Introduction to biopharmaceutical.pptx

Introduction to biopharmaceuticals
Biologics
History

1. PHARMACEUTICAL BIOTECHNOLOGY Semester-VI COVID-19 is highlighting the importance of the biotechnology field. Today, leaders from across the globe are leaning on biotechnology and pharmaceutical companies with hopes of possible solutions for the COVID-19 pandemic that range from diagnostic assays and therapeutics to prophylactic vaccines. Indian Biotechnologists, researchers and manufacturers have accepted this challenge and have already made vaccine against the COVID-19 onslaught.

2. Unit 1 Pharmaceuticals, biologics & biopharmaceuticals Introduction to pharmaceutical products Biopharmaceuticals and pharmaceutical biotechnology History of the pharmaceutical industry The age of biopharmaceuticals Biopharmaceuticals: Current status and future prospects

3. Biotechnology encompasses any techniques that use living organisms in the production of products having beneficial to human being Drug is “ a chemical substance that interacts with a living system and produces a biological response” Drug product : As defined by FDA “a finished dosage form that contains the active ingredient generally but not necessarily in association with inactive ingredients” Pharmaceutics : Branch of pharmacy which deals with Study Fabrication Systematic approach to get an effective and stable formulation without disturbing its quality Deals with technology involved in large scale manufacturing

4. Drugs may be good or bad Morphine is a drug of abuse, but is clinically most effective painkiller, if still dangerous Heroin was the “heroic” drug until the severe dependency issues All drugs are toxins and have side effects and can be subject to abuse The effectiveness is measured by its therapeutic index–the balance of benefit against undesired effects Very effective drugs lose their appeal if they also kill the patient

5. Classification of drug: Ethical drugs: Those associated with the regulated pharma industry Generally prescription medicines covered by patents Generic drugs: Those ethical medicines off patent(patent has expired) Generic medicines are those produced without a license from the innovator company when the patent or market exclusivity rights on the innovator product have expired They are the same as prescription medicine when it comes to bioavailability, routes of administration, form and factor, and even performance Ethical/Prescription Medicines, on the other hand, are medicines that are only available on the prescription of a doctor The significant difference between the two is the price Generic medicines tend to be cheaper and are usually available at high discounts from the manufacturer/brand .

6. Pharmaceutical biotechnology consist of the combination of two branches which Are “PHARMACEUTICAL SCIENCE” and “BIOTECHNOLOGY” Classic example of biotechnological drugs-proteins obtained from recombinant DNA technology Biotechnology now encompasses the use of tissue culture, living cells or cell enzymes to make a defined product Principles of biotechnology are applied to the development of drugs A majority of therapeutic drugs in the current market are bioformulations , such as antibodies, nucleic acid products and vaccines Future of pharmaceuticals belongs to protein based therapeutics

7. Pharmaceutical : A compound manufactured for use as a medicinal drug Biopharmaceutical/Biologics: A biological macromolecule or cellular component, such as a blood product, hormone used as a pharmaceutical Pharmaceutical drug product manufactured in, extracted from, or semi-synthesized from biological sources Composed of sugar, proteins, nucleic acids and maybe of living entities as cells and tissues Issue: Some of the aspects of a biologic may be undefined due to its complexity

8. A biopharmaceutical which consists of sugars, proteins, nucleic acids, living cells, or tissues, is a medicinal product manufactured in extracted or semi-synthesized from biological sources like humans, animals, or microorganisms Different from traditional drugs synthesized from chemical processes, the majority of biopharmaceutical products are derived from biological processes including the extraction from living systems or the production by recombinant DNA technologies Transgenic organisms, especially plants, animals, or microorganisms are potentially used to produce biopharmaceuticals

9. First generation biopharmaceuticals are un-engineered murine monoclonal antibodies Simple replacement proteins displaying an identical amino acid sequence to a native human protein Modern biopharmaceuticals are engineered, second-generation products Engineering can entail alteration of amino acid sequence, glyco -component of a glycosylated protein, or the covalent attachment of chemical moieties such as polyethylene glycol Engineering has been applied in order to alter immunological or pharmacokinetic profile of protein, or in order to generate novel fusion products

10. Introduction to pharmaceutical products Pharmaceutical substances form the backbone of modern medicinal therapy Most traditional pharmaceuticals are low molecular mass organic chemicals Some (e.g. aspirin)-originally isolated from biological sources Most are now manufactured by direct chemical synthesis

11. Traditional pharmaceutical sector Two types of manufacturing companies Chemical synthesis plants Biotechnology based units Produce drugs from biological sources Described as products of biotechnology Products of biotechnology or chemical synthesis becomes somewhat artificial Certain semi-synthetic antibiotics are produced by chemical modification of natural antibiotics produced by fermentation technology

12. Biopharmaceuticals and pharmaceutical biotechnology ‘ Biologic ’- Pharmaceutical product produced by biotechnological endeavor Generally refers to medicinal products derived from blood, as well as vaccines, toxins and allergen products Some traditional biotechnology-derived pharmaceutical products fall outside the strict definition e.g. hormones, antibiotics and plant metabolites The term ‘ biopharmaceutical ’ was first used in the 1980s

13. To describe a class of therapeutic protein produced by modern biotechnological techniques, specifically via genetic engineering or by hybridoma technology ‘Therapeutic protein synthesized in engineered (non-naturally occurring) biological systems’ More recently-nucleic acids used for purposes of gene therapy too are generally referred to as ‘biopharmaceuticals’. The term ‘biopharmaceutical’ refers to protein or nucleic acid based pharmaceutical substances used for therapeutic or in vivo diagnostic purposes, which are produced by means other than direct extraction from natural (non-engineered) biological sources

14. Term ‘biotechnology medicine’ is defined here as ‘any pharmaceutical product used for a therapeutic or in vivo diagnostic purpose, which is produced in full or in part by either traditional or modern biotechnological means’. Antibiotics extracted from fungi Therapeutic proteins extracted from native source material (e.g. insulin from pig pancreas) Products produced by genetic engineering (e.g. recombinant insulin)

15. B iosimilar medicine: A biosimilar medicine is a medicine which is similar to a biological medicine that has already been authorized (the ‘biological reference medicine’) Active substance of a biosimilar medicine is similar to the one of the biological reference medicine Term used for a biologic drug that is produced using a different cell-line, or different process than the one that originally produced Used in same dose to treat the same disease Similar but not identical Biosimilar are similar to the original biologic but not generic Due to difference in initial raw material

16. A brief history of drug discovery Medications were based mainly on herbal products (3000 BC) 400 BC Hippocrates introduced the concepts of medical diagnosis, prognosis, and advanced medical ethics 900-1000 The Arabic scientist, Avicenna, recorded an encyclopaedia of medical description and treatment 1700s William Withering introduced digitalis, an extract from the plant foxglove, for treatment of cardiac problems

17. 1768 John Hunter noted that scurvy was caused by the lack of vitamin C He prescribed the consumption of lemon juice to treat scurvy 1796 British physician, Dr Edward Jenner, discovered vaccination He successfully experimented with smallpox inoculations German pharmacist Friedrich Wilhelm Sertürner isolated morphine from opium, and it became both the first pure naturally derived medicine and the first to be commercialised

18. 1864 Louis Pasteur discovered that microorganisms cause diseases Devised vaccination against rabies 1891 Paul Ehrlich coined the term chemotherapy and Used synthetic chemicals to try and cure disease 1899 Aspirin was created and used for the treatment of fever

19. 1928 Alexander Fleming discovered that Penicillium mould was active against Staphylococcus bacteria 1955-1960 First effective polio vaccines developed by Jonas Salk and Albert Sabin 1961 Ibuprofen was first synthesised 1970 Vaccines against rubella, chicken pox, pneumonia and meningitis were developed

20. 1986 Hepatitis B vaccine was the first vaccine to be routinely produced by recombinant DNA technology 2006 HPV ( Human papillomavirus  )vaccine was developed  

21. Origin •The origin of the Pharmaceutical industry can be traced back to the chemical industries (of the late nineteenth century) in the upper RhineValley of Switzerland •These industries were producing dyestuffs. •When dyestuffs were found to have antiseptic properties , a number of the industries turned into Pharmaceutical industries e.g. Hoffman- LaRoche , Sandoz, Ciba-Geigy etc. The first known drug store was opened by Arabian pharmacists in Baghdad in 754

22. History of the pharmaceutical industry Barely 60 years old From very modest beginnings it has grown rapidly-100 million dollar-7,00,00,00,000 rupees in mid of 80s Current value is likely double There are well in excess of 10,000 pharmaceutical companies in existence Although only about 100 of these can claim to be of true international significance Manufacturing in excess of 5000 individual pharmaceutical substances used routinely in medicine The first stages of development of the modern pharmaceutical industry can be traced back to the turn of the twentieth century

23. At that time (apart from folk cures), the medical community had only four drugs that were effective in treating specific diseases: Digitalis-from foxglove-to stimulate heart muscle Quinine-from the barks/roots of a plant (Cinchona sp.)-to treat malaria Pecacuanha (active ingredient is a mixture of alkaloids), used for treating dysentery-obtained from the bark/roots of the plant species Cephaelis Mercury, for the treatment of syphilis

24. Lack of appropriate safe and effective medicines Low life expectancy in those times Developments in biology Realization of the microbiological basis of many diseases Development in the principles of organic chemistry Future innovation in the pharmaceutical industry The successful synthesis of various artificial dyes, which proved to be therapeutically useful, led to the formation of pharmaceutical/chemical companies such as Bayer and Hoechst in the late 1800s Bayer-aspirin in 1895

25. Despite these early advances, it was not developed until 1930s The initial landmark discovery of this era -the discovery and chemical synthesis of the sulpha drugs These are a group of related molecules derived from the red dye, Prontosil rubrum These drugs proved effective in the treatment of a wide variety of bacterial infections Large-scale industrial production of insulin also commenced in the 1930s Industrial-scale penicillin manufacture in the early 1940

26. Ciba Geigy , Eli Lilly, Wellcome , Glaxo and Roche developed in this time Over the next two to three decades-development of drugs such as tetracyclines , corticosteroids, oral contraceptives, antidepressants etc. Most of these pharmaceutical substances are manufactured by direct chemical synthesis

27. The Sulfanilamide Disaster: In1937,S.E.Massengil Company created an elixir (liquid form) of the antibiotic sulphanilamide using diethylene glycol as solvent Diethylene glycol is a great solvent, but extremely toxic Unfortunately, at the time, there were no legal requirement to test the toxicity of the formulation Resulted in the deaths of more than 100 people in the U.S.

28. Story of Taxol : 1955 : Plant screening project to discover new anticancer agents Screening of 35,000 plants 1967: Identification of cytotoxic ingredient from the bark of Pacific yew tree- Taxol (Generic name) 1969 : 10 g of pure compound from 1,200 kg of bark 1988: A remarkable response rate of 30% in patients with Effective for cancers like ovarian, breast, and lung Ecological concerns a bout the impact on yew populations Currently produced by plant cell culture technology developed by Phyton Biotech. The use of Taxus cell-line in a large fermentation tank

29. Indian pharmaceutical industry Indian pharmaceutical industry is the world's second-largest by volume Lead the manufacturing sector of India First pharmaceutical company are Bengal Chemicals and Pharmaceutical Works Still exists today as one of 5 government-owned drug manufacturers Started in Calcutta in 1930 The government started to encourage the growth of drug manufacturing by Indian companies in the early 1960s. and with the Patents Act in 1970

30. Present Indian Market Size- Rs . 400 Billion

31. Top ten pharmaceutical organizations in India Sun Pharma Industries-Vadodara Lupin Labs- Ankleshwar and Mumbai Dr. Reddy's Laboratories-Hyderabad CIPLA-Mumbai Aurobindo Pharma -Pondicherry Cadila Healthcare-Ahmedabad GlaxoSmithKline Pharma -Mumbai Torrent Pharma -Ahmedabad Wockhardt - Mumbai Ipca Laboratories-Mumbai

32. Milestones in pharmaceutical industry 1895: Aspirin (Bayer) 1922 Discovery of Insulin 1930: Sulphanilamide (Sulpha drugs) 1930: Large scale production of insulin 1940: Penicillin Production

33. Age of biopharmaceuticals 1953: Structure of DNA 1973: Genetic Engineering 1975: Monoclonal Antibodies 1980: Recombinant Insulin >10.000 companies 100 international players 5000 pharmaceutical products Top 5 drugs are bio-pharmaceuticals\ 50% of top 100 are bio-pharmaceuticals >10.000 companies 100 international players 5000 pharmaceutical products Top 5 drugs are bio-pharmaceuticals\ 50% of top 100 are bio-pharmaceuticals HUMULIN : Human insulin rDNA origin] Human insulin is produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of  Escherichia coli HUMULIN is a suspension of crystals produced from combining human insulin and protamine sulfate under appropriate conditions for crystal formation The amino acid sequence of HUMULIN N is identical to human insulin

34. Biomedical research-broaden our understanding of the molecular mechanisms underlining both health and disease Research undertaken since the 1950s has pinpointed a host of proteins produced naturally in the body which have obvious therapeutic applications e.g. interferons , interleukins, which regulate the immune response; growth factors such as erythropoietin, which stimulates red blood cell production; and neurotrophic factors, which regulate the development and maintenance of neural tissue While the pharmaceutical potential of these regulatory molecules was generally appreciated, their widespread medical application was in most cases rendered impractical due to the tiny quantities in which they were naturally produced

35. Recombinant DNA technology and monoclonal antibody technology overcame many such difficulties Marked the beginning of a new era of the pharmaceutical sciences Recombinant DNA technology has had a four-fold positive impact upon the production of pharmaceutically important proteins Many proteins of therapeutic potential are produced naturally in the body in minute quantities e.g. Interferons , Interleukins and colony-stimulating factors(CSFs) Recombinant production allows the manufacture of any protein in whatever quantity it is required

36. Overcomes the problem of source availability Recombinant production allows the manufacture of any protein in whatever quantity Overcomes problems of product safety Direct extraction of product from some native biological sources has, in the past, led to the unknowing transmission of disease e.g. transmission of blood-borne pathogens such as hepatitis B, C and HIV via infected blood products and the transmission of Creutzfeldt – Jakob disease to persons receiving human growth hormone preparations derived from human pituitaries

37. Provides an alternative to direct extraction from inappropriate/dangerous source material A number of therapeutic proteins have traditionally been extracted from human urine e.g. fertility hormone FSH Urine is not considered a particularly desirable source of pharmaceutical products While several products obtained from this source remain on the market, recombinant forms have now also been approved

38. Other potential biopharmaceuticals are produced naturally in total dangerous sources Ancrod , for example, is a protein displaying anti-coagulant activity and, hence, is of potential clinical use; however, it is produced naturally by the Malaysian pit viper ( current brand name: Viprinex ) Recombinant production in less dangerous organisms, such as Escherichia coli or Saccharomyces cerevisiae

39. Site-directed mutagenesis facilitate the logical introduction of pre-defined changes in a protein’s amino acid sequence Such changes can be minimal, such as the insertion, deletion or alteration of a single amino acid residue, or can be more substantial, e.g. the alteration or deletion of an entire domain, or the generation of a novel hybrid protein Such changes can be made for a number of reasons and several engineered products have now gained marketing approval Despite the undoubted advantages of recombinant production, it remains the case that many protein-based products extracted directly from native source material remain on the market These products have proved safe and effective

40. In certain circumstances, direct extraction of native source material can prove equally/more attractive than recombinant production This may be for an economic reason, e.g. if the protein is produced in very large quantities by the native source and is easy to extract/purify, as is the case for human serum albumin Some blood factor preparations purified from donor blood actually contain several different blood factors and hence can be used to treat several haemophilia patient types Recombinant blood factor preparations, on the other hand, contain a single blood factor and hence can be used to treat only one haemophilia type

41. Genetic engineering and monoclonal antibody technology underpinned the establishment of literally hundreds of start-up biopharmaceutical companies in the late 1970s and early 1980s Many of these fledgling companies were founded by academics/technical experts to take commercial advantage of developments in the biotechnological arena Most of these early companies displayed significant technical expertise, but lacked experience in the practicalities of the drug development process Most of the well-established large pharmaceutical companies, on the other hand, were slow to invest heavily in biotech research and development However, as the actual and potential therapeutic significance of biopharmaceuticals became evident, many of these companies did diversify into this area

42. Most either purchased small established biopharmaceutical concerns or formed strategic alliances An example was the long term alliance formed by Genentech and the well-established pharmaceutical company, Eli Lilly. Genentech developed recombinant human insulin, which was then marketed by Eli Lilly under the trade name, Humulin Some biopharmaceutical substances showed little efficacy in treating their target condition, and/or exhibited unacceptable side effects……. Mergers and acquisitions also led to the disappearance of several biopharmaceutical concerns

43. Amgen, Biogen and Genentech……………. Three pioneering biopharmaceutical companies Founded in the 1980s as AMGen (Applied Molecular Genetics) Amgen now employs over 9000 people worldwide, making it one of the largest dedicated biotechnology companies in existence Its headquarters are situated in Thousand Oaks, California Focus upon developing novel (mainly protein) therapeutics for application in oncology, inflammation, bone disease, neurology, metabolism and nephrology Six of its recombinant products had been approved for general medical use Aranesp ’ and ‘ Epogen ’ ‘ Neupogen ’ and ‘ Neulasta ‘ Kineret ’ Anti-rheumatoid arthritis fusion protein, Enbrel

44. Biogen was founded in Geneva, Switzerland in 1978 by a group of leading molecular biologists Headquarters are located in Paris and it employs in excess of 2000 people worldwide Developed and directly markets the interferon-based product, ‘ Avonex ’ A number of hepatitis B-based vaccines sold by SmithKline Beecham (SKB) and Merck By 2001, worldwide sales of Biogen -discovered products had reached US$ 3 billion Biogen reinvests ca. 33% of its revenues back into R&D and has ongoing collaborations with several other pharmaceutical and biotechnology companies

45. Genentech was founded in 1976 by scientist Herbert Boyer and the venture capitalist, Robert Swanson Headquartered in San Francisco, it employs almost 5000 staff worldwide Has 10 protein-based products on the market These include human growth hormones (‘ Nutropin ’) Antibody-based products ‘Herceptin’ and ‘ Rituxan ’ Thrombolytic agents ‘ Activase ’ and ‘ TNKase ’ Has 20 or so products in clinical trials In 2001, it generated some US$ 2.2 billion in revenues, 24% of which it reinvested in R&D

46. Biopharmaceuticals: Current status and future prospects Approximately one in every four new drugs now coming on the market is a biopharmaceutical By mid 2006, some 160 biopharmaceutical products had gained marketing approval Biopharmaceutical market size is $239.8 Billion in 2019, growing at a CAGR of 13.28% during the forecast period 2020-2025. e.g. Procrit (treatment of anaemia-US$ 4.0 billion) Intron A (treatment of leukaemia-US$ 0.3 billion), Humulin (treatment of diabetes-insulin-US$ 1.0 billion) etc. The market value is estimated to surpass US$50 billion by 2010 Products include a range of hormones, blood factors and thrombolytic agents, as well as vaccines and monoclonal antibodies

47. The rapid pace of scientific advancements enables a greater insight about diseases at the molecular level. As a result, Biopharmaceutical companies execute basic research in collaboration with researchers to seek powerful tools and molecular medicines to better understand human diseases. While the basic science offers a foundation of drug developments, the biopharmaceutical industry is thus, largely driven by an increasing number of chronic diseases, growing geriatric population and rising awareness towards targeted therapy. Furthermore, to effectively address untreatable diseases, the demand for biopharmaceutical medicines across the world accelerates Biopharmaceuticals in the global market.

48. Among them many are protein-based therapeutic agents Two nucleic-acid-based products: ‘ Vitravene ', an antisense oligonucleotide, and ` Macugen ', an aptamer . Many additional nucleic-acid-based products for use in gene therapy or antisense technology are in clinical trials Many of the initial biopharmaceuticals approved were simple replacement proteins (e.g. blood factors and human insulin) Understanding of the relationship between protein structure and function has facilitated the more recent introduction of several engineered therapeutic proteins Majority of approved recombinant proteins have been produced in the bacterium E. coli , the yeast S. cerevisiae or in animal cell lines Chinese hamster ovary (CHO) cells or baby hamster kidney (BHK) cells

49. Most biopharmaceuticals approved to date are intended for human use, a number of products destined for veterinary application also Example-recombinant bovine GH ( Somatotrophin ), was approved in the USA in the early 1990s and used to increase milk yields from dairy cattle At least 1000 potential biopharmaceuticals are currently being evaluated in clinical trials Most protein-based products likely to gain marketing approval over the next 2-3 years will he produced in engineered E . coil, S. cerevisiae or animal cell lines Plant-based transgenic expression systems may potentially come to the fore, particularly for the production of oral vaccines

50. Technological developments in genomics, proteomics have impact upon the early stages of drug development By linking changes in gene/protein expression to various disease states, technologies will identify new drug targets for such diseases Many/most such targets will themselves be proteins, and drugs will be designed / developed specifically to interact with They may be protein based or (more often) low molecular mass ligands Future innovations have impact upon pharmaceutical biotechnology include the development of alternative product production systems, alternative methods of delivery and the development of engineered cell-based therapies, particularly stem cell therapy Protein-based biotechnology products produced to date are produced in either microbial or in animal cell lines Work continues on the production of such products in transgenic based production systems, specifically either transgenic plants or animals

51. Virtually all therapeutic proteins must enter the blood in order to promote a therapeutic effect Such products must usually be administered parenterally (administered by some means other than oral or rectal intake, particularly intravenously or by injection) However, research continues on the development of non-parenteral routes which may prove more convenient, less costly and obtain on proved patient compliance. Alternative potential delivery routes include transdermal, nasal, oral and buccal (relating to the mouth) approaches Most progress to date has been recorded with pulmonary-based delivery systems An inhaled insulin product (' Exubera ') was approved in 2006 for the treatment of type I and II diabetes .

52. A small number of whole-cell-based therapeutic products have also been approved to date. All contain mature, fully differentiated cells extracted from a native biological source. Improved techniques now allow the harvest of embryonic and, indeed, adult stem cells, bringing the development of stem cell-based drugs one step closer. However, the use of stem cells to replace human cells or even entire tissues/organs remains a long term goal. Overall, therefore, products of pharmaceutical biotechnology play an important role in the clinic and are likely to assume an even greater relative importance in the future