Current Biopharmaceutical CMC Issues What the PDA is Doing and How You Can Help

1. Current Biopharmaceutical CMC IssuesWhat the PDA is Doing and How You Can Help John Geigert, Ph.D., RAC, President BioPharmaceutical Quality Solutions Presentation to PDA West Coast Chapter November 15, 2007

2. PDA is …. Goggle search! • Personal Digital Assistant • Posterior Descending Artery • Potato Dextrose Agar • Public Display of Affection • Parenteral Drug Association (PDA)

3. PDA is biotech! Goggle search! PDA web Biotechnology Advisory Board ( BioAB) The PDA Biotechnology Advisory Board (BioAB) is supported by and works closely with the PDA Scientific and Regulatory Affairs Department The BioAB is both ... www.pda.org/webmodules/webarticles/templates/new... - 23k - Similar pages http://www.pda.org/webmodules/webarticles/templates/new_sci_tech_bioab.aspx?articleid=102&zoneid=37 [PDF]PDA BIOTECHNOLOGY ADVISORY BOARD PDA BIOTECHNOLOGY ADVISORY BOARD. CHAIR. Gail Sofer. Director, Regulatory Compliance. GE Healthcare. 800 Centennial Avenue. Piscataway, NJ 08555 ... www.pda.org/biotech/BIOAB_INFO/pdfs/2007/2007_... - Similar pages http://www.pda.org/biotech/BIOAB_INFO/pdfs/2007/2007_BioAB_Roster.pdf PDA Workshop on Biotech Process Validation - Gate2Biotech.co... Join industry and regulatory experts to discuss current issues in biotech process validation. The topics include: How much validation is necessary at each ... www.gate2biotech.com/pda-workshop-on-biotech-pro... - 20k - Similar pages http://www.gate2biotech.com/pda-workshop-on-biotech-process-validation/ [PDF]3 ISCT Cell Therapy Commercialization Committee ... liaisons from other organizations such as ASTM, PDA Biotech Advisory Committee,. PhARMA, and BIO. Committee. Subcommittee. Subcommittee. Subcommittee ... www.celltherapysociety.org/files/PDF/Committees/Meeti... - Similar pages http://www.celltherapysociety.org/files/PDF/Committees/Meeting_Summary_for_Website_2006_12_01.pdf

4. PDA has been actively supporting biotech PDA Chapters PDA West Coast Chapter – launched in 1989 President: Robert Garnick President-Elect: John Geigert

5. PDA has been actively supporting biotech Technical Reports – General Application to Biotech

6. PDA has been actively supporting biotech Technical Reports – Specific to Biotech

7. TR 41: Virus FiltrationIndustry-Wide Harmonization of a Test to Classify Large Virus Filters(~ 50 nm)

8. TR 42: Process Validation of Protein ManufacturingClinical Phase-Dependent Process Validation Strategy

9. PDA has been actively supporting biotech Commenting on Key Regulatory Guidances

10. PDA has been actively supporting biotech Biotech Advisory Board (BioAB) Reports directly to the PDA Board of Directors Mission: to identify areas of concern in the area of biotech for PDA members to get involved!

11. Biotech Advisory Board Some biotech concerns being pursued by PDA • Biopharmaceutical reprocessing

13. Current Biopharmaceutical CMC Issues Biopharmaceutical Reprocessing For many years, reprocessing was common in the biopharmaceutical industry – repeat of HPLC purification process steps refiltration of product solutions if filter integrity test failed Issue of reprocessing “lit up” about 7 years ago when several biopharmaceutical companies received 483s and Warning Letters addressing inappropriate reprocessing procedures (lack of validation/not obtaining FDA approval) FDA emphasized in major conferences that refiltering of biotech processes was not ‘repeating’ but ‘reprocessing’

14. Current Biopharmaceutical CMC Issues Biopharmaceutical Reprocessing – pendulum swinging As an industry, there was a major pullback from performing process revalidation! Even after 7 years, there is no clear guidance from the FDA on how to properly carry out reprocessing! Lack of regulatory guidance is leading to a wide range of application (misapplication) in the biotech industry What would you do if a process step failed? Would you be too scared to reprocess?

15. PDA Ongoing Efforts Biopharmaceutical Reprocessing PDA Task Force (since 2005) Biopharmaceutical Reprocessing Coming in 2008: Technical Report describing best practices across the global industry; describe benefits of proactive reprocessing planning Case Studies included in Technical Report (what to do when the process step fails): Chromatography of final purification step Viral filtration Lyophilization of drug substance Sterile filtration of formulated bulk drug

16. Biotech Advisory Board Some biotech concerns being pursued by PDA • Challenge of adventitious agent control

18. Current Biopharmaceutical CMC Issues Virus Safety Evaluation – still misunderstood or poorly understood even in the 21st century! Vitragan (hyaluronidase extracted from the testes of sheep)

19. PDA Ongoing Efforts Virus Safety Clearance PDA Task Force Virus Filters – Nomenclature for Small Virus Filtration (~ 10 – 20 nm) • Similar pattern to that developed for large virus filters • Using bacteriophage as ‘representative agent’ • PDA supporting filter testing work at FDA (CRADA)

20. PDA Ongoing Efforts Virus Safety Clearance PDA Task Force Virus Spike Preparation Standardization • Development of industry-wide standards for the proper preparation of the virus spikes used in virus clearance studies • Use of Serum Free Media to reduce contaminants • Filtration to decrease aggregation

21. PDA Ongoing Efforts Virus Safety Clearance PDA Task Force Virus Safety Clearance for Clinical Trial Materials

22. Current Biopharmaceutical CMC Issues Mycoplasma – smallest bacteria with no cell wall A real manufacturing risk! • Reported Cases of • Mycoplasma Contamination Abbott Labs: Abbokinase manufactured from HNK cells Large-scale bioreactors: IDEC, Serono Early seed culture steps: Amgen, Genentech

23. Current Biopharmaceutical CMC Issues Challenge of adventitious agents - mycoplasma! 21st century: minimize or eliminate animal- and human-derived materials in the biotech culturing process Transmissible spongiform encephalopathy (TSE) Manufacturers are switching over to plant-derived proteins: soybean peptones

24. Current Biopharmaceutical CMC Issues Challenge of adventitious agents - mycoplasma! But soybeans are exposed to adventitious agents from the farm to the mill to the bottle on your shelf! Have we traded one adventitious agent concern (TSE) for another (mycoplasma)?

25. PDA Ongoing Efforts Mycoplasma – 4 Task Forces • Peptone and Complex Media as a Source of Mycoplasma Contamination • Plant-derived proteins are not adventitious agent free! FDA Q&A on cGMP, Level 2 Guidance 2005

26. PDA Ongoing Efforts Mycoplasma – 4 Task Forces Standardization of Mycoplasma Filters Industry-wide harmonization of best-practice testing to classify mycoplasma-removing 0.1 µ filters (similar approach to the virus filter standardization) (Acholeplasma laidlawii ATCC)

27. PDA Ongoing Efforts Mycoplasma – 4 Task Forces • Alternate Mycoplasma Test Methods for Product Release • (Official) in-vitro cell culture test (45 days) • NAT (PCR) • Enzyme Activity Need global regulatory approval to replace in vitro cell culture test EMEA accepting of PCR, but FDA is not!

28. PDA Ongoing Efforts Mycoplasma – 4 Task Forces • Emerging Mycoplasma Issues in Plants and Insects • Expanding applications of plant and insect cell culture to rapidly produce biopharmaceuticals • (vaccines, bioterror defense products) • What is the risk due to mycoplasma in these cell cultures? • (not from animal-origin mycoplasmas but from plant- and insect-derived mycoplasmas)

29. PDA Ongoing Efforts Mycoplasma Task Forces Task Forces sponsoring a major workshop on these mycoplasma issues at the PDA Annual Conference In Colorado Springs April 2008 Don’t want to miss! Task Forces are preparing a “White Paper” on the Mycoplasma Issues in the 21st Century Awareness for our industry!

30. Biotech Advisory Board Some biotech concerns being pursued by PDA • Biotech analytical test methods • Development/Technology Transfer (BioAB) • Validation for Commercial Products (SAB) Task forces just getting organized!

31. How you can help! Get Involved! PDA is always looking for experienced, knowledgeable members who can volunteer and be active participants!

32. For further information, contact www.PDA.org Thank you!