1. Current Considerations on Plasma for Further Manufacturing Obtained from Whole Blood Donors Alan E. Williams, Ph.D. Associate Director for Regulatory Affairs, OBRR, CBER, FDA Blood Products Advisory Committee April 28-29, 2011 1

2. Plasma for Further Manufacturing Fractionated plasma products are manufactured from two distinct plasma pathways in the US –Source Plasma (SP) constitutes 90% of the fractionated plasma product starting material in the US SP is collected by plasmapheresis exclusively for use in further manufacturing, generally from paid, frequent donors. Frequent SP donors must meet specific donation standards to ensure donor health. SP is frozen immediately after collection to preserve labile plasma proteins (e.g. FVIII). 2

3. Plasma for Further Manufacturing (cont.) Recovered plasma (RP) constitutes the remaining 10% of plasma fractionation starting material RP is an unlicensed product obtained from conversion at any time of unused Whole Blood (WB) Fresh Frozen Plasma (FFP - frozen within 8hrs), PF24 - plasma frozen within 24 hrs, or other WB plasma. RP may also be derived from apheresis FFP (frozen within 8 hrs) after its one year outdate. (Defined in regulation) Once RP produced, there is limited regulatory oversight. Product standards are defined in “Short Supply Agreements” (SSA) between the Blood Establishment and the fractionator, and manufactured products may be injectable or non-injectable. 3

4. Seeking Improvements to the Recovered Plasma Paradigm 1. Conversion of apheresis plasma for transfusion at any time for use in further manufacturing would enable more efficient inventory control at blood establishments. – increased plasma collection on mobile units –overall increase in plasma availability –conflicts with current regulatory definition of SP

5. Seeking Improvements to the Recovered Plasma Paradigm 2. FDA seeks to establish standards for WB- derived plasma shipped for further manufacturing into injectable plasma derivatives to reduce variability of the starting material.

6. Seeking Improvements to the Recovered Plasma Paradigm 3. Ensure that collections from WB donors are generally intended for transfusion consistent with donor expectations.

7. Seeking Improvements to the Recovered Plasma Paradigm 4. The blood community has requested that FDA consider defining a new plasma product (with a different name) that would replace RP with plasma products more closely resembling Source Plasma

8. History Defining major new plasma product standards has been complex 2004 FDA-sponsored Plasma Workshop to discuss plasma quality as a possible variable for fractionation Concurrent and Component Plasma product concepts described at April, 2009 BPAC 8

9. CONCURRENT PLASMA

10. April, 2009 BPAC : Concurrent Plasma (CCP) April, 2009 - CCP was proposed by FDA as plasma for further manufacturing separated from licensed Whole Blood collection, plasma collected concurrently with cellular components by apheresis, or one-way conversion (at any time) of existing licensed FFP or WB-PF24 collected concurrently with a cellular product. –“Intent” of collection for transfusion is inherent in Concurrent Plasma definition. –FDA described a multi-tiered approach to product labeling. 10

11. Concurrent Plasma (CCP) BPAC recommended clarification of product standards and simplification of labeling for concurrent plasma April, 2011 - Concurrent Plasma product standards and labeling are the major topic for discussion at today’s session. Mark Weinstein, OBRR FDA Freezing temperature (-20 degrees C) Time to freezing (24, 72 hrs) Shelf life (up to 3 years) FVIII content (70 IU/ml) 11

12. COMPONENT PLASMA

13. April, 2009 BPAC : Component Plasma (CMP) April, 2009 - Component Plasma was proposed by FDA as plasma collected as a sole plasmapheresis product from WB donors or through conversion at an time of FFP collected from WB donors as a sole plasmapheresis product. BPAC expressed concerns about collection of plasma for fractionation as sole product from WB donors due to donor expectation of donation for use in transfusion 13

14. Current FDA Consideration Component Plasma (CMP) April, 2011 – Licensed apheresis FFP collected as a sole product can be converted to Component Plasma for further manufacturing after its one year outdate –Parallels current FFP conversion policy –Preserves concept of WB donation generally intended for transfusion –Solo FFP collection uncommon per blood community - FFP-stand alone collections likely to be male and AB (likely to be transfused) 14

15. Current FDA Consideration Component Plasma (CMP) April, 2011 - –Standards for Component Plasma are inherently met since derived only from FFP (frozen within 8 hours), or potential equivalent –CP product shelf life will be 3 years from date of collection 15

16. RECOVERED PLASMA

17. Recovered Plasma April, 2011 - Any Plasma not meeting standards for CCP or CMP may still be shipped for further manufacturing under short supply agreement. Limited to use for non-injectables.

18. Concurrent and Component Plasma Overall FDA Considerations √ Product names - Concurrent and Component Plasma √ Define pathway for immediate conversion of concurrently collected apheresis FFP collected under WB donor standards and (potentially a future FP24) √ Assure that transfusion remains the primary intent of WB donation (BPAC 2009) √ Promote high quality starting material to make injectable plasma derivatives 18

19. Concurrent and Component Plasma Overall Considerations (cont.) √ Investigate effects of time to freeze, time to separation, freezing and storage temperature √ Labeling and processing compatible with current blood center and fractionation operations ( Labeling simplified per BPAC recommendation April, 2009) √ Additional standards under consideration are largely consistent with current fractionator practices for accepted plasma starting material 19

20. Concurrent and Component Plasma Overall Considerations (cont.) √ Consider harmonization with EU plasma standards – desirable but not mandatory √ Retain regulatory pathway for plasma not meeting CCP or CMP standards to be used for non-injectable products 20

21. Current Sources of Plasma for US Plasma Derivative Manufacture Phlebotomy Whole Blood Source Plasma ( Infrequent) Unlicensed recovered plasma Plasma Derivatives or non-injectableproducts Plasma for Transfusion (24 h Plasma, FFP, PlasmaCryo Reduced) Current Sources of Plasma for US Plasma Derivative Manufacture Automated Apheresis Plasma for Transfusion (ApheresisFFP) collected + RBC,Plts Convert anytime Whole Blood Donor Standards Automated Plasmapheresis Source Plasma Donor Standards 1 year before conversion Source Plasma

22. Current Sources of Plasma for US Plasma Derivative Manufacture Phlebotomy Whole Blood Source Plasma ( Infrequent) Unlicensed recovered plasma Plasma Derivatives or non-injectableproducts Plasma for Transfusion (24 h Plasma, FFP, PlasmaCryo Reduced) Current Sources of Plasma for US Plasma Derivative Manufacture Automated Apheresis Plasma for Transfusion (ApheresisFFP) collected + RBC,Plts Convert anytime Whole Blood Donor Standards 1 year outdate

23. 23 Recovered Plasma option also remains available for non-injectable products

25. FDA Current Consideration Sources of Plasma for US Plasma Derivative Manufacture Under Whole Blood Donor Standards

26. ISSUE FDA seeks the advice of the Committee on appropriate manufacturing standards for plasma products collected from Whole Blood donors to make injectable plasma derived products. 26