Industrial biotechnology (IB), the third wave of biotechnology, uses biological systems for the production of chemicals, materials and energy. This technology is mainly based on biocatalysis (the use of enzymes to catalyse chemical reactions) and fermentation technology (directed use of microorganisms), in combination with molecular genetics, enzyme engineering and metabolic engineering. It enables to bring down (reduce) material and energy consumption, as well as pollution and waste generation for the same level of industrial production. Technologies include the use of plants and enzymes to generate industrial products.
Currently, IB exhibits the maximum extent of penetration in the pharmaceutical sector (15 per cent). New technologies have proven to be a boon for the pharmaceutical industry in the use of better biological production methods. Since the pharmaceutical products are of high value, added inputs in research and development (R&D) can easily be recovered. The pharmaceutical sector is thus proving to be the model for the industrial development of biotechnology.
Application areas of IB in pharma industry
Antibiotics: As per the most widely accepted definition, an antibiotic is a chemical substance produced by a microorgansims that has the capacity, in low concentration, to inhibit or kill, selectively, other microorganisms. Antibiotics are currently the third largest selling class of drugs, with a worldwide market between US $7 and $22 billion. Today there are in excess of 100 antibiotics available in the market, including ?-lactams, aminoglycosides, quinolones, macrolides, lincosamides, sulfonamides, tetracyclines and peptides and glycopeptides. In general, antibiotics are produced on a large scale by three well known and defined methodologies - fermentation process, semi-synthetic process and synthetic process - utilising plants and microbes.
Biotechnology techniques like protoplast fusion are being employed for bringing together numerous desired microorganisms resulting in enhanced production of new hybrid antibiotics where genes coding for entirely different biosynthetic pathways are cloned in a single microorganism (e.g. streptomyces). Increased antibiotic production has also been achieved through genetic manipulation leading to the reduction of feedback inhibition in the biosynthetic pathway of antibiotic production. However, absence of suitable genetic manipulation methodologies for certain bacteria has led to increasing application of genomics and combinatorial approaches for their production. In these techniques artificial bacterial chromosomes (BAC) are used as vectors to transfer the bacterial DNA to amenable host strains which allows for their stable replication and manipulation. Also, newer and selective antibiotics are being developed based on improved understanding of cell-binding mechanisms of microbes.
Vaccines: The current (annual) global vaccine market is worth more than $3 billion. These are defined as pharmaceutical suspensions or solutions of an immunogenic substance or compound(s) intended to induce active immunity. Several vaccines are being produced for diseases like polio, diphtheria, whooping cough, tetanus, tuberculosis, rabies, cholera, typhoid, measles, mumps, rubella, rotavirus, hepatitis A and B etc. However, increased understanding of the molecular mechanisms underlying additional human diseases has necessitated vaccines to prevent/treat conditions like AIDS, cancer and malaria. The advent of genetic engineering, particularly the recombinant DNA technology, has rendered their availability a feasible task. These IB techniques have provided 'sub-unit' vaccines which are clinically safe, reproducible and available in abundant quantities. Examples of such recombinant vaccine products include Recombivax (rHBsAg produced in Saccharomyces cerevisiae) by Merck for the prevention of Hepatitis B and Infanrix-Hexa (combination vaccine, containing rHBsAg produced in S. cerevisiae as one component) by SmithKline Beecham for immunisation against diphtheria, tetanus, pertussis, polio, Haemophilus influenzae b and Hepatitis B etc.
Monoclonal antibodies: Monoclonal antibodies (mAb) produced by Hybridoma technology form one of the most investigated products of IB, with several pre-clinical and clinical trials in progress to confirm their selective therapeutic potential. Their applications are based on their ability to specifically recognise a cell surface antigen unique to the target cell type. They thus serve as molecular probes in new generation approaches for diagnosis, prognosis and therapy of human diseases. Examples of such approved products include Herceptin (Trastuzumab) by Genentech (USA) for the treatment of metastatic breast cancer; Mylotarg (Gemtuzumab zogamicin) by Wyeth-Ayerst for the treatment of acute myeloid leukaemia and Humaspect (Votumumab) by Organon Teknika for the detection of carcinoma of the colon or rectum etc.
GenePharming: Gene transfer technology has provided suitable means of transferring genes encoding (human) proteins into the genomes of domestic animals and chloroplasts of transgenic plants for production of therapeutic proteins and for the modification of production characteristics. The types of potential products produced by transgenic plants include vaccines such as Hepatitis B, Malaria, Cancer, HIV etc; antibodies such as secretory immunoglobin for treatment of dental caries (Tobacco) etc; enzymes; metabolites; recombinant hormones/proteins (human epidermal growth factor, human erythropoietin, human serum albumin etc) and other biopharmaceuticals such as anticoagulants (Human Protein C etc), protein/peptide inhibitors (human aprotinin, angiotensin converting enzyme etc), recombinant enzymes and nutraceuticals.
Biosensors & biochips: Biosensors combine the exquisite specificity of biological recognition probes and excellent sensitivity of laser-based optical detection to provide unambiguous identification and accurate quantification. The biologically responsive materials employed include antibody and DNA probes, enzymes, ligand binding and antigen-antibody reactions. Applications of this technology in the pharmaceutical sector include discovery of measurable signals in case of certain pathogens.
Biochips are a unique amalgamation of microchips and biotechnology. It comprises proteins, antibodies or nucleic acids on solid substrates that exhibit the capacity to identify and attach to particular DNA sequences or antigens. Some of its applications in pharma industry include drug discovery, testing, genotyping, as immune-diagnostics for early cancer detection, early detection of diabetes, cystic fibrosis, parkinson's disease and alzheimer's disease etc.
Biopolymers: These comprise long-chain compounds (proteins, nucleic acids and polysaccharides) composed of covalently linked organic molecule subunits like sugars, amino acids and nucleic acids that are synthesised by living organisms. Biopolymers are playing an increasingly pivotal role in medicine and pharmacy with applications in surgical dressings, long lasting implants, dental applications, tissue engineering, regeneration medicine and drug carrier systems etc. They offer numerous benefits such as being renewable, sustainable, carbon neutral and biodegradable, while some are compostable. Examples of biopolymers employed in pharma industry include lignins and polyisoprenoids (melanin etc); polyesters (polylactides, polyglycolide and copolyesters with lactide, polyanhydrides etc); polysaccharides (curdlan, dextran, levan, hyaluronan, carrageenan, chitin and chitosan, alginates etc); polyamides and complex proteinaceous materials (poly-gamma-glutamic acid, collagens and gelatines etc) etc.
Human protein replacements & therapies: Genetically linked diseases can now be cured by identifying the deficient protein and employing DNA technology to synthesise and restore the missing protein. Examples include humulin (genetically engineered insulin manufactured by Eli Lilly Company for the treatment of diabetes), protropin and humatrope (genetically engineered human growth hormone manufactured by Genentech and Eli Lilly for the treatment of dwarfism) kogenate and recombinate (genetically engineered factor VIII manufactured by Miles Laboratories and Genetics Institue Massachussets, for the treatment of hemophilia A).
Also, new innovative drugs based on DNA technology are now employed. Some of them include tissue plasminogen activator (Activase) for coronary thrombosis, alpha interferon for treatment of leukaemia, kaposi's sarcoma in AIDS patients, malignant melanoma, multiple myeloma and certain kidney cancers. Similarly interferon b-1b has been licensed for use in multiple sclerosis. Antisense molecules which combine with and neutralise mRNA molecules in the target cells thus blocking their replication also belong to this class and have been employed for the treatment of AIDS, cancer, Crohn's disease etc.
Significance of IB in Indian Pharma
In India, IB has contributed tremendously to the growth of pharmaceutical sector with the biopharmaceutical sector expanding rapidly in 2008. The Indian companies currently manufacture a wide range of biopharmaceutical products, including recombinant insulin, erythropoietin, granulocye colony stimulating factor, recombinant hepatitis-B vaccine, streptokinase, interferon alpha-2b, rituximab and an anti-EGFR MAb product. Revenues in this sector exceed $25 billion with an annual growth rate of more than 25 per cent. In 2008 around 58 per cent of the Indian biopharmaceutical products and services were exported or certified for export. Moreover, the country's developments in R&D, clinical research, production capacity and patent rights show a promising future for these products.
In the last year, companies like Avesthagen in Bangalore, Panacea Biotec in Mumbai and Biocon in Punjab announced plans to set up new R&D facilities. Also, development of biotech parks with R&D facilities, such as Bangalore Helix and the Genome Valley are on full swing. Companies like Dr. Reddy's in Andhra Pradesh, USV in Mumbai, Avesthagen in Bangalore and Cadila Pharma in Ahmedabad have exhibited a growth in their production capacity of biologics. In another move Intas at Ahmedabad has received EU GMP certification and has become India's first and only local biopharmaceutical company ready for the launch of a range of oncology biogenerics in European market. Besides, Bangalore-based Biocon has announced the commencement early-stage clinical trials of oral insulin as well as a monoclonal antibody against rheumatoid arthritis and psoriasis.
Conclusion
Industrial biotechnology has offered a wide gamut of products to the pharma industry and its capacity to offer new products and services to pharma sector seems to be ever rising. Future technical advances promise the availability of even a wider array of gene therapy and antisense technology based pharmaceutical products for diseases in early stages of research. The technique also promises the discovery of newer dug targets and therapeutic systems by linking the changes in gene/protein expression to various disease conditions. However certain issues like acceptance by general public; involvement of present and future stake holders; prediction of safety, ethical, economic and regulatory issues; support by authorities through consistent R&D policies and identification of institutions to address these limitations, need to be addressed to harness the untapped potential of IB for the progress of pharmaceutical industry.
(The authors are with Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga, Mumbai)