Current Considerations on Plasma for Further Manufacturing Obtained from Whole Blood Donors
28 April 2011
M. Allene Carr-Greer, Director, Regulatory Affairs on behalf of the AABB Interorganizational Plasma Task Force
Thank you for the opportunity to provide input to this discussion today. This statement is presented on behalf of the AABB Interorganizational Plasma Task Force that welcomes this movement toward licensure of plasma for further manufacturing. Task Force membership includes representatives from AABB, American Red Cross, America's Blood Centers, Blood Centers of America, Blood Systems, Inc., Department of Defense, Hema-Quebec, Plasma Protein Therapeutics Association, and Manufacturers' Representatives from Baxter BioScience, Octapharma and CSL Plasma.
Since 2002, members of the blood banking and plasma community have interacted with Food and Drug Administration (FDA) in various venues in an effort to establish a pathway to licensure for the product (Recovered Plasma) that is currently distributed under short supply agreement. A formal proposal for Plasma for Further Manufacture was developed and presented to a workshop sponsored by FDA in 2004 and the subsequent docket for the development of plasma standards. The current task force revised the proposal in 2007, submitted it to a docket created for a proposed rule on blood components intended for transfusion or for further manufacturing use and presented it for the BPAC's consideration in 2009.
Following the April 2009 BPAC meeting chair of the task force, Susan L. Wilkinson, communicated with Dr. Epstein to reiterate comments made at the meeting, that is to say that the framework presented by FDA provided the necessary regulatory pathway to allow for plasma that is not needed for transfusion to be sent for manufacture into other life-saving plasma products, and expressed concern regarding the complexity in some of the structure. Dr. Wilkinson further noted that the process for relabeling apheresis plasma originally collected for transfusion to products for further manufacturing appeared to be error prone.
The Issue Summary published in preparation for this meeting describes the structure for a licensed product(s) rather than the current one that has minimal oversight in the Code of Federal Regulations (CFR). The opportunity to manage these products through biologics license applications rather than contracts and short supply agreements is a great improvement and is appreciated. Should FDA develop a regulatory pathway, we wholeheartedly endorse the consideration for variances under 21 CFR 640.120 to allow blood establishments to implement the changes at a time prior to publication of final regulations. We do note several items that we believe would benefit from additional discussion and/or would facilitate implementation of this new regulatory pathway.
FDA considerations include unidirectional labeling of the plasma product from use for transfusion to use for further manufacturing. The task force agrees that this is likely the predominant direction labeling would take. However, there are events that affect inventory management and could result in a deficit of transfusible product where the need could be filled by relabeling the plasma for further manufacturing to its original plasma for transfusion product name/code. This need could arise if the establishment loses the contents of a freezer through malfunction or disaster, or a hospital customer(s) has an unexpected need for large volumes of plasma for transfusion or therapeutic purposes. The age of the plasma and the freezing/storage conditions would have to be suitable for the transfusible plasma product for this to be allowed. Current CFR requirements for recordkeeping, and computer controls of these parameters exist. There is no biologic or scientific rationale not to allow bidirectional labeling of conforming plasma. Given the amount of time it takes to revise regulations once they are created it is unwise to create a barrier to effective inventory management by determining through regulation that labeling can occur in one direction, only.
The proposal to differentiate the products for further manufacturing [Concurrent Plasma (CCP) and Component Plasma (CMP)] creates a dichotomy for two products that in reality are the same component. They are collected from donors qualified under the same set of regulations, processed and stored under the same conditions, and the products are used the same in transfusion practice. Blood establishments cannot collect stand-alone plasma from donors any more frequently than is allowed under the guidelines for infrequent plasmapheresis that have been in place since 1982. The European Union and others do not differentiate between apheresis plasma collections and creating two different products would lead to further disharmony with the EU. As there is no scientific or biologic basis for setting limits on when a product is converted to plasma for further manufacturing we reiterate our belief that it would be unwise to create a barrier to effective inventory management by arbitrarily assigning a waiting period before allowing a product to be relabeled. CMP is biologically the same product as CCP.
The proposal to differentiate the products through use of labeling as CCP and CMP has also created a Good Manufacturing Practice (GMP) error prone process when apheresis Fresh Frozen Plasma (FFP) products need to be relabeled for further manufacturing. Figure 2 in the Issue Summary provides a visual of the products that could be collected manually or by automated methods, the amount of time involved before the product could be converted to a plasma for further manufacturing and what the product for further manufacturing would be called. When looking at the automated apheresis products it appears that the FFP product collected with a cellular product is called by a different name than the FFP product collected as a stand-alone product. But both products are labeled and placed in the freezer as apheresis FFP. This is true even for products labeled with ISBT-128. There is no information on the apheresis FFP label to note a difference between the two. Establishments will have to introduce additional computer controls or reports to ensure that a stand-alone plasma is not relabeled prior to expiration. The inherent GMP challenges in this proposal are an additional reason it is best to have one product name for plasma for further manufacturing.
Language from the European Pharmacopoeia concerning Factor VIII levels for plasma used to make labile products was cited in the Issue Summary and a parenthetical statement was added reflecting indecision about frequency of the testing and which establishment should perform the testing. This text does not reflect mandatory requirements of the EP and is variably applied by the fractionators. Recent conversation within the task force (including representation from fractionators) indicates that this test, intended to demonstrate adequate quality of the starting material for fractionation, could either be done by the blood establishment or by the fractionator as part of the in-process quality control on starting pools for fractionation. Responsibility for testing should be left to the fractionator to define in the contract with the blood center. We note that blood establishments do not perform Factor VIII levels on Fresh Frozen Plasma or Plasma Frozen Within 24 Hours After Phlebotomy. Factor VIII levels are performed for purposes of quality control on Cryoprecipitated AHF manufacturing and these data are/have been presented here today.
Freezing at -20 C will require modifications for some establishments and sufficient time should be allowed in the implementation of any new product standards for establishments to make the modifications.
As a comment, we note that FFP collections at mobile sites are primarily constrained due to the need to get the product into the freezer within the timelines required by the directions for use for the blood collection, processing, and storage system.
Again, we thank you for the opportunity to participate in the discussion. I would like to emphasize that the comments today are intended to facilitate implementation of this new regulatory pathway. The task force appreciates the time that has been spent moving this issue forward and we look forward to having this licensed product(s) for further manufacturing.