Recombinant DNA Therapeutic Products

Code No: TMS167 Price: Rs1100/- Category: Biotechnology


Summary  : Recombinant DNA (rDNA) technology or Genetic Engineering is an umbrella term for a set of experimental techniques that enable individual genes and DNA sequences to be manipulated resulting in genetically modified organisms (GMO) and products. There have been many potential applications of rDNA in medicine, agriculture and industry. Conventionally proteins and other biological products, processed from human or animal serum or tissues, often are of low purity. Production of therapeutic products by the rDNA technology has several advantages such as provision of drugs that could not be produced by conventional methods, manufacture of sufficient quantities of drugs and provision for manufacture of safe drugs. The global sale of recombinant pharmaceutical products has been very impressive with total value of approx. Rs 21253 billion in 1996. In India, nine products have been approved for marketing – insulin (diabetes drug), alpha interferon (cancer drug), hepatitis B vaccine, GMCSF, G-CSF, blood clotting factor 7, erythropoietin (drug used in kidney failure), streptokinase (drug administered in heart attacks) and human growth hormone. All these products except Hepatitis -B are being imported. In 1996-97 the total import of these products was of 237 crores. The four major recombinant products with high market potential in India are human insulin, alpha interferon, and erythropoietin. In India technology has been developed in different centres like ICGEB (insulin), IMTech Chandigarh (streptokinase), and Bharat biotech. The study is beneficial to Biotechnology scientists, medical institutions, pharmaceuticals and doctors

Year of Publication : 2002

Table Of Contents : CHAPTER 1: INTRODUCTION; CHAPTER 2: RECOMBINANT DNA TECHNOLOGY AND ITS ADVANTAGES- Principles of rDNA technology, Advantages of rDNA therapeutics; CHAPTER 3: APPLICATIONS OF rDNA THERAPEUTICS PRODUCTS - Introduction, Hormones, Cytokines, Plasminogen activators, Blood clotting factors, Growth factor(s), Therapeutic vaccines; CHAPTER 4: STATUS OF TECHNOLOGY AVAILABILITY IN INDIA - Need for indigenous technologies, Status of research and development, Development of commercially viable rDNA technology, Proposed linkages for technology development, Likely centres in India; CHAPTER 5: CURRENT MARKET STATUS AND POTENTIAL - Introduction, Approved recombinant products, Market status and potential, Analysis of price structure, Industry scenario; CHAPTER 6: PATENT SCENARIO AND TRENDS - Status of Indian Patents Act, Impact of new patent regime on Indian pharmaceutical industry including biotechnology, Patent scenario in other countries, Expected trends in rDNA therapeutics; CHAPTER 7: REGULATORY ISSUES RELATED TO RECOMBINANT THERAPEUTIC PRODUCTS IN INDIA - Introduction, The essence of the clinical trials, Drugs and cosmetics Rules 1988 (8th Amendment), Coverage of biosafety rules nad regulations, Current biosafety guidelines, Implementation of guidelines for research activities, Large scale industrial processes and operations, Risk assessment, Import and shipment, Price control issues, Legal constraints; CHAPTER 8: Identification of gaps and proposed strategy

Recombinant DNA technology has made a revolutionary impact in the area of healthcare by enabling mass production of safe, pure and more effective versions of various biochemicals used as therapeutics. It has helped in the production of new therapeutics as well as safer and/or effective versions of conventionally produced therapeutics. Further, since the recombinant therapeutics are identical to human proteins they do not induce unwanted immunological responses and are free from risk of infection as is commonly observed in case of similar products isolated from non-human sources.

At present about 30 recornbinant therapeutics have been approved globally for commercial use. In India 12 of these are presently being marketed. All of these except hepatitis B vaccine are being imported and consumed. The indigenous production of hepatitis B vaccine was initiated by Shantha Biotechnics Ltd., which resulted in the reduction in price of the imported vaccine from Rs. 487 per dose (in 1996) by SmithKIine Beecham to an average of Rs. 150 per dose. This has lead to increased consumption and three more companies have started indigenous production. The Indian products have now a higher market share. Keeping in view the above, it is imperative that other products are also indegenised expeditiously so that its benefits can be harnessed on a large scale. The present report includes the market status and potential of recombinant therapeutics which have been approved for use in our country. Status of technology development in India, the gaps for converting these into commercial viable technologies and strategies to bridge these gaps including the assessment of the cost, time and work involved have also been covered.

Methodology adopted consisted of desk research, Internet search, data collection through questionnaires, visits to selected institutions and interaction with experts. Efforts were made to establish contacts with all the leading industries as well as institutions working in this area. Discussions were also held with the regulatory authorities i.e. Department of Biotechnology, Ministry of Environment & Forests and Drug Controller's Office etc. The current consumption, major players, market potential and technology status etc. were arrived based on the information thus collected.

The globally approved recombinant therapeutics can be broadly categorized into blood factors, hormones, growth factors, interferons, interleukins, vaccines and other miscellaneous products. Besides the 30 approved products, it has been estimated that presently in excess of 500 products are undergoing clinical trials and it is likely that several of them will gain marketing approval each year in the near future. Greater use of combinations of recombinant therapeutics to treat specific diseases has also been projected. The therapeutic products approved in India are human insulin, streptokinase, erythropoietin, hepatitis B vaccine, human growth hormone, human interieukin, granulocyte colony stimulating factor (GCSF), granulocyte macrophage colony stimulating factor (GMCSF), alpha-interferon, Gamma-Interferon, blood factor VIII and follicle stimulating hormone (FSM. Shantha Biotechnies Pvt. Ltd., Bharat Biotech International, Wockhardt and Panacea Biotech have initiated the production of hepatitis B vaccine in the country whereas all other products are being imported as on date.

The estimated worldwide sale of these products have increased from Rs. 70.4 billion in 1990 to Rs. 330.4 billion in 2000 i.e. five time increase in the market value in a decade. Besides, an estimated annual increase of 15 - 20% in the market of already approved therapeutics, the total market is likely to increase considerably in view of approval of several new products and increasing applications of already approved products. In India, the current market of approved recombinant therapeutics has been estimated to be about Rs. 5357 million, which is approximately 1.6% of the world market and 3.2% of the total pharmaceutical market of Rs.165 billion in the country. The market of these 12 products is growing at the rate of 15% and is, likely to be around Rs. 9580 million by 2005. However, these figures reflect only about 15 - 20% of actual requirements in the country. Various factors such as lack of awareness, unaffordability and nonavailability of products are some of the reasons for the low market. Although, at present only hepatitis B vaccine is being manufactured in India, some others like cc-Inteferon, streptokinase, and erythropoietin are also expected to be locally produced shortly. As many as 10 pharmaceutical firms in the country have drawn up plans for large scale commercial production of recombinant therapeutic proteins. Leading firm namely Wockhardt, Cadila, Shantha Biotechnics, Bharat Biotech and Torrent are at advanced stages of developing production technologies. The aggregate investment in this segment in the next five years would be about Rs.5 billion.

Research and development has been initiated in India in several laboratories especially under the auspices of Department of Biotechnology, Govt. of India. Limited research activity has also been started by a few industries, although the status is way behind that of the developed countries. Certain R&D institutes have developed expression host and modified cell lines, which are expressing human growth hormone, insulin, epidermal growth factor and other important biologically active proteins. Some of these institutions have been able to obtain high level of expression of the recombinant proteins in E. coli and yeast. However, these technologies require further development especially in the area of downstream processing in order to make them commercially viable. It is expected that once the local capacities are in place, the market of these therapeutics would considerably increase as the products are likely to be available at much lower cost as compared to the imported products.

Most of the products being covered in this report have been patented before 1995 and therefore can be produced by Indian companies by developing their own clones and processes. In fact, the product patents for some of them such as insulin, interferons, human growth hormone, erythropoietin, will expire by 2005, when IPR regulations as per WTO norms comes into effect in India. Although, there has been an increase in patenting activity by Indian institutions and companies, there is a need for increased efforts for development of innovative products in the post WTO regime.

An assessment of work involved in the development of the known rDNA therapeutics in India indicates that an investigator may take two to five years depending upon the complexity and molecular weight of the targeted product. In the laboratories equipped with all the molecular biology equipments, an expenditure of Rs. 5 to 10 million is estimated for development of recombinant clone in E.coli. Rs. 10 to 30 million in yeast and Rs. 20 to 50 million in animal cell lines. In contrast, the cost of development of new products would be significantly higher. The US Pharmaceutical Manufacturers Association has estimated this cost to be around US$ 250 million in a time frame of ten years.

Several institutes have the potential for development of commercially viable technology for production of rDNA therapeutics. These include Institute of Microbial Technology (IMTECH), Chandigarh, Centre for Biochemical Technology (CBT), New Delhi, M. S. University, Baroda, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi etc. The infrastructure and expertise of some other institutes and hospitals can also be used for downstream processing and clinical trials.

In India, all the recombinant products are considered to be new products as per the current Indian Drugs Act, 1988 and therefore require the permission of the Drug Control Authorities for both import and local production for marketing purposes. As per the Biosafety Guidelines, the research work related to recombinant technology is overseen by DBT through Institutional Biosafety Committees (IBSC) and Review Committee on Genetic Manipulation (RCGM) whereas, the commercial/large scale applications are dealt with by the Genetic Engineering Approval Committee (GEAC) of the Ministry of Environment & Forests.

Although recombinant therapeutics are still not under any price control by the government, the Drug Price Control Order, 1995 (DPCO) lists insulin as one the bulk drugs for which government can fix the maximum sale price. Since, method of production of a bulk drug is not a parameter considered within DPCO, bulk insulin produced by recombinant technology also falls under the purview of the above order. However, it was found by comparing the prices of rDNA products in Indian versus international market that most of the products are being sold at much lower cost (three to seven times) in India as compared to the average cost in developed countries.

To conclude there exists a high market potential for recombinant therapeutics, which can be harnessed by indigenous technology development. This could be achieved to strengthening of linkages among various institutes having expertise in different disciplines related to recombinant DNA technology and increased interaction with the industry. Higher allocation of funds for developmental R&D as well as commercialization by the government, the industry and the financial institutions particularly the venture capitalists would go a long way in this direction.