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Challenges in the Changing Pharmaceutical Regulatory Scenario In India
Dr. J Ramniwas, CEO, Sai Pharma Solutions Inc, Vadodara Keeping in pace with the international regulatory scenario, the Indian pharmaceutical regulatory bodies have come out with major changes, which will play a pivotal role to put India on the top of the pharmaceutical map of the world. In pursuance of the same, the article describes the guidelines, implementation and revolutionary changes bring by the Indian Regulatory in the domestic Pharmaceutical Industry.

Indian Pharmaceutical Industry is one of the largest and most advanced among the developing countries. It has over the years made significant progress in infrastructure development, technological capability and hence produced a wide range of products. Understanding the regulatory scenario in this sector is extremely crucial not only due to the rapid and ongoing changes at the global level, largely with reference to Good Manufacturing Practices (GMP), Good Clinical Practices (GCP) and Good Laboratory Practices (GLP) but also due to the onus on the regulatory bodies to ensure a healthy supply of quality drugs at affordable prices to the Indian masses.

The Industry today is in the front rank of India's science-based industries with wide ranging capabilities in the complex field of drug manufacture and technology. It ranks very high in the third world, in terms of technology, quality and range of medicines manufactured. From simple headache pills to sophisticated antibiotics and complex cardiac compounds, almost every type of medicine is now made indigenously. Playing a key role in promoting and sustaining development in the vital field of medicines, Indian Pharmaceutical Industry boasts of quality producers and many units approved have been by regulatory authorities in USA, Japan, EU, Canada, Australia and UK. Now there is no such country in the world where Indian manufactured pharmaceutical products are not available.

Keeping in pace with the international regulatory scenario, the Indian pharmaceutical regulatory bodies have also come out with major changes. This initiative by the Indian regulatory bodies will play a pivotal role to put India on the top of the pharmaceutical map of the world. In pursuance of the same, they have published guidelines on the following topics and now they are in the implementation stage and they are going to bring about revolutionary changes in the Indian Pharmaceutical Industry.

Good Manufacturing Practices (Current Schedule M)
GMP aims to ensure that drugs and other pharmaceutical products are safe and effective. Since then, Good Manufacturing Practices (GMP) has been considered a seal of quality for pharmaceutical products. GMP has been adopted by many countries worldwide and that includes India which is now the second largest producer of pharmaceutical products in the world.

The revised Schedule M advises proper pressure differentials in the areas of operation, which can be achieved through dedicated air handling units with adequate number of air changes. These pressure differentials will help to eliminate/reduce the chances of cross contamination between the products. In addition to these, revised schedule M emphasises proper cleaning validation of the equipment and the processing areas whenever there is product change over. It is also mandatory to display status boards of each equipment material to avoid mixups, which leads to cross contamination. Current Schedule M also gives importance to the stability study of drug substances and drug products to claim the re-test date and expiry date. The Government of India has recognised Pharmaceutical Industry as a technology-driven industry and is focusing on the growth of the industry both for domestic as well as for the expanding global markets. To create a confidence about the quality of drug manufactured in this country, it is essential that the regulators of the country define standard, which are on par with global standards through proper legislation.

The Indian Pharmaceutical Industry will have to go a long way for the successful compliance of current schedule M but once compliance is achieved, the Indian pharmaceutical industry will be able to beat any GMP global standard. Change can be good or difficult at times; this largely depends on how prepared a person or an organisation is to adapt and survive with the new set up. Apparently, the small players in India’s pharmaceutical companies have to buckle down to be more equipped with the changes that GMP brings into their businesses.

Good Laboratory Practices (Schedule L1)
The Drugs & Cosmetics Rules were amended to incorporate Schedule L1 on Good Laboratory Practices and Requirements of premises and Equipments published under notification GSR 780 (E) dated 10th November 2010; a period of two years was granted for the Pharmaceutical industry to make necessary arrangement to comply with the requirement of Schedule L1 before these are made mandatory.

Rules laid by Schedule L1 are terse and minimum with an objective to improve the reliability of data without much adding to the cost to the company, particularly for the small to medium scale pharmaceutical industries in India. On the other hand, WHO eyes towards every small aspects of and related to the laboratory procedure with a view to assure the output scientifically proof.

Schedule L1 Good Laboratory Practices (GLP) requirements are applicable to laboratories attached to all manufacturers covered under rules 74 and 78 of Drugs & Cosmetics Rules, which include manufacture of ‘medical devices’, ‘diagnostic reagents’, ‘surgical dressings such as gauges and bandages’, ‘disinfectant fluids’ and ‘sanitising fluids’, etc and hold licenses in forms 25 and 28. These laboratories even though tiny sized, shall be in conformity with all GLP requirements even laboratories attached to the manufacturing units too.

This will be particularly useful to the laboratories that already comply with the requirements of Schedule L1 and want to move ahead towards WHO compliance.

Good Clinical Practices (GCP)
Clinical research is the key to the discovery of latest diagnostic methods and to develop modern drugs for treatment of diseases. Good Clinical Practices (GCP) is an ethical and scientific quality standard for designing, conducting and recording trials that involve the participation of human subjects. Compliance with this standard provides assurance to public that the rights, safety and well being of trial subjects are protected, consistent with the principles enshrined in the Declaration of Helsinki and ensures that clinical trial data is credible.

It has been widely recognised that India offers unique opportunities for conducting clinical trials in view of the large patient pool, well-trained and enthusiastic investigators and premiere medical institutes available in the country along with considerable low per patient trial cost, as compared to developed countries. The current GCP guidelines of India are at par with ICH guidelines of GCP and these guidelines would open new vistas to companies who want to locate their clinical programme in this country. However, this is very challenging but helps making a niche in the clinical trial business with global acceptance.

Drug Registration and Regulatory Submission Guidelines
Drugs defined as New Drugs under the Drugs and Cosmetics Act are subjected to bioavailability/bioequivalence (BA/BE) evaluations through clinical trials, which are reviewed by the Drugs Controller General (India). A drug has a New Drug status for four years from the date of first permission. After four years, the State Licensing Authority grants license but they do not insists for BA/BE and clinical trial studies which are essential to establish the efficacy of the drugs. Central Drugs Standard Control Organisation (CDSCO) has come out with new draft guidelines on the approval of clinical trials and new drugs.

CDSCO has decided to adopt Common Technical Document (CTD) format for technical requirements for registration of pharmaceutical products for human use. The same is in use for biological products since 2009 and now this guidance document describes the format for preparation of CTD for marking approval of pharmaceuticals for human use other than biological products. It is apparent that Indian Pharmaceutical Regulatory bodies will be able to expedite the review process of new drug application marketing approval. These guidelines are applicable to for import, manufacture and marketing approval of new drug applications.

The adoption of Drug Master File (DMF) and drug product dossier concepts CTD format in tune with the global requirements will help the Indian pharmaceutical Industry to contribute production and speedy entry to the global markets and simultaneously Indian patients would also receive quality and safe medicines. The Indian Regulatory Agencies and Regulatory Affairs professionals will be of immense importance to address these challenges in the right perspective to make Indian Pharmaceutical Manufacturers competent and regulatory savvy.

Pharmacovigilance Programme of India (PvPI) for Assuring Drug Safety
The CDSCO, Directorate General of Health Services, under the aegis of Ministry of Health & Family Welfare, Government of India, in collaboration with Indian Pharmacopeia commission (IPC), Ghaziabad is initiating a nation-wide Pharmacovigilance programme for protecting the health of the patients by assuring drug safety. The programme shall be coordinated by the IPC, Ghaziabad as a National Coordinating Centre (NCC). The centre will operate under the supervision of a Steering Committee.

Since, there are considerable social and economic consequences of Adverse Drug Reactions (ADRs) there is a need to engage health-care professionals, in a well structured programme to build synergies for monitoring ADRs. The purpose of the Pharmacovigilance Programme of India is to collect, collate and analyse data to arrive at an inference to recommend regulatory interventions, besides communicating risks to healthcare professionals and the public.

IPR Issues Concerning Global Pharma Market
As per World Trade Organization (WTO), from the year 2005, India granted product patent recognition to all New Chemical Entities (NCEs) i.e., bulk drugs developed then onwards. This introduction of product patent regime from January 2005 is leading into long-term growth for the future, which mandated patent protection on both products and processes for a period of 20 years. Under this new law, India will be forced to recognise not only new patents but also any patents filed after January 1, 1995. Under changed environment, the industry is being forced to adapt its business model to recent changes in the operating environment.

India’s Patents Act should ensure that it does not exceed the requirements of Trade-Related Aspects Of Intellectual Property Rights (TRIPS), and that prioritizes access to medicines and public health, while retaining the right to participate in the compulsory license scenario. India should lead a movement of developing nations and create a Trade-Related Aspects Of Intellectual Property Rights (TRIPS) south and G-20 alliance is a step in that direction.

Price Control
The Pharmaceutical Price Control Policy carried forward earlier governmental initiatives in terms of ensuring quality drugs at reasonable prices, strengthening of indigenous capability for cost-effective production, reducing trade barriers and providing active encouragement to in-house R&D efforts of domestic firms. The objective is to increase revenue and lower prices of medicines by using fiscal deterrent on Maximum Retail Price (MRP).

This change may have had some impact in terms of magnifying the advantage to industries located in the excise free zones. This also succeeded in attracting some small pharmaceutical firms to these zones. This development indicates the heightened sensitivity of the government towards consumer access to medicines at reasonable prices and keeping a check on profit mongering by the industry.

In addition to the Quality (GMP, GLP, GCP), Intellectual Property Rights (IPR) and drug price control change initiative by the Indian Pharmaceutical Regulatory Agencies, the Indian Pharmaceutical manufacturers will have to face the challenges in the subsequent areas to remain in completion in to the global market, which are listed below:

Quality by Design – New Perspective to Product Development: With the advent of ICH-Q8 and ICH-Q11, guidelines have revolutionised the product development concept and Quality design has become the buzzword in the pharmaceutical world and to that India is no exception. The US Food and Drug Administration (FDA) is planning to make the submission of Quality by Design (QbD) document mandatory for all the New Drug Application (NDA) applicants from January 2013. All the manufacturers exporting to the US, will now have to submit an entire set of documents supporting their product, right from its inception stage to the US regulatory authority while filing for approval. The documents submitted should support the companies claim on how effective and efficacious their product is from the design stage itself. Failing which there are chances of their application being rejected by the FDA officials.

QbD is a concept that is introduced by the US FDA with an aim to understand the design and development of the pharmaceutical formulations and manufacturing processes to help ensure quality of the end product. On this occasion, the International Pharmaceutical Excipients Council (IPEC) has urged all the Indian manufacturers exporting to the US to update and prepare themselves on the procedural requirements so that they will not be taken by surprise while filing any NDA applications.

Design of Experiments (DOE) is the most effective method to achieve product and pro¬cess efficiency and optimisation. Design of Experiment (DOE) studies can help develop process development knowledge by revealing relationships, including multifactorial interactions, between the variable inputs (e.g., component characteristics or processing parameters) and the resulting outputs (e.g., in-process material, intermediates, or the final product).

The application of Quality by Design principles is beginning to be well established in the pharmaceutical industry. In particular, the demonstration of the science and risk-based approaches being applied to specific subsets of the drug product design or processing has been discussed intensively during the past several years. Therefore, it is now time to widen the scope of QbD across multiple unit operations, including important aspects of the drug substance.

Model development and implementation is a core principle to employing a QbD approach in drug product design and process scale-up. The advantages in taking this approach are realised through the ease of visualisation or mathematical expression of data sets for greater process understanding, which leads to clear decision making and results in superior product quality.

There are several model types that can be developed and used at every stage in the QbD process. A favored approach is to begin with the end in mind by outlining up front a clear plan toward model design and development for the drug product process, considering how each model will be used, limitations, assumptions, qualification, and maintenance. The experimental approach to the development of each model should consider the type of model (mechanistic or empirical), selected variables, scale dependency and relationship to the overall drug product process. Once a model has been developed, steps are needed toward implementation through qualification of the model and evaluating uncertainty in predictions. Finally, for models selected for use in commercial manufacture, a maintenance plan is needed to support product life cycle.

New Concept in Facility Design:
Manufacturing plants will increasingly utilise modular building strategies. Facilities will include disposable process equipment, enclosed clean rooms around process equipment, and lean design concepts. This approach provides significant cost savings and reduces start-up time frames for new facilities. Designing outcomes into manufacturing processes via quality-by-design concepts will be critical to reducing costs, increasing efficiencies, and assuring regulatory compliance.

Flexible facility design will contribute to reduced financial risk as products progress from Phase 1 to Phase 3. Traditional approaches require investment of millions of dollars into a facility for a product to be manufactured in the hope that the candidate will succeed in Phase 3 testing. While agile and adaptable facility designs will become more widespread, dedicated manufacturing facilities will still be required under certain conditions, including large-volume products with high API and/ or drug product demands, manufacture of highly potent or toxic drug substances, and the need for specialised processes.

The Indian pharmaceutical industry shall ensure that essential drugs at affordable prices are available to the vast population of this sub-continent and also continue providing employment for millions. India shall implement all the rules and regulations, which guide, monitor and control the activities of the providers of the healthcare system in the country and shall examine the way to bring them up to international standards.

The government should implement the recommendations of Mashelkar committee and constitute the Central Drug Authority at the earliest. The basic course of education should be designed to ensure that the newly qualifi ed pharmacist has the necessary knowledge and skills to commence practicing competently in a variety of settings including community and hospital pharmacy and the pharmaceutical industry. Continuing professional development must then be a lifelong commitment for every practicing pharmacist.

Concept of National schools of pharmacy should be established to develop and introduce model curriculum. Pharmacists should become knowledgeable to participate in medication management and outcome monitoring. Pharmacy profession should orient concept of pharmacy practice at community and hospital pharmacies through appropriate training and compensation.

The pharmacy profession will make the clinical trial industry in India to grow to over a billion dollars in the next fi ve years and position itself as a destination of choice for CRO services by way of strict implementation of patent laws, single window clearance of clinical trial protocols by regulatory clearances and shall accord industry status to this sector. India will emerge as a major global player in the fi eld of pharmaceuticals exports and as a provider of quality medicines at low costs. It shall also emerge as a major player in the generic drugs market in USA and Europe. India shall attain new heights in herbal drugs research in shaping Indian Systems of Medicine into a popular system of medicine of the future for holistic health care and ensuring health care for all - especially for the welfare of the poor.

The focus of Indian Pharmaceutical Regulatory bodies is now shifting towards the risk management and science based GMP regulations with the affordability of quality medicines. The need of the hour is to change the attitude by the Indian Pharmaceutical Manufactures from 'What will happen to others, will also happen to me' to 'We resolve to make our industries compliant to regulatory requirements by converting industries research and innovation driven'. This too is true that when our intentions are clear and our efforts are consistent in the right direction, nothing is impossible.

All changes and challenges are always tough but facing them with determination yields a long lasting success!