India is poised for growth in biotechnology with an abundance of government initiatives and biotech parks under construction in cities like Hyderabad, Bangalore, and Pune. Biotech professionals, including many CEOs of Indian companies, convened recently in HiTech City, near Hyderabad, for “BioAsia 2007”.
Varaprasad Reddy, a biotech pioneer, founded Shantha Biotech (www.shanthabiotech.com)in 1993. The company developed a Hep B vaccine, which was marketed in 1997. The company also developed interferon alpha, EPO, and several other vaccines. In 2006, Mérieux Alliance, a France-based company, acquired a 60% controlling stake in Shantha.
Regulatory Guidelines for Biosimilars
Intas Biopharma’s (www.intasbiopharma.com)facility in Ahmedabad is used for manufacturing C-GSF and EPO. Dr. Dhananjay Patankar, CTO of Intas Biopharma, was a member of the Mashelkar Task force that recently helped draft the regulatory guidelines for approval of biosimilar products in India. According to Dr. Patanakar, the path required for approval of a biotech product is as follows: (1) the Department of Biotechnology approves protocols up to animal toxicity studies; (2) the Drug Controller General of India approves clinical trials and final product for marketing; and (3) The Food and Drug Control Administration, a state governing body, approves the manufacturing license based on a GMP audit, similar to the ELA concept in U.S. All these approvals can be completed within a year.
In addition, equivalence has to be shown in clinical trial subjects in randomized double-blind studies with placebo, licensed products, and new products. Approval for biosimilar products requires only Phase III clinical trials for 100 patients, and the cost for this is approximately $100,000 per 100 patients.
Bharat Biotech (www.bharatbiotech.com), founded by Dr. Krishna Ella, has three recombinant products on the market including r-EGF and r-streptokinase and is now focusing on vaccine production. According to Dr. Ella and other CEOs, India does not have well-established R&D programs, and innovation will be the key to success. Several companies are contemplating rushing to get biosimilar products into the market in India.
There are over seven companies producing recombinant products, Reddy reported. However, only one or two companies have generated their own clones and cell lines. Many of the companies license recombinant clones from CMOs in Cuba or other countries. All companies that manufacture and market insulin and the Hep B vaccine in India are using Pichia or Hansenula yeast. It is not clear why Indian companies use these yeast species as there are no FDA-approved therapeutic proteins from Pichia or Hansenula in the U.S. or Europe.
Insulin, the Hep B vaccine, GM-CSF, and several other FDA-approved therapeutic products are manufactured using S. cerevisiae. Nevertheless, since the introduction of these products from Indian companies, the cost of insulin and Hep B vaccine has dramatically lowered in the Indian market, and now these products are available for mass production in India.
There is no EMEA- or FDA-approved GMP plant for manufacturing recombinant proteins in India, said Dinesh Dua, former president of Wockhardt.
Products currently on the market are EPO with sales of $22M, c-GSF with sales of $11M, interferon at $22M, streptokinase with sales of $16M, and insulin with $55M in sales, and the market is growing at a rate of 20–30%. Potential blockbusters might be EPO, peg-GCSF, insulin, streptokinase or other thrombolytic agents, and mAbs that are off patent in the U.S.
India has the largest number (>70) of U.S. FDA-approved plants outside of the U.S. (for small molecules) and also a large number of ANDA approvals. However, the expertise required for manufacturing biologicals is vastly different and not yet available within the Indian biopharma industry. Most of the CEOs at BioAsia 2007 agreed that the most interesting challenge ahead will be to understand and implement the regulatory requirements for biosimilars in order to market them in regulated markets.
Shasun (www.shasun.com) has a facility in Chennai and is expanding to house fermentors for new expression systems. Jatin Vimal, heads the biotechnology unit for Shasun, and said the company can tap into its pegylation expertise to produce more stable recombinant proteins. The company’s chemists have been successful in synthesizing various PEG moieties, and its protein chemists have experience optimizing and characterizing conjugation reactions.
According to Vimal, research efforts are also under way for developing novel third-generation PEG moieties at Shasun that could impart favorable properties for conjugation and protein pharmacokinetics.
Anu Acharya founded Ocimum Biosolutions (www.ocimumbio.com), which now has offices in the U.S. and Europe. The company is a provider of software for laboratory information management systems, bioinformatics solutions, and microarrays.
Rajesh Jain, CEO of Panacea Biotec (www.panaceabiotec.com), said his company’s focus is not to rush to market with biosimilar products, but rather to innovate. In his opinion, there are hardly any visible efforts by the biopharmaceutical industry to develop de novo new biomolecules in spite of the fact that India has a product patent regime in place. Panacea has five R&D centers focusing on different areas of development, and the focus of its Biopharmaceutical Research Center is to develop novel products that will respond to infections or diseases prevalent in the Indian population.
Multinational companies have already established a presence in India in areas such as equity participation, contract manufacturing, research relationships, joint product development, commercialization and manufacturing relationships, and product/technology in-licensing and out-licensing. As the cost of bringing a biosimilar product to market in India is approximately $10–20 million, according to Dr. Ella, India expects accelerated growth in biotechnology in the next decade.