2.  Therapeutic or preventive medicine derived from living cells using recombinant DNA technology  Conventional pharmaceuticals are generally small molecules.  Biopharmaceuticals are typically proteins, peptide, nucleic acids or inactivated viruses/bacteria

3. 3 BIOLOGICS Diagnostics and Gene Products Gene Therapy /Stem cells Monoclonal Anti Bodies (Mabs) Recombinent Proteins Vaccines Harmones & Enzymes FAMILY OF BIOPHARMACEUTICALS

4. BIOLOGICALS Conventional drugs MOLECULAR SIZE 5000-200000daltons10-1000daltons MOLECULAR STRUCTURE Exhibit complex spatial structures, which are difficult to determine Simple spatial structures which are easy to determine COMPLEXITY impurities, leechables,by- products etc are present Relatively pure components CLINICAL BEHAVIOUR Complicated modes of action Well understood mode of action MANUFACTURING PROCESS specific and complex biological processeschemistry synthesis BATCH-TO-BATCH VARIATIONS No two batches will be entirely identical Small to negligible variations in efficient production COST OF MANUFACTURING HighRelatively low PRICE Costly(10000-200000USD/year treatment)Relatively less

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11. Top Ten Players in Biotech. Field Amgen Roche/Genentech Johnson & Johnson Novo Nordisk Lilly Sanofi-Aventis Abbott Serono(Merck) Schering Plough Wyeth 11

12. BIO SIMILARS What are they? Biosimilars Biogenerics Follow on Biologics Follow on Proteins Follow-on innovators products, developed by parties other than original developers using either identical or different manufacturing processes The products must be bioequivalent or comparable to the original innovative products in terms of preclinical, PK/PD as well as safety and efficacya 12

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18. KEY PLAYERS IN BIOSIMILARS Hospira Teva Sandoz Barr Lab Dr. Reddy Cangene 18

19. How Is a biosimilar Product Developed? Upstream –Cell line development –Fermentation Downstream –Purification –Fill and Finish 19 Continue

20. How Is a biosimilar Product Developed? Comprehensive analytical characterization and comparability study Clinical study –Preclinical –Clinical Submission 20

21. 1. Cell Line Development (The Fundamental) Analyze the DNA sequence of the targeted protein based on the published literature information Synthesize the cDNA Construct the vector 21 Continue

22. Transfer the vector into the cell Positive cell line screening and selection High yield cell line selection Cell bank characterization and storage Master cell bank and working cell bank 22 1. Cell Line Development (The Fundamental )

23. 2. The Fermentation Process Development Bioreactor selections Culture medium optimization High yield culture conditions Process scale up (difficulty), extensive comparability study need to be done 23

24. 3. Protein Purification Cell broken Removal of cells Capture of proteins Removal of virus 24 Continue

25. 3. Protein Purification Primary purification Secondary purification Lyophilization of purified proteins Characterization 25

26. 4. Fill Finish Formulation development Freezing/thawing impact Manufacturing process development Mixing and holding time Filter compatibility 26 Continue

27. 4. Fill Finish Microbial retention Lyocycle development Package selection Device development Stability testing 27

28. 5. EXTENSIVE COMPARABILITY STUDY With innovator products When cell line changes When culture medium changes When culture condition changes 28 Continue

29. 5. EXTENSIVE COMPARABILITY STUDY When master and working cell bank generation changes When fermentation process changes When scaled up When facility changes Using stressed samples 29

30. 6. CLINICAL TRIALS (LENGTHY AND EXPENSIVE) Preclinical study –Toxicology in animals Phase I Study –PK/PD in healthy subjects 30 Continue

31. 6. Clinical Trials (Lengthy and Expensive) Phase III Study –Safety/Efficacy –All indications –In patients –Immunogenecitystudy –Post-market monitoring 31

32. 7. Submissions No clear regulatory pathway in US. Product specific in EU FDA treat it as BLA 32 Continue

33. 7. Submissions Pre-IND meetings and scientific advisory meeting are needed Expensive submission fee 33

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35. CHALLENGES (CONTINUED) No interchangeability, brand marketing required Injectablemanufacturing capability Microbial and Mammalian cell fermentation facilities in large scale Overall, high barriers to entry, but high margin Public demanding for affordable biological drugs 35

36. CHALLENGES (CONTINUED) High cost, longer term Technology derived Complicated analytical techniques “innovative like” clinical studies Effective brand patent protection for over 20 years Enter the market at risk (no paragraph IV ) 36

37. Summary Biosimilars are the trend Have drawn extensive attentions from public, regulatory bodies, governments and certainly pharmaceutical companies Challenging, cost, but worth to develop Has created huge opportunities for the organizations and CRO who are engaged in the Analysis and Characterizations of Biological Molecules and cell culture 37 DO NOT MISS THE OPPORTUNITY

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