Food and Drug Administration staff from the Center for Biologics Evaluation and Research (CBER) met with representatives from AABB at the FDA White Oak Campus to discuss topics of mutual concern regarding donor safety, patient safety, and product manufacturing. The FDA schedules only one full liaison committee meeting annually and an optional executive level meeting.
Hemoglobin (HB) Requirements for Blood Donors
The 22 May 2015 Final Rule, titled “Requirements for Blood and Blood Components Intended for Transfusion or for Further Manufacturing Use,” effective 23 May 2016, describes HB requirements in 21 CFR 630.10(f)(3). The minimal HB requirement for female donors remains 12.5 g/dL; however, male donors will be assessed against new minimum criteria of 13.0 g/dL. In addition, the “Final Rule” contains the following language regarding collection of blood from female donors with HB levels less than 12.5 g/dL:
“Recognizing that lower levels are also within normal limits for female donors, you may collect blood from female allogeneic donors who have a hemoglobin level between 12.0 and 12.5 grams per deciliter of blood, or a hematocrit value between 36 and 38 percent, provided that you have taken additional steps to assure that this alternative standard is adequate to ensure that the health of the donor will not be adversely affected due to the donation, in accordance with a procedure that has been found acceptable for this purpose by FDA.”
21 September 2015 AABB FDA Liaison Committee meeting, the committee discussed the topic of collecting female donors with HB levels less than 12.5 g/dL. AABB agreed to create a representative working group to develop templates / algorithms that describe a variety of additional steps that blood centers can undertake, in addition to measuring HB prior to blood donation that will be acceptable to meet these requirements of the “Final Rule”. The working group, which includes representatives from the American Red Cross (ARC) and America’s Blood Centers (ABC) as well as an FDA liaison, has almost completed the development of the templates. The templates will be posted on a new web page on the AABB
Regulatory/Government Affairs site and will be available for any blood collection establishment to use as the basis for a Prior Approval Supplement (PAS) submission to the FDA, along with standard operating procedures that contain the details particular to their own establishment. The templates are not intended to represent the only methods that the FDA may find suitable. Blood centers will be encouraged to contact
email@example.com with other procedures they submitted and which were approved by the FDA, so these approved procedures can be shared on the same web page. FDA representatives concurred that this approach is consistent with their understanding, although there is no guaranteed outcome of the PAS review.
AABB’s Donor Health and Safety Committee has established a working group to collect data from blood centers to capture the impact to the donor base of the change in eligibility requirements for male donors. Concerns include a loss of male plasma and platelet donors at a time when female donors are used less often for these collections due to TRALI mitigation efforts, as well as a loss of donors of compatible units for sickle cell recipients and other rare unit inventories. AABB will share with the FDA the results of the data collection.
Guidance Documents Pending on the 2016 CBER Guidance Agenda
“Relabeling of Apheresis Plasma Intended for Transfusion to Concurrent Plasma for Further Manufacture; draft guidance” – There has been and continues to be frequent product approvals obtained by apheresis device manufacturers for new plasma products that can be manufactured on apheresis collection devices. With each approval obtained, there is ever-increasing pressure for blood centers to move on to the new platform and away from the older plasma components that can be relabeled “Recovered Plasma” and shipped for further manufacturing. The advancements in apheresis device product approvals, some of which result in plasma being collected by apheresis even when a donor is recruited for platelets (e.g. platelets collected in platelet additive solution), are not supported by a regulatory pathway that allows the plasma not needed for transfusion to be sent for further manufacturing in a timely, efficient and consistent manner as other plasma products. In addition, blood centers struggle with periods of excess frozen plasma inventory for a variety of reasons. This commonly occurs due to increased collections to support therapeutic exchanges. Regardless of the reason, when the plasma product is collected using apheresis technology, blood establishments need a regulatory pathway that allows them to relabel for further manufacturing of the excess product that is not needed for transfusion.
AABB participants noted that the regulatory pathway under development by the FDA is not without concern, as explained in the AABB Interorganizational Plasma Task Force Statement to the Blood Products Advisory Committee (BPAC) in April 2011. Fresh frozen plasma collected concurrently with a cellular product will be labeled the same as an FFP that may be collected as a stand-alone product. The proposed requirement to relabel them as two separate products for further manufacturing will create unnecessary good manufacturing practice issues, administrative burden, and additional costs. FDA participants noted that the pathway to be outlined in the draft guidance will reconcile with the Code of Federal Regulation requirements regarding the intent for use of the product at the time of collection: transfusion vs. further manufacturing.
“Labeling of Red Cell Units with Historical Antigen Typing Results; draft guidance” – As reported in the summary of the
February 2015 meeting with the FDA, the agency has approved at least one standard operating procedure for the use of tie tags for historical antigen results (other than ABO/Rh), without testing the current donation, if units from two previous donations were tested by the collection facility and found to be concordant. The acknowledgement that blood establishment processes and procedures exist to assure the linkage of donor test results and donor records, is encouraging. However, blood establishments would like to be able to provide the results via (International Society for Blood Transfusion (ISBT) labeling. In the discussion with FDA, several questions were raised. For instance, what did the AABB work group recommend if investigational or unlicensed reagents are used to generate a historical test result? The work group presentation to the
December 2012 BPAC recommended that the labeling should indicate when reagents that are not FDA approved (unlicensed – either serologic or DNA) are used. FDA also asked for input on the use of ISBT 128 Test History Data Structure. The structure allows the user to encode whether the testing was performed on the current sample, historic samples, or both. AABB participants committed to bringing this question back to work group for discussion.
Strategies for Implementation of Antibody and Nucleic Acid-based testing for
Babesia microti in Blood Donors
This emerging infectious disease topic was not included on the CBER Guidance Agenda released for 2016. The FDA participants noted that the
May 2015 BPAC recommended to the agency a policy that included universal use of an antibody test but geographically bounded PCR testing. Until such time as there is a licensed test(s) available the agency does not have recommendations for its use, although a geographically bounded approach could be considered.
Zika Response – Perspectives and Challenges
AABB, along with ABC and the ARC, previously provided the agency with a
letter expressing concerns regarding the lack of a uniform approach for the designation of Zika active areas in the United States as described in the
February 2016 guidance document. The lack of a uniform approach means that blood establishments are unable to anticipate and direct resources toward appropriate blood safety interventions. The organizations will submit comments to the February final guidance to correspond with the concerns contained in the 02 May letter and suggest amendments to several of the recommendations. AABB and FDA participants at the meeting discussed several ongoing efforts to work with partners at various public health / government agencies to achieve a uniform approach that will support blood safety that included triggers to determine active areas, and methodology to de-trigger areas of active transmission. FDA is participating in an
AABB-sponsored Zika symposium to be held in the Washington, D.C. area on 10 June.
Pathogen Reduction – Perspectives and Challenges
There was a brief discussion of the following issues:
- The technology is slowly becoming available, and being implemented at collection centers due to the stepwise approach to product approvals for platelets and plasma.
- There has been uncertainty regarding the use of pathogen reduction vs irradiation for the mitigation of transfusion-associated graft versus host disease. On this topic, the FDA noted that they have not approved an intended use claim but did allow presentation of data in the package insert.
- AABB noted challenges identified by hospital transfusion services that include management of multiple inventories.
Food and Drug Administration
Peter Marks, MD, PhD, Director, Office of the Center Director (OD), Center for Biologics Evaluation and Research (CBER)
Diane Maloney, JD, Associate Director for Policy, OD, CBER
Jay Epstein, MD, Director, Office of Blood Research and Review (OBRR), CBER
Nicole C. Verdun, MD, Acting Deputy Director, OBRR
Orieji Illoh, MD, Deputy Director, Division of Blood Components and Devices, OBRR
Cynthia Whitmarsh, CSO, Manufacturers Assistance and Technical Training Branch, Office of Communications, Outreach and Development, CBER
Donna M. Regan, MT(ASCP)SBB, President
Miriam A. Markowitz, CEO
Jean Otter, Vice President, Transfusion Medicine Standards and Accreditation, Regulatory
M. Allene Carr-Greer, Director, Regulatory Affairs