1. Current CBER Safeguards for Blood Products: Approach to Products Containing or Exposed to Bovine Materials TSE Advisory Committee February 13, 2004 Dorothy Scott, M.D. Office of Blood Research and Review, CBER

2. Minimizing Risk of BSE Exposure to Products Sourcing materials –Geographic Source –Tissue Source –Tissue collection technique –Herd source/monitoring TSE clearance during manufacturing Equipment cleaning between batches

3. CBER Sourcing Recommendations CBER letters to manufacturers recommending not to source bovine materials from BSE countries (from 1993) As BSE detected in more countries, instantaneous source switching not possible –Time required to locate and contract new sources of material –Raw materials have to be qualified –Availability concerns

4. Scope of Blood Products Containing or Exposed to Bovine Materials: Examples Active substance –Some hemostatic products (contain bovine thrombin, bovine aprotonin) Excipients or Adjuvants Raw and starting materials; reagents –Cell culture reagents: fetal bovine serum, bovine insulin, bovine serum albumin –Manufacturing reagents: tallow derivatives, bone derivatives Equipment qualification materials –Media fill material

5. OBRR Actions to Minimize Risk of BSE Agent in Blood Products – Sourcing Manufacturers requested to source bovine materials from non-BSE countries Manufacturers encouraged to use non-bovine materials whenever possible IND and BLA product reviewers assess presence of ruminant materials, geographic source, tissue source, and make recommendations

6. OBRR/CBER Actions to Minimize Risk of BSE Agent in Blood Products – Facility Issues TSEAC Review of facility/equipment cleaning methods with respect to TSE’s July 18, 2003 Conclusion: that current facility cleaning methods, e.g. the use of solutions of sodium hydroxide or sodium hypochlorite followed by extensive rinsing cycles, are adequate to minimize the possibility that an infectious dose of the vCJD agent may be carried over from one manufactured lot into the next –Inspections – raw material sourcing confirmed; facility equipment cleaning methods assessed

7. OBRR Actions to Minimize Risk of BSE Agent in Blood Products – TSE Clearance TSEAC endorsed FDA consideration of labeling claims for TSE clearance in plasma derivatives, based upon specific demonstration of TSE removal during manufacturing TSE clearance study submissions encouraged by OBRR –Submissions received, evaluations in progress

8. Published TSE Clearance Studies for Plasma Derivatives (1) 1.Brown, P et al. The distribution of infectivity in blood components and plasma derivatives in experimental models of transmissible spongiform encephalopathy. Transfusion 1998 38:810-6 2.Brown, P et al. Further studies of blood infectivity in an experimental model of transmissible spongiform encephalopathy, with an explanation of why blood components do not transmit CJD in humans. Transfusion 1999 39: 1169-78 3.Lee, DC et al. Monitoring plasma processing steps with a sensitive Western blot assay for the detection of prion protein. J. Virol. Meth. 2000 84: 77-89 4.Foster, PR et al. Assessment of the potential of plasma fractionation processes to remove causative agents of transmissible spongiform encephalopathy. Transfusion Science 2000 22:53-56 5.Foster, PR et al. Assessment of the potential of plasma fractionation processes to remove causative agents of transmissible spongiform encephalopathy. Vox Sanguinis 2000 78:86-95 6.Lee, DC et al. A direct relationship between the partitioning of the pathogenic prion protein and transmissible spongiform encephalopathy infectivity during the purification of plasma proteins. Transfusion 2001 41: 449-55

9. Published TSE Clearance Studies for Plasma Derivatives (2) 7.Cai, K et al. Solvent-dependent precipitation of prion protein. Biochem Biophys. Acta 2002 1597: 28-35 8.Stenland, JS et al. Partitioning of human and sheep forms of the pathogenic prion protein during the purification of therapeutic proteins from human plasma. Transfusion 2002 42:1497-1500 9.Vey, M et al. Purity of spiking agent affects partitioning of prions in plasma protein purification. Biologicals 2002 30:187-96 10.Reichl, HE et al. Studies on the removal of a BSE-derived agent by processes used in the manufacture of human immunoglobulin. Vox Sanguinis 2002 83:137-45 11.Van Holten RW et al. Evaluation of depth filtration to remove prion challenge from an immune globulin preparation. Vox Sang 2002 85:20-4. 12.Burnouf T et al. Nanofiltration of single plasma donations: feasibility study. Vox Sang 2003 84:111-119. 13.Trijo, SR, et al. Evaluation of virus and prion reduction in a new intravenous immunoglobulin manufacturing process. Vox Sang 2003 84:176-87.

10. Labeling and Transmissible Agents in Plasma Derivatives Labeling –May provide estimate of risk of transmission of infectious agents –Discusses measures taken to reduce risks –May include results of clearance studies –Allows the public to make a more informed decision on risk/benefit Labeling claims typically undergo thorough scientific/regulatory review prior to implementation Labeling claims for pathogen removal in the past have been based upon rigorous and specific scientific evidence

11. Current Recommended Labeling for Plasma Derivatives Guidance 01/09/02: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products * “Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g. viruses, and theoretically, the Creutzfeldt-Jakob disease agent.” http://www.fda.gov/cber/gdlns/cjdvcjd.htm

12. EMEA Proposed Guidelines for TSE Clearance Studies (1) Use of actual production material for scaled-down clearance studies Scaled-down models appropriate Spiked infectious material should not be more than 10% of final volume Studies should be in accordance with Good Laboratory Practices Partitioning of infectivity should be demonstrated Infectivity reduction factors of < 1 log should be considered insufficient

13. EMEA Proposed Guidelines for TSE Clearance Studies (2) Combined-step studies should help support decision to accept additivity of two or more steps Combined steps [important] where a prior step may alter context or infectivity of TSE agent, possibly affecting removal by subsequent step (“conditioning”) Rationale should be given for TSE strain selected; rodent models are generally acceptable Microsomal fractions for spiking “may be preferred,” but other membrane-associated spikes may be used; a rationale should be provided for the form of spiking agent selected

14. EMEA Proposed Guidelines for TSE Clearance Studies (3) Bioassays for infectivity are suggested to confirm TSE agent clearance, but Prp sc assays may also be used to identify steps most likely to remove infectivity or as a surrogate assay for infectivity (when demonstrated for the TSE being studied) Studies should focus first on products manufactured by processes that appear to have the lowest overall capacity to remove TSE agents

15. EMEA Proposed Guidelines for TSE Clearance Studies (4) “All Manufacturers must critically evaluate their manufacturing processes in light of published data. Modification on the process might be considered. It is highly desirable that, in the light of this information, key manufacturing steps with potentially the highest removal capacity are experimentally investigated.”

16. EMEA Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents Via Human and Veterinary Medicinal Products (1/28/04) Overall risk assessment must take into account –Animal sourcing –Source of tissue –TSE clearance in manufacturing –Route of product administration –Quantity of animal material in product –Maximum therapeutic dosage –Intended use of product and its clinical benefit Final determination of regulatory compliance rests with the competent authority

17. EMEA Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents Via Human and Veterinary Medicinal Products (1/28/04) Source animals – “source from countries with the lowest possible GBR risk unless the use of material from higher GBR countries is justified.” –GBR I (highly unlikely) or GBR II (unlikely but not excluded) countries “safest” –“Negligible risk herds” considered in conjunction with GBR classification http://europa.eu.int/comm/food/fs/sc/ssc/out56_en.html http://europa.eu.int/comm/food/fs/sc/ssc/out56_en.html No possible BSE exposure via feed, etc. No epidemiological link to BSE cases

18. EMEA Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents Via Human and Veterinary Medicinal Products (1/28/04) Source tissue: subdivided into –Category A – high infectivity (CNS and certain other tissues, similar to specified risk materials) –Category B – lower infectivity tissues –Category C – tissues with no detectable infectivity Sourcing from Category A tissues shall not be used unless justified

19. EMEA Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents Via Human and Veterinary Medicinal Products (1/28/04) Source tissue considerations in risk assessment –Possibility cross-contamination with high risk tissues –Stunning/slaughtering techniques –Measures adopted to avoid contamination during collection of tissues “It is prudent to source from young animals” “Procedures should be in place to ensure … auditing suppliers of starting/raw materials”

20. EMEA Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents Via Human and Veterinary Medicinal Products (1/28/04) Special sections for –Collagen –Gelatin –Bovine blood derivatives Traceability to slaughterhouse and farms GBR I and II source unless otherwise justified Stunning methods must be described Tallow Milk and milk derivatives Wool Derivatives Amino Acids