for laboratory applications, whether for developing new formulations or for scale-up tests. It achieves a maximum output of 1,750 tablets per hour in configurations for mono-layer, multilayer or core tablets. The compression cycles have been speeded up by more than 60% and the maximum compression force increased to 50 kN in order to simulate high speed presses. Compression force profiles for all standard rotary presses like the Romaco Kilian KTP 420X can now be determined at full power. ANALIS, Pharma Bio World

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Chemtech Hyderabad World Expo 2017

HYDERABAD - 2017

GUJARAT - 2018

13-15, December 2017 Venue: Hyderabad, India

23-25, January 2018 20-23, February 2019 Venue: Ahmedabad, Gujarat, India Venue: Mumbai, India

MUMBAI - 2019

GUJARAT - 2018

MUMBAI - 2019

23-25, January 2018 20-23, February 2019 Venue: Ahmedabad, Gujarat, India Venue: Mumbai, India

Dear Readers, Launched by Chemtech Foundation in 1992, Pharma Bio World (PBW) features contents from Pharmaceutical and Biotechnology industries. PBW provides in-depth information on business practices, latest trends, technologies, research & innovation and processes across the entire industry pipeline.

Romaco Kilian STYL’ONE Evolution single-stroke press

Romaco Innojet VENTILUS® V 5 processing machine

the intelligent PAT software, calculates all relevant tableting parameters based on compression force or displacement controlled cycles. The remarkable precision of the test batches means powder properties can be analysed very realistically. The STYL’ONE Evolution can thus also be utilised to optimise processes or troubleshoot errors.

flow conditions inside the cylindrical product container enable extremely gentle intermixing of the batch and hence play a crucial role here. The air flow bed technology ensures accurate control of the product movement and equally precise application of the spray liquids. The process air is controlled by the ORBITER booster, an ingenious container bottom consisting of overlapping circular plates.

Together with the ROTOJET, the central bottom spray nozzle, the booster forms an innovative functional unit that meets all the requirements for linear scale-ups.

Romaco Innojet VENTILUS® V 5 processing machine The VENTILUS® V 5 processing machine from Romaco Innojet is suitable for both aqueous polymer solutions and hot melt coating formulations. The laboratoryscale version of the Romaco Innojet VENTILUS® V 5 is used for particle sizes from 10 µm to 2 mm. Only one product container is required for the granulation, drying and coating steps. Due to its special design and enhanced processing efficiency, the VENTILUS® V 5 allows up to 85% shorter batch times with hot melt coating applications and up to 25% with polymer coatings. The homogeneous Pharma Bio World

(Romaco is a leading international supplier of processing and packaging equipment specialising in engineering technologies for pharmaceutical solids.

The group provides individual machines and turnkey solutions for manufacturing and packing powders, granulates, pellets, tablets, capsules, syringes and medical devices. Romaco also serves the food and chemical industries.)

Each monthly edition of PBW covers a separate area of pharma and biotech industry and includes articles from a range of peers, consultants and commentators, interview with industry experts, Market research analyzing industry trends, News Features, News Updates, Product Trends, Events Diary and Bookshelf.

Target readers for PBW are Drug manufacturers, Intermediates, Pharma machinery/equipment manufacturers and suppliers, Pharma packaging firms, Research institutes, Academic institutes, Biotechnology firms, Consultants and Government bodies.

You are most welcome to share editorial content with us such as technical articles, case studies and product write-ups. The length of the article should not exceed 1500 words with maximum three illustrations, images, graphs, charts etc. All the images should be high-resolution (300 DPI) and attached separately in JPEG or JPG format.

Have a look at our editorial calendar on our website www.pharmabioworld.com.

To know more about Chemtech Foundation, Jasubhai Media and other publications and events, please visit our website – www. chemtechonline.com Thank you, Regards, Thomas Antony Editor Jasubhai Media Pvt Ltd Tel: +91-22-40373636 E-mail: thomas_antony@jasubhai.com

November 2018 ► 47

news, events, etc Thermo Fisher Scientific Announces Lonza Launches the Next-Generation Collaboration to Simplify Analysis of Electronic Batch Record Execution Platform Complex Therapeutic Proteins at Cell and Gene Therapy Manufacturing Thermo Fisher Scientific, the world leader in serving science, and Forum 2018 Symphogen, a clinical-stage antibody oncology-focused company, have entered into a two-year collaborative partnership to deliver validated, platform workflows for simplified characterization and quality monitoring of complex therapeutic proteins.

Building on a decade-long relationship, the new collaboration will develop protein analysis workflows to accelerate drug development for biopharmaceutical innovators, biosimilar manufacturers, contract research organizations, and contract development and manufacturing organizations.

Symphogen will use the Thermo Scientific Q Exactive Plus Orbitrap liquid chromatography-tandem mass spectrometry (LC-MS/MS) system with BioPharma Option to create, test and validate platform workflows for intact and native mass analysis of therapeutic monoclonal antibody (mAb) mixtures. Additional focus will be placed on the development of automated multi-attribute method (MAM) workflows for monitoring critical quality attributes of proteins using high-resolution accurate-mass mass spectrometry in a quality control environment.

"The growing demand for more targeted and personalized treatment modalities results in the development of increasingly complex drug products, requiring research and development of advanced workflows to monitor their structure, manufacturing variation and quality," said John Rontree, senior director pharma & biopharma, chromatography and mass spectrometry, Thermo Fisher Scientific.

"The collaboration with Symphogen, in addition to our commitment to the opening of Global Customer Solution Centers, will enable us to jointly leverage our established mass spectrometry technology, along with the expertise of our customers, to develop and implement novel, easy-to-use analytical strategies for complex mAb mixtures needed by drug manufacturers to drive the development of new therapies for cancer patients."

"Through this collaboration, we can leverage the knowledge and world-class technology provided by Thermo Fisher to effectively address our needs," said Dan Bach Kristensen, Ph.D., principal scientist, Symphogen. "The exceptional spectral resolution enabled by the Q Exactive BioPharma mass spectrometry platform means we now have a highly powerful tool for simple, reliable characterization and quality monitoring of complex biopharmaceutical products."

The Q Exactive Plus Orbitrap LC-MS/MS system is the latest addition to the Thermo Fisher portfolio of products used by Symphogen, which includes Thermo Scientific ultra high-performance liquid chromatography (UHPLC) systems and Thermo Scientific Chromeleon Chromatography Data Systems (CDS).

48 ◄ November 2018

Lonza unveiled its next-generation electronic batch record execution platform, the MODA-ES™ Software Platform, at the Cell & Gene Therapy Manufacturing Forum in London (UK). Building on Lonza’s extensive informatics know-how and vast experience as a contract manufacturing organization (CMO), the new platform offers a flexible and cost-effective solution for consolidating and managing batch and quality data produced across cell and gene therapy manufacturing processes.

Conventional methods of data collection and management, whether electronic or manual, can limit efficiency and productivity significantly and result in workflow deviations. Cell and gene therapy manufacturers typically rely on hybrid solutions of paper combined with multiple electronic systems to collect, store and manage the large amount of batch data they produce. However, the lack of integration between these systems means that users need to manually transfer data from one system to the other, which can be an error-prone and timeconsuming procedure. Additionally, paper records are still extensively used to capture batch data, often resulting in missing or incorrect entries, calculation errors, and long review and approval times.

The new MODA-ES™ Software Platform has been designed to consolidate all cell and gene therapy manufacturing batch data, as well as batch-related quality control data, into a single record with an easy-to-use review and approval interface for expedited product release. With data integrity compliance and traceability at its core, the solution captures trends key quality and performance metrics, while eliminating errors associated with manual and paper-based approaches. The MODA-ESTM Platform is flexible, easy to configure, and scalable from clinical through to commercial production.

"The MODA-ES™ Electronic Batch Record Execution Platform brings to cell and gene therapy manufacturers the flexibility and informatics tools they desire to scale their processes without compromising safety or compliance," said Mike Goetter, General Manager, Informatics, Lonza Pharma & Biotech – Bioscience Solutions. "Built on Lonza’s unique manufacturing and quality control expertise and with a low total cost of ownership, the platform will enable the entire cell and gene therapy development and production industry to go paperless."

The solution’s key features are Workflow-driven data entry applicable to batch records, sterility tests and cleaning forms; A modular design allowing individual modules to be created, validated and used across different processes; Standard methods for processing products of the same family, with the flexibility to vary the raw materials, fill volumes and equipment types; An electronic checklist enabling real-time review and approval; Data-integrity alert capability to trigger timely intervention and resolution of issues; Seamless integration with other cGMP compliant electronic systems, as well as with analytical equipment, for effortless, reliable data transfer.

Pharma Bio World

news, events, etc Indian Pharma sector growth to moderate Third edition of India Pharma Week all set to start at Delhi from Dec 9 -14, 2018 at 7-9% CAGR over FY’2018-21 period The growth trajectory for the Indian pharmaceutical industry is likely to be moderate at 7-9% over FY2018 to FY2021, on the back of healthy demand from the domestic market given increasing spend on healthcare along with improving access though constrained by regulatory interventions and slowing growth from the US given the relatively moderate growth prospects. According to an ICRA report covering a sample of 21 firms in the industry the concerns in the domestic market pertain to price control and mandatory genericisation whereas US concerns pertain to relatively moderate proportion of large size drugs going off patent, increased competition leading to price erosion albeit at moderate pace, generic adoption reaching saturation levels and; regulatory overhang along with base effect catching up.

The revenue growth from US remained sluggish during Q1FY2019 at 1.5% compared to 4.0% in FY2017 and -13.1% in FY2018 despite consolidation benefits. The growth momentum for US business is likely to remain in low single digit for FY2019, led by limited near term first to file (FTF) generic opportunities, pricing pressures and product rationalization for US base business. The base business in US continuing to face high single digit price erosion (compared to low double digit earlier) and regulatory overhang for select companies.

Aggregate revenues of sample grew at 15.4% in Q1FY2019 vis-à-vis the prior year as against FY2018 growth of 0.1%. The year on year revenue growth for Q1FY2019 reflect low base for domestic business. The first quarter’s growth last year was incrementally impacted by domestic trade channel de-stocking in view of GST implementation leading to loss of 2025 days of sales in addition to US generic business facing steep pricing pressure. The aggregate domestic growth was 27.2% in Q1FY2019 compared to 4.6% in FY2018 and -8.8% in Q1 FY2018. Besides low base, growth during Q1FY2019 was also supported by volume growth and new product launches. The growth during Q1FY2019 was also supported by 3.4% WPI linked price increase on National List of Essential Medicines (NLEM) portfolio. Growth from European markets benefitted from higher tender wins, new product introduction in B2B segments and low base effect though healthcare reforms resulting in price cuts continue to pose challenge. Unlike in the past, when several Indian pharma companies ramped up their R&D spend, targeting pipeline of specialty drugs, niche molecules and complex therapies, this time around companies are optimising their R&D spend. This is led by challenging US market conditions characterized by steep pricing pressures, high competitive intensity led by faster ANDA approvals and lower than expected revenue growth. Also with competitive pressures expected to sustain in the near to medium term, companies are exiting product development of easy to manufacture, simple generics with multiple players and focusing on complex generics and specialty products.

The aggregate R&D spends of top few domestic companies which had increased from 5.9% of sales in FY2011 to close to 9.0% in FY2017, moderated to 8.8% during FY2018 and further to 8.6% in Q1FY2019.

ICRA expects R&D budgets to remain at 8.6%-8.8% given the growing focus both on regulated markets and complex molecules/therapy segments such as injectables, inhalers, dermatology, controlled-release substances and bio-similars.

Pharma Bio World

UBM India, India's leading B2B exhibition organizer, is all set to bring in the third edition of the India Pharma Week, a week-long celebration packed with avant-garde events from December 9-14, alongside the 12th edition of its flagship expo CPhI and P-MEC India (December 12-14).

South Asia’s largest pharma event will be held for the first time at the India Expo Centre, Greater Noida, with all its attendant facilities, moving away from the commercial capital of Mumbai. This will enable all the key stakeholders and professionals of the pharma industry the convenience to congregate at the marquee show, network and celebrate the industry under one giant umbrella for an entire week.

Commemorating 12 years of the CPhI & P-MEC India expo, the India Pharma Week will organize more than seven events and activities pertaining to the streams of business, knowledge, leadership, innovation, recognition and networking in the field of pharma. As a tribute to the city in which it was born and reared, the India Pharma Week will tee off with a Pharma Leaders Golf in Mumbai. The scene of action will then be shifted to Greater Noida where the IPW will be packed with a series of dynamic engagements such as Pharma Connect Congress, Women in Pharma, India Pharma Awards, Networking Evening, the CPhI & P-MEC India Exhibition and a closed-door CEO Roundtable, among others. The shift to the Delhi-NCR region will help the magnum opus further develop and nurture a complete pharma ecosystem in the sectoral pockets of the North, also keeping in mind its power corridors.

Since its inception in 2006, the CPhI & P-MEC India exhibition has grown remarkably larger over the years with exhibitors and visitors from Indian and overseas engaging over significant levels of business.

It has been approved and comprehensively assisted in its endeavors by governing bodies such as Pharmexcil, CIPI and IDMA. This year's edition will witness participation from more than 1,600 exhibitors from over 42 countries. Special pavilions by Pharmexcil, CCCMHPI & CCPIT will form an intrinsic part of the expo. The India Pharma Week with its mélange of events was launched in 2016 to celebrate CPhI & P-MEC’s 10 years of existence. Onsite, several innovative engagement platforms such as Supplier Finder, CPhI TV, Live Streaming, Mobile Apps, Tech Walls, Matchmaking - Live Pharma Connect, Exhibitor Showcase, and Innovation Gallery among others are sure to make the visitor experience an engaging and memorable one.

Speaking on IPW 2018, Yogesh Mudras, managing director, UBM India said, “I am delighted to announce the third edition of the weeklong India Pharma Week - an unrivalled offering to the world of exhibitions - along with the CPhI & P-MEC India, UBM’s flagship engagement platform, and the world’s leading Pharmaceutical networking event in the DelhiNCR region at a world class venue that an elite congress such as the one at IPW richly deserve. The shift to the region, in close geographical proximity to the Centre, policy makers, consulates and government bodies will enhance our community building efforts. Apart from the business, and the medley of captivating events, key discussion areas will include ‘Growth of Indian Pharmaceutical industry: Vision 2020’, ‘Transforming the Pharma industry architecture through collaborations’, and ‘Strategies to strengthen regulatory policies in India’ among many others, for the community to ruminate and act upon”.

November 2018 ► 49

events diary    

  

Date: 20 – 23 February 2019 Venue: Bombay Exhibition Center, Mumbai

Dates: 20-22 August 2019 Venue: (GUCEC), Ahmedabad,

BioPharma World Expo 2019 will be a perfect destination for Bioprocess Solution Providers, CROs/CMOs, Clinical Trial Supply Chain Providers, Cold Chain Packaging & Cargo, Global Pharma, Regulatory Consultants, Analytical Instrument Manufacturers, Local Biotechs & Start-ups, Quality Control Consultants, Academics, and Regulators to showcase and promote their product and services as well as offer unique opportunity to meet, network and discuss current industry trends, establish business partnerships and be updated on investment opportunities in India.

The concurrent conference tracks will explore areas like biosimilars and vaccines development, antibodies, orphan drugs, stem cells, innovations in biologics manufacturing and regulatory compliance; growing issues in generic drug manufacturing and more.  Amrita Patkar Event Coordinator Tel: 91-22- 4037 3617 Email: amrita_patil@jasubhai.com

PharmaTech Expo 2018 & LabTech Expo 2018 is an International Exhibition on pharma machinery, lab, analytical, pharma formulations, nutraceutical and packaging equipment.

This will give opportunities to suppliers, manufacturers, industrialists, entrepreneurs, buyers and consultants to assemble at this common platform. The focus will be on the Pharmaceutical Formulations, Nutraceuticals, API’s, Cosmetic and Ayurveda sector.

      Expo



Date: 16 th - 17 th April 2019 Venue: Mumbai Exhibition Centre, Mumbai

Dates: 04-08 December 2019 Venue: The Exhibition Centre, Gandhinagar, Gujarat

Analytica Anacon India and India Lab Expo are together the biggest show in laboratory technology, analysis and biotechnology in India. The international trade fair is the most important industry gathering in India. Get to know the entire range of topics that pertain to laboratories in research and industry. This is a trade fair which showcases chromatographies, spectroscopes, microscopes and imaging, bioinformatics, medicine and diagnostics, life sciences, analytical instrumentation systems, instruments for physical and chemical analysis, laboratory furniture, equipment, machines, laboratory diagnostics, etc.

ENGIMACH is a leading engineering and machine tools show and showcase engineering products and services, heavy and light machines, machinery equipment and accessories, tools and parts, technological devices and products, engineering tools and allied products and services. It is the most trusted machines and tools show that exhibits latest products and services, latest innovations and technologies.

It is an ideal event that witnesses the best buyer and seller partnership and is a dynamic platform.

 Messe Muenchen India Pvt Ltd INIZIO 507 & 508, 5th Floor Cardinal Gracias Road Opp: P&G Bldg Chakala, Andheri (E) Mumbai 400 099

 K And D Communications Ltd Kailash-A Sumangalam Society, 3 rd Floor Above HDFC Bank, Opp: Drive-In Cinema, Bodakdev Ahmedabad, Gujarat

th

rd

50 ◄ November 2018

 PharmaTechnologyIndex.com Pvt Ltd 701-702 Corporate House Nr Dinesh Hall, Income Tax Ashram Rd Ahmedabad, Gujarat

Pharma Bio World

Thermoplastic Elastomer Tube (TPE) Imaprene is opaque tubing especially known for its excellent flexibility and flex crack resistance. Imaprene is manufactured by using advance grade thermoplastic elastomer. It is manufactured and packaged in dust-free environment of ISO 9001 QMS, ISO 14001 and OHSAS 18001 Certified facility. It has excellent chemical and solvent resistance (Ex. IPA). It is superior flex crack resistance and durable for any application. It has smooth bore to ensure least contamination.

It is non-toxic and non-haemolytic and is highly recommended for medical, food and pharma applications. It is sterlizable by using different techniques like autoclaving, ethylene oxide and gamma radition.

For more information, please contact: Ami Polymer Pvt Ltd 319 Mahesh Indl Estate, Opp: Silver Park Mira-Bhayander Road, Mira Road (E) Thane, Maharashtra 401 104 Tel: 022-28555107, 28555631, 28555914 E-mail: mktg@amipolymer.com

Silicone Diaphragms Medical-grade, platinum cured silicone is widely accepted in pharma and biotech applications and is often used throughout the plant. Like all of their diaphragm materials, silicone diaphragms meet USP Class VI and FDA 21 CFR 177.2600 Standards. It is suitable for biomedical/pharma applications. All diaphragms meet the standards for quality, purity, lack of toxicity, strength and consistency.

For more information, please contact: Ami Polymer Pvt Ltd 319 Mahesh Indl Estate, Opp: Silver Park Mira-Bhayander Road, Mira Road (E) Thane, Maharashtra 401 104 Tel: 022-28555107, 28555631, 28555914 E-mail: mktg@amipolymer.com

Stepper Motor Module B&R offers new stepper motor module from the X20 Series With the X20SM1436-1 module, B&R has added to its portfolio a new X20 module for direct control of stepper motors. The module can be used to operate stepper motors with operating voltages from 18 to 60 V DC at rated currents up to 2.5 A. In addition, the integrated current reduction function increases performance and reduces energy consumption.

With the current reduction function, B&R has integrated sensorless, load-dependent current control, which significantly increases the performance of the module. By regulating the current downwards depending on the operating situation and load, the module allows energy savings of up to 75 per cent.

The current reduction function also significantly reduces power dissipation and heat accumulation in the module. At the same time, current control also results in the stepper motor running more smoothly. For self-protection, the stepper motor module has an inrush current limiter and a motor outlet with short circuit and overload protection.

The module has four digital 24 V DC inputs. Three of them can be configured as ABR encoder inputs with a counter frequency of 50 kHz for 4x evaluation. In addition, all digital inputs have open circuit monitoring, which increases operational security. To detect slippage, the module has been equipped with stall detection.

For more information, please contact: B&R Industrial Automation Pvt Ltd 8 Tara Heights, Mumbai-Pune Road Wakdewadi, Pune, Maharashtra 411 003 Tel: 020-41478-999 Fax: 91-020-41478-998 E-mail: pooja.patil@br-automation.com

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Oil-free Air-compressors ELGi Equipment offers range of oil-free air-compressors and reiterate its commitment to enabling energy-efficiency and meeting high purity air demands.

ELGi’s oil-free range comprises of machines ranging from 60 and 100 HP with 7 and 8.8 bar pressure options. The air-cooled designed will ensure ease of installation at all customers, while the aluminium coolers will ensure efficient cooling. High-efficiency NEMA motors power the machines with separate ducting for noise reduction. ELGi is one of five companies in the world with a proprietary oil-free Airend design. The new models are supported by ELGi’s class leading four year Airend warranty and a strong service network. The added models will ensure that ELGi is able to service all oil-free air needs in the market.

These compressors are used across a variety of manufacturing applications, witnessing strong demand from the food and beverage sector, owing to mandatory health and safety requirements. An industry focus on economical manufacturing methods, lower installation and maintenance costs are also contributing to the growth.

For more information, please contact: Elgi Equipment Ltd Trichy Road, Singanallur Coimbatore, Tamil Nadu 641 005 Tel: 0422-2589555 Fax: 91-0422-2573697, 2589401 E-mail: enquiry@elgi.com

Teststrip Packaging Sanner offers its portfolio of user-friendly desiccant and teststrip packaging solutions for pharma and healthcare products. After the successful introduction of the desiccant solutions AdCap and AdPack to the Indian market, Sanner of India now also offers teststrip packaging solutions.

Apart from integrated desiccants, Sanner also provides a variety of desiccant drop-in solutions: thanks to their smooth shape and high insertion speeds, the AdCap desiccant capsules ensure excellent handling properties. In addition, the drop-in capsules provide a 30 per cent higher humidity adsorption compared to conventional capsules. The AdPack desiccant sachets made of Tyvek material combine barrier protection, durability and breathability with high moisture adsorption.

Sanner has successfully introduced different teststrip packaging solutions to the Indian market and has expanded its customer base continuously. The user-friendly packaging with FlipTop closures is especially well received. They are easy to open and can be re-closed intuitively, ensuring a safe handling even of sensitive teststrips.

For more information, please contact: Commha Consulting GmbH & Co KG Poststraße 48, 69115 Heidelberg Germany Tel: +49 (0) 6221 18779-27 E-mail: sanner@commhaconsulting.com

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Vacuum Drying System Complete vacuum drying systems are available to meet the needs of each application. The systems typically include a mixer/blender, filter, condenser, vacuum pump and condensate receiving vessel. Complete skid mounted systems are available with controls. Illustrated is a vertical blender combined with the ancillary items mentioned above. All Ross mixers and blenders are available with complete vacuum and control systems.

For more information, please contact:

Ross Process Equipment Pvt Ltd Plot No: D-233/3, Chakan Indl Area Phase II,Village: Bhamboli Tal: Khed, Dist: Pune Maharashtra 410 501 Tel: 02135-628400, 628401, 628402, 628403 E-mail: mail@rossmixers

Q Exactive HF Benchtop Orbitrap MS The Thermo Scientific Q Exactive HF mass spectrometer is the next generation HRAM benchtop system with an ultra high-field Orbitrap detector, providing greater speed, productivity and confidence for both qualitative and quantitative.

For more information, please contact: Thermo Fisher Scientific India Pvt Ltd 102, 104, Delphi ‘C’ Wing Hiranandani Business Park Powai, Mumbai 400 076 Tel: 022-67429494, Fax: 91-022-67429405 E-mail: sagar.chavan@thermofisher.com

Centrifugal Pump NeoMag is a high-performance, magnetically coupled standard centrifugal pump made from SS with a borosilicate canister, the patented BOROHARDCAN. The single-stage, non-selfpriming NeoMag pump has been developed based on the latest findings in fluid and hydraulic technology. The installation and replacement are simple thanks to modular design.

With the NeoMag pump energy savings of up to 30% are possible, since the BOROHARDCAN consists of an electrically non-conductive material, whereby it does not generate any eddy currents. Hence, the pump as well as the motor and the coupling can be dimensioned smaller than before. This reduces not only the investment costs, but also the subsequent costs during operation.

The NeoMag pump technology is hermetically sealed via the magnetic coupling and the canister, and therefore functions absolutely leakage-free and almost wear-free. The NeoMag pump is equipped with a soft start feature, which prevents an unnecessary stress on the aggregate. During the development of the NeoMag, it was possible to increase the hydraulic efficiency by various geometric optimisations, eg, of the impeller, to just over 70%. Such an optimisation offers further energy and cost saving potentials.

It finds application in water management, industrial and chemical applications, petro chemistry/mineral oil, process engineering and technology, pharma industry, biotechnology and food industry.

For more information, please contact: Bedaflow Systems Pvt Ltd W-7, Sector-11 Noida, Uttar Pradesh 201 301 E-mail: info@bedaflow.com

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Bursting Strength Tester â&#x20AC;&#x201C; Analogue Bursting strength is a reliable index of the strength and performance of materials like paper, paper boards, corrugated boards and boxes, solid fibre boards, filter cloth, industrial fabric, leather, resin, etc.

PRESTO bursting strength tester is ideal for testing a wide range of materials to determine their quality, strength and performance. It is easy to operate. It is scientifically calibrated for reliability and is widely used by industries and institutions and stands out as proven and reliable equipment.

For more information, please contact: Presto Stantest Pvt Ltd I-42 DLF Indl Area, Phase I Delhi Mathura Road Faridabad, Haryana 121 003 Tel: 0129-4272727 E-mail: info@prestogroup.com

Bursting Strength Tester â&#x20AC;&#x201C; Digital Bursting strength is measured by giving a hydraulic pressure through a rubber diaphragm on a circular area of the specimen of CFB under test conditions. Force required bursting or complete rupture of the board is measured through a digital indicator. The quality of CFB is graded with the value of bursting strength. It is used for determining the bursting strength of paper, corrugated boxes and paper board, etc, by application of a hydraulic load under a rubber diaphragm of a specific area.

For more information, please contact: Presto Stantest Pvt Ltd I-42 DLF Indl Area, Phase I, Delhi Mathura Road Faridabad, Haryana 121 003 Tel: 0129-4272727 E-mail: info@prestogroup.com

Thermal Mass Flow Meter Thermal Mass Flow Meter is accurate, easy to install, having no moving parts and best suitable solution for measuring and controlling compressed air, oxygen, nitrogen, biogas, digester gases, ethane and natural gas flow. Heat dispersion (mass flow) technology provide proportional mass flow measurement resulting in higher accuracy performance at a lower cost than orifice flow meter, Vortex shedding flow meter and other gas flow measuring devices.

The thermal principle operates by observing the cooling effect of a gas flow as it passes over a heated transducer. The temperature sensor monitors the actual gas temperature whilst the heater transducer is maintained at a constant differential temperature by caring the required current from electronic to maintain the differential temperature. Greater the flow, greater will be cooling effect and power required to maintain the differential temperature.

The energy required maintaining this temperature differential is directly proportional to the mass flow rate. Thus, there is no need for additional temperature or pressure compensation in thermal mass flow meter. This meter is also used for compressed air flow measurement.

For more information, please contact:

Process Control Devices Plot No: 22, Rautara Indl Estate B/s Hanuman Hotel, Shil-Mahape Road Shilphata, Thane, Maharashtra 400 612 E-mail: sales@pcd-flowmeter.com / sales.pcdpl@gmail.com

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Standard Pressure Gauges Adarsh Industries offers standard pressure gauges (MM Series) in mild steel (MS) case and brass working parts; dial sizes: 40, 50, 63, 100, 150 and 250 mm; bottom direct, bottom surface, back direct, back panel, back clamp mounting.

Standard gauges are suitable for general purpose applications for gas and liquid media which do not corrode brass and having an environment which is not harsh to MS case. It is commonly used on equipment like pumps, compressors, boilers, pneumatic and hydraulic machines, etc.

For more information, please contact:

Adarsh Industries 307 Shankala Indl Estate Gogatewadi, Off Aarey Road Goregaon (E), Mumbai 400 063 Tel: 022-29275496 Fax: 91-022-29275558 E-mail: sales@adarshpressuregauge.com

Dual Shaft Mixer The dual shaft mixer includes an anchor agitator and a high speed disperser.

The anchor feeds product into the high speed disperser blade and ensures that the mixture is constantly in motion. The anchor can be provided with scrapers to remove materials from the interior vessel walls to enhance the heat transfer capabilities of the mixer. Both agitators are available for variable speed operation.

A second high speed dispersion mixer can also be added for increased shear. Multiple blades on each of the disperser shafts can also provide added mixing.

For more information, please contact: Ross Process Equipment Pvt Ltd Plot No: D-233/3, Chakan Indl Area Phase II,Village: Bhamboli, Tal: Khed Dist: Pune, Maharashtra 410 501 Tel: 02135-628400, 628401, 628402, 628403 E-mail: mail@rossmixers

Sectional Overhead Doors Avians industrial sectional doors with 80 mm thick panels are highly insulated and are particularly suitable for refrigerated warehouses in the food sector. Typically, the energy required to maintain a constant temperature inside these buildings is exceptionally high. These doors help in reduction of energy cost by minimizing heat or cold loss. And due to its great stability, the special door is particularly suitable for windy areas, eg, in coastal regions.

Industrial sectional doors prevents dust, air and water providing complete sealing, High precision hinges made of galvanized steel, roller guide with adjustable ball bearing rollers are provided for smooth movement of the door.

Diversified pedestrian movement can be ensured with easy-to-integrate side and wicket doors. Intelligent safety edge mechanism stops the door if it comes into contact with an obstacle. All doors are incorporated with EN safety standards/Sectional overhead doors are made of high grade pre-coated galvanized steel. Their industrial sectional doors can achieve sound insulation up to a certain limit.

For more information, please contact: Avians Innovations Technology Pvt Ltd Gat No: 60/61, Dehu-Moshi Road, Chikhali Pune, Maharashtra 412 114 Tel: 020-71400600 Fax: 91-020-71400654

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Valve Manifold For many applications, Cipriani Harrison supplies valve clusters (manifold) mounted on the SS frame. There are number of advantages in the prefabricated manifold: uniform and better quality of welding and surface finish; valve clusters (manifold) can be pre-tested before dispatch; and cost-effective solution and lower start-up time for system/plant.

For more information, please contact:

Cipriani Harrison Valves Pvt Ltd Sub Plot No: 2, Besides Margin Impex Ltd, Nr Phase IV GIDC Estate, V U Nager Anand, Gujarat 388 121 Tel: 02692-235082, 235182, Fax: 91-02692-236385 E-mail: info@harrisonengineers.com

External Gear Pump The self-priming external gear pump ZPA is particularly suitable for uncritical media without fillers, which are compatible to the used standard materials, and is an ideal solution for bottling and filling. A combination to multiple flow pumps is possible as the combination with high-pressure radial piston pumps.

It finds application in filling, bottling and filtration, heating circuits, cooling circuits, lubrication and oil hydraulics.

For more information, please contact: Bedaflow Systems Pvt Ltd W-7, Sector-11 Noida, Uttar Pradesh 201 301 E-mail: info@bedaflow.com

Transparent Sectional Overhead Doors Avians range of sectional overhead doors are incomplete without an aesthetically pleasing variation called as transparent sectional overhead doors. Transparent sectional door allows a clear vision for the people to showcase the inner appearance and enabling them to have a clear outside view as well.

show-rooms and many other applications.

Avians transparent sectional overhead doors are designed to be used in areas where optimal daylight is desirable and consequently solves the light problems of warehouse buildings,

Along with the desired purposes it serves, it also enriches the appearance of the premises, with elegant transparency and stylish presentation of their product. Transparent sectional overhead doors sections are made of extruded, anodized or painted aluminium sections. They are equipped with single or double acrylic windows to form specially designed aluminium “box type” design.

Intelligent safety edge mechanism stops the door if it comes into contact with an obstacle.

For more information, please contact: Avians Innovations Technology Pvt Ltd Gat No: 60/61, Dehu-Moshi Road, Chikhali Pune, Maharashtra 412 114 Tel: 020-71400600 Fax: 91-020-71400654

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bookshelf Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing Editors: Hamid Mollah, Harold Baseman and Mike Long Price: $194.36 No of pages: 416 pages (Paperback) Publisher: Wiley (1st Edition) About the book: Risk management is essential for safe and efficient pharmaceutical and biopharmaceutical manufacturing, control and distribution. With this book as their guide, readers involved in all facets of drug manufacturing have a single, expertly written and organized resource to guide them through all facets of risk management and analysis. It sets forth a solid foundation in risk management concepts and then explains how these concepts are applied to drug manufacturing.

This book features contributions from leading international experts in risk management and drug manufacturing.

These contributions reflect the latest research, practices and industry standards as well as the authors’ firsthand experience. With its unique focus on the application of risk management to biopharmaceutical and pharmaceutical manufacturing, this book is an essential resource for pharmaceutical and process engineers as well as safety and compliance professionals involved in drug manufacturing

The Talent Management Handbook Authors: Lance A Berger and Dorothy Berger Price: $51.23 No of pages: 704 pages (Hardcover) Publisher: McGraw-Hill Education (3 rd Edition) About the book: This handbook is the established go-to guide for HR professionals, managers and leaders looking for the best ways to use talent management programs to develop a culture of excellence. This 3rd Edition features new and updated chapters based on fresh approaches and material for identifying, recruiting, positioning and developing highly qualified, motivated people to meet current and future business requirements. Filled with expert advice the book offers a roadmap for developing a comprehensive approach to talent management that will guide professionals in the coming years.

Talent Management Handbook Author: Terry Bickham Price: $76.49 No of pages: 336 pages (Hardcover) Publisher: Association for Talent Development About the book: The complex and ever-changing nature of today’s - and tomorrow’s - workforce demands that all involved in talent management rethink how to attract, engage and grow future talent. This forward-looking handbook captures talent management’s evolution from a series of transactions to a fluid process that includes talent development. With 20-plus chapters written by more than 30 contributors, the ATD Talent Management Handbook challenges you to think about the talent model of the future through the lens of different workforce models. It offers progressive thoughts on the current state of talent management and on how the function needs to adapt.

Leaders, practitioners and consultants alike will find useful insights and answers to relevant talent management challenges.

Edited by learning and development authority Terry Bickham, this handbook covers the entire talent management cycle, from talent acquisition and engagement to leadership development and succession planning. ATD’s first handbook on talent management, this book includes a foreword

by ATD President and CEO Tony Bingham, highlighting the foundational components of talent development and its role within talent management.

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R.N.I. No.: MAHENG/2002/08502. Date of Publication: 26th of every month. Postal Registration No: MCS/207/2017-19 Posted at Patrika Channel Sorting Office, Mumbai 400001, on 27th of every month. Total Pages No.: 60