India has become a major producer of generics drugs and is now the largest exporter of generics in the world.1 These exports go to over 160 countries, including the United States, Australia, Russia, and nations in Asia, the Middle East, Africa, and Latin America. Forty percent of generics demand in the US is met by Indian companies.2 India’s top manufacturers are also entering the biosimilars market, with more than 50 biosimilar products approved by the Central Drugs Standard Control Organization (CDSCO), India’s pharmaceutical regulatory body. The market for Indian biosimilars has been largely domestic or emerging markets, but manufacturers are setting their sights on the lucrative EU and US markets.

However, quality issues remain a challenge, which manufacturers are working hard to address. Quality concerns will play an especially important role in the global acceptance of Indian biosimilars, due to their more complex manufacturing process. Following lapses in quality standards and data-related issues as pointed out by the US FDA, Indian drug makers have invested in modern technologies and automated processes and have mostly adopted world-class operating systems to ensure deviations are minimized, according to Vikas Dandekar, Editor, ET Prime, published by The Economic Times of India. Maintaining consistency, being inspection-ready at all times, and maintaining a culture of quality are ongoing challenges.

According to Dandekar, large companies are leading the way in creating a “culture of quality” by implementing changes such as electronic batch records, daily staff meetings to understand how better quality can be assured and standardized, and identifying the root causes of quality issues to fix problems where they originate. Automation is being introduced wherever human intervention can be eliminated.

One company that has led the way in creating a culture of quality is Zydus Cadila. After addressing concerns surrounding aseptic procedures expressed in a 2015 FDA warning letter, the company has had zero citations in three subsequent audits, said Dr. Ranjana Pathak, President of Global Quality, Medical Affairs, and Pharmacovigilance at Cipla Pharmaceuticals. One strategy Zydus Cadila has used to improve quality manufacturing is the GEMBA technique, a strategy that encourages management to visit the manufacturing area for direct observation of procedures and processes in place.

Pathak stated that a culture of quality at Cipla is being built by way of learning and development. Individuals are sent for both external and in-house training, and the company has created Learning Academies for chemists, microbiologists, and production operators. “This has proven to be very beneficial to the ‘do it right first’ concept,” said Pathak, although he conceded that “our work is not complete—this journey is arduous and long.” Pathak added that the company has also improved transparency by making quality-related data sharing a top priority. Monthly Quality Council meetings are held to discuss findings of internal audits and results of all key quality indicators so that the company can course-correct where needed and stress the need for accountability and ownership.

GMP Growth

The Indian government has expressed interest in joining the Pharmaceutical Inspection Convention and Pharmaceutical Cooperation Scheme (PIC/S). Membership is open to any regulatory agency that has a system of Good Manufacturing Practices (GMP) inspection controls in place that is equivalent to the requirements of current PIC/S members.3  This interest signifies a growing acknowledgment of the need for transparent compliance with the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) quality guidelines such as ICH-Q10, which provides guidance on implementing quality systems to ensure successful implementation of GMP throughout the product life cycle.

Another key step toward integration of GMP guidelines by Indian manufacturers is the recent draft update by the CDSCO of Schedule M. Several changes have been brought about to streamline drug regulatory mechanism in India. Recently, draft Drugs & Cosmetics (Amendment) Rules, 2018, to upgrade Schedule M of the Drugs & Cosmetics Rules, 1945 on “Good Manufacturing Practices and Requirements of Premises, Plant and Equipment for Pharmaceutical Products”4 and the draft guidelines on “Good Distribution Practices for Pharmaceutical Products”5 have been released. Once firmed up, both will be significant steps toward ensuring quality standards, according to Kanchana TK, Director General of the Organisation of Pharmaceutical Producers of India, an advocacy body that represents research-based pharmaceutical companies in India.

Standards Expanded

On 3 April 2017, the Drugs & Cosmetics Rules were amended to require bioequivalency testing of generic drugs that fall into Category II (low solubility and high permeability) or Category IV (low solubility and low permeability) in the biopharmaceutical classification system. This means that generics manufacturers are now required to demonstrate that the rate and extent of their product’s absorption is not statistically different from those of a reference product when administered at the same molar dose. This brings the CDSCO in line with almost all other regulatory authorities, including the FDA and the European Medicines Agency (EMA). The rationale behind requiring bioequivalency testing for generics lies in the fact that even though the chemical structure of the active pharmaceutical ingredient of a generic drug is identical to that of the reference product, the formulation may be different, which could affect absorption and therefore impact both safety and efficacy.

In 2012, India issued Guidelines on Similar Biologics. The standards set forth in this initial guideline were relaxed in a 2016 revision.6 Biologics continue to be treated almost like a chemical product and are regulated under the Drugs & Cosmetics Act, 1940, and the Drugs & Cosmetics Rules, 1945,” Kanchana said. Marketing approvals for a biosimilar product are granted on the basis of data available from other countries and based on similarity being established in India by way of comparative clinical trials. The only additional requirement for biosimilars manufactured in India is the requirement for preclinical approval by the Review Committee on Genetic Manipulation. To ensure the quality of all biologic products, it is critical that the CDSCO move toward regulating them under a separate set of regulations, said Kanchana.

While drug regulations are evolving, India has a long way to go.

Despite the lack of strong guidelines for biosimilars, some Indian companies are meeting global standards for biosimilar production, Dandekar pointed out. After receiving observations from the FDA regarding its biosimilars processes, Indian drug maker Biocon was able to quickly make corrections and go on to gain several FDA biosimilar approvals, with filing from its partner Mylan.

While drug regulations are evolving, India has a long way to go. Further, it is only through strict implementation and enforcement of these changing regulations that the quality standard of drugs can be ensured, said Kanchana. And to release the product into the global market, Indian companies must meet international standards, which recent cultural changes should ensure that they do. According to Dandekar, the industry has already demonstrated a serious commitment to consistent drug quality through multiple efforts ranging from training of staff to investing in facilities upgrades. One area of training of particular importance is the collaborative effort between CDSCO and the FDA to train additional Indian FDA inspectors of pharmaceutical manufacturing facilities.6 These trainings will help to ensure that there are sufficient numbers of inspectors on the ground who are versed in international techniques for conducting inspections. The Indian government is investing in hiring additional inspectors and enhancing their training through programs such as the FDA collaboration.

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