Abstract: Use of Biotechnology for production of Biotech, drugs has its advent in India only in the past 10-12 years. The core research in this field is not very substantial. India, however, can look at grabbing the opportunity of production of off-patent drugs or those likely to be off cover in near future. These drugs "biogenerics" offer vast market potential of US$ 8-10 billion. On the other hand there are many challenges in this area pertaining to the production and bioequivalence studies of these molecules, which is a very complex issue unlike the traditional generics of synthetic origin. Besides this the Indian scenario and its likely line of action has been discussed.

In the wake of the tremendous biotechnological revolution, coupled with GATT & WTO leading to globalization, the drugs and pharmaceuticals industry in India is one of the most important sectors that will be influenced. Already, focus is on the drugs going off patent in the coming 10-15 years, and many Indian companies are trying to encash on these opportunities as a safer bet than resorting to the New Drug Discovery Research.

Thus, in the areas of the traditional synthetic drugs many companies are concentrating their interests and are in a race to perform bioequivalence studies and file ANDAs to enjoy marketing exclusivity for a limited period in their post patent expiry periods.

On similar lines the post-GATT & WTO era is envisaged to witness lot of focus on drugs of biotechnological origin going off patent, i.e. bio-generics. Bio-generics are an important opportunity, as was generics earlier. Several large drugs would go off patent in the next three to five years. These would include first generation interferons and interleukins that already enjoy substantial markets. Moreover, biogeneric companies, just like their counterparts in the traditional synthetic drugs, would also like to enjoy marketing exclusivity for limited periods of the post patent expiry, by quickly filing the biogeneric ANDAs.

This indeed sounds good enough, and appears to be an excellent opportunity for the Indian biotech pharma companies to reap a good harvest from the fact that over US$ 8 billion worth of bio-drugs will lose patent protection in the next five years.

Is the issue of Biogenerics an excellent opportunity or a challenge?
Opportunity:
The table featured here is a representative of a few examples of drugs of biotech origins worth over US$ 8-10 billion (at patented drug prices) that are already off-patent or set for patent expiry by 2005. Though this is a smaller opportunity compared to traditional drug patent expirations (over US$ 35-40 billion over the same period), nonetheless a large market is waiting to be tapped by bio-generic companies, world over including the Indians

Challenges
In case of traditional generics of synthetic chemical origin the applicant has to only prove the bio-equivalence of this with the patented product. The applicant can use the clinical data submitted by the patent holder to the FDA and draw inferences from this regarding the efficacy and safety of its generic substitute. In most cases, the manufacturing process used (as long as it is c-GMP compliant) has no bearing on the drug''s potency and mechanism of action.

However, in the case of bio-generics, having the same product would not necessarily mean having a bio-equivalent product, or one with a clinical profile similar to the patented drug. For example, there are three beta-interferons in the market, but each has its distinct profile with regard to potency, efficacy and side effects, and each of their labels reads, differently, both on warnings as well as on dosage. Similarly, there are various forms of insulin, each modified by proprietary manufacturing processes.

This is because of a fundamental fact that most of these products are proteins in nature, which are complex molecules, and the actual make-up of the protein, its mechanism of action, its expression all depends on their source as well as the manufacturing process employed. These include the cell line (which particular human/ animal cell has been used to synthesize the protein) used as well as the culture employed to grow the cell lines. Culture media is often proprietary and can impact carbohydrate structure in a significant way. It can also impact the way in which proteins combine with carbohydrates to form glyco-proteins (erythropoeitin, for example, is a glycoprotein)

Follow-on or generic companies may not have access to proprietary assays developed by the patent holder to test a biologic''s composition. This poses a very important question as to whether the applicant company for the Bio-generic will have to conduct at least some clinical trials to establish bio-equivalence?

The Indian Scenario
While Indian companies are beginning to acquire the skills necessary for commercial production of biological products, core research into genetic science has so far not evolved in India. Indian companies are currently working on proven protein/ enzyme targets from their international counterparts and attempting to prepare copies of the same. The challenge, thus far, for Indian biotechnology has been to work out a viable production cycle for these products. Given the complexities of protein synthesis, and the strong impact of manufacturing, processes (such as cell lines, and growth cultures) on protein expression, it is not easy to move from a validated, identified and characterized protein to a marketable product in a short span of time.

The Indian Biotech Pharma Sector is basically divided into three types or pockets. First constitutes of the already established generic companies like Wockhardt, Dr. Reddy''s, Cipla, Zydus Cadila, which have started separate biotech divisions and plan to build up their biotech portfolio.

Second type is that of the pharma companies that have significant biotech sales, including the resale of imported products. This set includes US Vitamins, Fulford India, and Piramal Healthcare.

The most important is the third type with significant contribution so far and include a well-focused and solely dedicated approach only pertaining to biotechnology products. This set includes Shantha Biotech, Bharat Biotech, Biocon, Avesthagen, Panacea Biotech and others.

While Indian companies are beginning to acquire skills necessary for commercial production of biological products, core research into genetic science has so far not evolved in India. Recombinant DNA technology is one area in whose few pockets India has developed skills, e.g., Hyderabad-based Shantha Biotech has produced and commercialized successfully the hepatitis B vaccine and then alpha-interferon which promises to be a powerful tool to help Indian companies launch many of the large bio-drugs going off patent in the next few years. Indian companies in near future can also focus on developing "me-too drugs" or "Analogs" of already established and proven patented drugs of biotech origin. This can be done by playing or tweaking with the protein of the drug by slightly altering its amino acid sequence with additions/ subtractions to it.

Further, the Indian companies can also focus on following:-
- To consolidate on indigenous technology developed for Hepatitis B vaccine & erythropoetin.

- Also to drive hard and consolidate on interferons for cancer and human insulin for diabetes. Significant potential can be visualized in these two products as presently whatever are sold in India are totally imported and hold great demand in the country. To summarize, the area of biogenerics is free of potential opportunities provided we meet the various challenges it poses.

- The authors are with Sinhgad College of Pharmacy, Pune