As the patent protection or market exclusivity of the first generation biopharmaceuticals expires over the next few years, the rush for manufacturing the biogenerics has become enormous. Assuming that the market penetration rate for biogenerics would be same as that for generics, there exists a US $2.00 billion industry. Although biogenerics are difficult to make and regulatory procedures are still not in place, a large number of companies in the world (Table-I) and most of the Indian biotech companies are already making biogenerics. What makes biogenerics so attractive clinically and economically are the inherent qualities of these molecules. What are biogenerics Biogenerics are the copied version of the biopharmaceuticals. Biopharmaceuticals, in turn, are the drugs/vaccines/ biologicals derived from living organisms through biotechnological tools. These are known to be more specific, less toxic and offer better survival benefits, disease modification & pharmaco-economic benefits to patients than the traditional pharma products. At the same time, they are complex molecules and are difficult to consistently manufacture in quality and quantity. Table-I Companies producing biogenerics Company Product/s Cangene (Canada) All existing molecules; limited clinical trials also GeneMedix (UK); ties with Chinese institutes All existing molecules: Microbix (Canada) All existing molecules Rhein Biotech (German); ties with India & Argentina Hepatitis B; Teva (Israel); ties with Bio-Technology General, USA Market HGH LG Chemicals (Korean); ties with Western companies EPO; insulin & interferons Stada (German); ties with DSM Biologics, Canada Bulk active substances; erythropoietin, filgrastim, interferon alpha & interferon beta. E.Merck (German); ties with Technofarma, Argentina HCG, interferon in early eighties Source: Compiled from -The future of Biogenerics A large number of biopharmaceuticals are already available i.e. alpha inter-feron, erythropoietin, human growth hormone, human insulin, granulocyte-macrophage colony stimulating factor, recombinant hepatitis vaccine and some interleukins. Patents protect all these products. However, a number of these will either loose patent protection or market exclusivity soon opening the door for the manufacture of generic biopharmaceuticals i.e. biogenerics (Table-II). Like generics, biogenerics are : ?pharmaceutical preparations involving a biologically active substance stemmingfrom modern biotech tools; ?essentially similar to an original biopharmaceu-tical whose substance patent has expired; ?could be approved through a simplified abbreviated registration process; ?sold under the generic substance name as opposed to a brand name (e.g., EPO as opposed to Epogen). Table-II Products that face patent expiry by 2007 BRAND NAME GENERIC NAME MARKETER PATENT EXPIRY Cerezyme/Ceredase Alglucerase Genzyme 2001 Humulin Human insulin Eli Lilly 2001 Intron A Interferon alpha-2b Schering-Plough 2002 Avonex Interferon beta-1a Biogen 2003 Humatrope Somatropin Eli Lilly 2003 Genotropin Somatropin Genentech/Pharmacia/ 2003 Betaseron Interferon beta-1b Chiron 2003 Nutropin Somatropin Genentech 2003 Epogen/ Procrit Epoetin alfa Amgen, Johnson & Johnson, and Sankyo 2004 Recormon Epoetin beta Roche 2005 Novolin Human insulin Novo Nordisk 2005 Activase Alteplase Genentech, Boehringer Ingelheim, Mitsubishi, and Kyowa Hakko Kogyo 2005 Protropin Somatrem Genentech 2005 Neupogen Filgrastim Amgen and Roche 2006 Engerix-B Hepatitis B vaccine GSK 2006 Filgrastim GM-CSF Amgen 2007 Source: Compiled from References 1,2,3,4 Why Biogenerics Biogenerics are ideal candidates meeting the criteria for the successful development of generics such as: ? a good global biogeneric market of about US $2 billion. Even the individual product meet market specification for success i.e. EPO still shows sale of app. $3 billion and interferon alpha more than $600 million; ? an increased demand from the consumers as these are cheaper versions; ?relatively low manufacturing cost resulting into good discounts on generic version; ?simple non-proprietary formulation. Challenges Despite several advantages, a number of key issues emerge while dealing with biogenerics, important among which are: Patents Patent coverage for biopharmaceuticals represents a thorny path for biogenerics as most of the biotech patents are complex and unclear; Monopoly by the originators The biopharmaceuticals innovators have been successfully able to preserve their franchises through legal manipulations and lobbying, which include: ? Propagating the approach "the process makes the product"; ? Adopting an aggressive legal stand and suing any patent infringement eg. Amgen defending EPO''s position against Genetic Institutes and now against Transkaryotic Therapies; ? Repositioning the molecule through new enhanced formulations offering tangible benefits eg. Novartis with Neoral, its blockbuster transplantation drug; ? Accelerating the introduction of a second-generation product, and possibly phasing out the original molecule: Amgen''s stra-tegy with NESP, the novel eryth-ropoiesis stimulating protein currently under registration. Comparability problems Hatch-Waxman rule cannot be applied in case of biogenerics. The rule allows generic manufacturers to submit Abbreviated New Drug Application, ANDA, in US for approval to market a generic product. The process does not require firms to replicate extensive clinical trials with generics, but they must prove the essential similarity and conduct tests to prove its bioequivalence to the brand name drug. In case of biogenerics, such comparisons are difficult to make. Most biogenerics being proteins, essential similarity need not only be in composition but in conformation as well. Lack of bioequivalence Usually, a biopharma product is process specific. The expression/vector system, production and purification process, facility/ equipment, analytical techniques etc. used by the copying firm are usually different from those of the brand manufacturer. Such changes may affect the amino-acid sequence, physico-chemical and biological properties of the end product. Even minor modifications in a bioprocess such as changes in agitation or aeration systems, reactor size, operating conditions or culture media, changes in the cell line or microbial system as well as different post-translational proces-ses such as glycosylation, purification, folding or impurity profiles may change the functioning of the molecule and could result in an altered safety and efficacy profile. In order to evaluate these parameters, the second manufacturer may require conducting extensive and expensive clinical trials to gain regulatory approval defeating the basic purpose of making a biogeneric. Lack of Specific Regulations An abbreviated process for generic biopharmaceuticals does not exist even in countries like US and Europe. In the U.S., biologicals are approved by Center for Biologics Evaluation and Research (CBER) under the Public Health Act, whereas the conventional drugs are regulated by Center for Drug Evaluation and Research (CDER) under the U.S. Food, Drug and Cosmetic Acts. While the "biologics" approved under the CDER are theoretically subject to generic competition, biologicals approved under the CBER are specifically excluded from the generic abbreviated approval process applied for synthetics on the assumption that current bioanalytical methods are not adequate to assess biopharmaceutical equivalence. The company who has to make a biogeneric may have to go through the same process as the innovator. Interestingly, some well-characterized recombinant proteins such as growth hormone and insulin have been registered as pharmaceutical drugs in the US through the CDER creating a kind of anomaly. The first draft of the European guidelines on comparability of biotechnology-derived proteins, drawn up in 2000 by the Commi-ttee for Proprietary Medicinal Products (CPMP) at the EMEA (European Medicines Evaluation Agency) suggested that there are no ''universally'' applicable guidelines and each product may have to be reviewed on a case-by-case basis. India into Biogenerics Biogenerics is one of the several opportunities India wishes to tap in coming years. The Indian competitive advantage stems from the highly competitive downstream processing skills and low manufacturing cost base i.e. almost 50 percent lower than those of generic manufacturers in the West. Major biotech companies as well as pharma giants are all set to take advantage of this boom. The Indian Government has granted marketing as well as manufacturing license to about 25 recombinant therapeutics including recombinant insulin, human growth hormone, interferons, hepatitis B vaccine, interleukins & Tumor Necrosis Factor. Several of these are already in the market through indigenous production i.e. hepatitis B, Interferon alpha, EPO, Filgrastim etc. and others are in the pipeline. Biogenerics production in India Shantha Biotechnics, Hyderabad - The company has the distinction of producing the first recombinant product in the country i.e. Hepatitis B vaccine (Shanvac). It has also put alpha interferon 2b (Shanferon) in the market. Several other products, namely GM-CSF, HGH, r-insulin, streptokinase etc. are in the pipeline. Bharat Biotech International Limited - BBIL has its for Revac-B, a recombinant Hepatitis B vaccine in the market. The company has developed a new therapeutic molecule, Lysostaphin, and is working towards typhoid vaccine, streptokinase, EGF and recombinant human insulin as biogenerics. Wockhardt - Collaborating with Rhein Biotech, Wockhardt successfully developed and launched its recombinant Hepatitis-B vaccine, BIOVAC-B in 2000. Its second recombinant biopharmaceutical EPOX [r-erythropoietin] was launched in March 2001. The company is targeting the launch of at least one recombinant product every year, for the next 3-4 years. Dr Reddy''s Laboratory - An internationally known generic firm, DRL has entered into biogenerics and recently launched its first biotechnology product, GRASTIM (filgrastim), GM-CSF. There are about 10 other products at various stages of development in key therapeutic segments such as cancer, immunology, cardiovascular and diabetes. Biocon - Traditionally, a fermentation company, the company has initiated bioprocessing and biopharmmanufacturing activities and is working towards human r-insulin (through a joint venture with Shantha Biotech), streptokinase, G-CSF and EPO. Cipla - Cipla, one of the World Health Organization''s preferred anti-AIDS drug suppliers is planning to market and manufacture biogenerics including interferon, erythropoietin and hepatitis vaccines. Regulations on Biogenerics in India India follows a three-tier system of Institutional BioSafety Committee (IBSC), Review Committee on Genetic Manipulation (RCGM) and Genetic Engineering Approval Committee (GEAC) for clearance and regulation of the recombinant products. Most of the biopharmaceuticals being produced in the country are biogenerics. All biogenerics cleared so far i.e. Hepatitis B vaccine, erythropoietin, GM-CSF, alpha interferon etc. have followed the approval procedure, which are a mix of the ones required for New Biological Entity (NBE) and generics. The molecules/vaccines have been cleared through three-tier mechanism adopting special abbreviated procedures and constituting special committees. This has been possible as the gold standard in the form of original products was available to evaluate the physico-chemical and bioequivalence properties of these entities. How far these procedures may apply to new molecules is still to be seen. The first NBE that is going to face the approval system would be the anthrax vaccine. Hence, despite a large number of biogenerics being produced indigenously, the regulatory mechanisms are not very clear as to what has to be followed in case of biogenerics vis-à-vis NBE. Future Direction The dogma that the "process makes the biotech-product" has been challenged and the concept of "product comparability" is more gradually being more accepted than "essential similarity" for biogeneric products. It has also been experienced that comparable biologics can be obtained through different processes. There are at least five HGH products currently available, each by different companies i.e. Pharmacia, Ferring, Lilly, Nova and Serono, based on distinct processes and involving different expression systems, namely Standard E.coli; Special strain of E.coli and transformed mouse cell line, resulting into a 191-amino acid long human pituitary growth hormone showing the same profiles in terms of amino acid sequence, potency, safety and efficacy. Today, it is, hence, possible to demonstrate through pharmacokinetic, pharmacodynamic, and clinical studies that the biopharmaceutical versions are comparable and bioequivalent to the original product leaving vast scope on biogenerics open for biogeneric firms. However, there is an urgent need for regulatory standards in both developed as well as developing world to realize this potential. --- The author is Director, Deptt. of Biotechnology, New Delhi