Dear FDA Dockets Manager:
AABB is an international, not-for-profit association representing individuals and institutions involved in the field of transfusion medicine and cellular therapies. The association is committed to improving health by developing and delivering standards, accreditation and educational programs that focus on optimizing patient and donor care and safety. AABB membership consists of nearly 2,000 institutions and 8,000 individuals, including physicians, nurses, scientists, researchers, administrators, medical technologists and other health care providers. AABB members are located in more than 80 countries.
AABB appreciates the opportunity to provide comments on this draft guidance document and, in developing the comments, has relied on expertise from member blood banks, transfusion services and blood centers of varying sizes. AABB comments include several general comments, as well as specific ones directed to identified sections of the draft guidance.
First, the level of validation and monthly quality control (QC) required by the recommendations in this draft guidance seem to be overly cautious and at odds with other agency goals of developing risk-based policies. Through the approval process, device and filter manufacturers have already satisfied FDA that their device or filter can achieve the desired leukoreduction result/residual white blood cell (WBC) content, and recovery of the desired cellular component, thus making the levels of validation and QC recommended in the draft guidance redundant and overly burdensome.
Second, AABB and FDA agree that it is advantageous to provide pre-storage leukocytes reduced components in preference to bedside filtered blood components based on quality and safety considerations. AABB, however, is concerned that the requirements of these draft recommendations will make it very difficult for some smaller establishments to prepare, label and provide pre-storage leukocytes reduced components. Under this draft guidance, a new procedure must be validated using a statistically valid method; the only method recognized is the binomial approach.
Third, the QC requirements contained in the draft guidance recommendations are an enormous undertaking for a small establishment. While the alternative hypergeometric distribution plan, contained in the Appendix, will be helpful to some facilities, there are establishments that collect volumes below the population size indicated on the table and/or will fit one of the smaller population sizes, but only if they perform 100% QC. In addition to performing 100% QC, these establishments will likely not have the indicated additional number of products required to be counted in a QC period in the event of a QC failure, should one occur. Finally, it is disappointing that the Quality Assurance and Monitoring draft guidance recommendations focus so heavily on product testing, given the clearance/approval of the devices used to make these products.
Again, AABB's concerns with the prescriptive approach to QC, as well as other recommendations, stem from our conviction that it is better to provide transfusion recipients with pre-storage leukocytes reduced components than bedside filtered blood components and our belief that some of the recommendations contained in this draft guidance document create unnecessary barriers for small blood establishments who are today providing pre-storage leukocytes reduced components.
Comments to specific recommendations in the guidance document are arranged in the following format:
Section – language from draft guidance reprinted with page number and other identifying information.
Recommendation/Request for Clarification – recommendation or clarification request.
Supporting Information – rationale in support of the recommendation/clarification request.
I. Introduction – "This guidance applies to Whole Blood, Red Blood Cells, Plasma and Platelets1 manufactured from Whole Blood or collected by automated methods2."
1The guidance document entitled "Guidance for Industry and FDA Staff: Collection of Platelets by Automated Methods," dated December 2007 document contains our recommendations for validating; quality assurance and monitoring; labeling and licensure for leukocyte reduction of Platelet, Pheresis products. http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm073382.htm, accessed January 25, 2011.
Recommendation – The Introduction paragraph should clearly state that this guidance does not apply to Apheresis Platelets.
Supporting Information – The footnote listed above, and used throughout the draft guidance, references the 2007 guidance that provides recommendations for validation, quality assurance and monitoring, labeling and licensure for leukocyte reduction of Apheresis Platelets; however we believe it would better serve blood establishments to state this fact in the Introduction.
II. Background A (3) – "We recommend the use of a mixing device during blood collection."
Recommendation – Section should be reworded: "We recommend that establishments should have appropriate Standard Operating Procedures in place to ensure adequate mixing during blood collection."
Supporting Information – The use of manual or automated mixing should be acceptable to prevent the formation of micro-clots. There are no references provided with the draft recommendation to explain a scientific basis for the recommendation. At the 2001 BPAC meeting, The Montreal Centre of Canadian Blood Transfusion presented a synopsis of an evaluation indicating that manual methods provide a thorough mixing of blood and anticoagulant.
II. Background A (4) – "We are providing an option for supplemental labeling of blood components (not applicable to Whole Blood derived Platelets) when the residual WBC count of an individual component has been determined by direct count to be <1.10 x 106."
Recommendation – The optional, supplemental labeling (<1.10 x 106) section should be removed from this guidance.
Supporting Information – As in the 2001 draft, no rationale is provided for this specification limit. Removing it from the draft guidance does not preclude any blood provider from counting a product and providing the ordering hospital/clinician a report of the residual WBC content via a tie tag.
II. Background A (5) – "We recommend that Red Blood Cell recovery or content should be calculated by Red Blood Cell mass (weight x hematocrit) unless otherwise instructed in the manufacturer's direction for use."
Recommendation – The calculation of Red Blood Cell mass should be expanded to include the comparison of components pre- and post-filtration weights as an option unless otherwise instructed in the manufacturer's directions for use.
Supporting Information – Using a weight x hematocrit calculation for red cell mass poses an issue because hematocrit can be affected by component sampling errors. The use of pre-filtration and post-filtration weights avoids component sampling errors.
II. Background E Definitions – Non-process failure
Recommendation/Clarification – Establishments would benefit from a further discussion of what the FDA considers a non-process failure and how the result affects the replacement of the sample in the validation or QC plan. The current draft includes one example of a donor specific characteristic such as HbS, but clarification could also include a discussion of events such as donors with higher than usual WBC or platelet counts.
Supporting Information – Strengthening the definition would assist establishments with the investigation of Product Performance Qualification failures. See also III Validation of the Leukocyte Reduction Process G.
II. Background E Definitions - Residual White Blood Cell (WBC) count
Recommendation – The phrase should be Residual White Blood Cell (WBC) content. (The definition appears to be appropriate.)
III. Validation of the Leukocyte Reduction Process F. – "Conformance to product standards must be assessed by a statistically valid method (see 21 CFR 211.160(b)). In the absence of a validation method (plan) provided by the manufacturer, you should develop a statistically valid plan based on 95% confidence that more than 95% of the components will meet the recommended results."
Recommendation – Alternatives to the binomial approach should be all allowed.
Supporting Information – Acceptable alternatives should reflect the overall number of products produced. For example, use of the binomial approach and testing of 60 consecutive units, is excessive for a small establishment collecting 100 units per month. The time required for validation would be lengthy and, should one failure occur, another 71 units would need to be tested. Additional components from the process being validated (co-components) and validation of the process at a different site will require an additional "60 consecutive unit" series to be initiated and followed. Per the requirements of V. Labeling, only components prepared by a validated method may be labeled "Leukocytes Reduced," yet the requirement to use a binomial approach makes it very difficult for small establishments to validate a process that will enable them to label products as "Leukocytes Reduced." See also IV Quality Assurance and Monitoring A.
IV. Quality Assurance and Monitoring A. – "A QA program should include in-process monitoring of the manufacturing procedures and QC testing."
Recommendation/Clarification – Alternatives for quality control monitoring should take into consideration the number of products collected and leukoreduced by the establishment.
Supporting Information – The hypergeometric distribution plan, which takes into account the number of products collected within a QC period (population size), does not work for some small establishments. There are establishments that collect volumes below the population size indicated on the hypergeometric table and/or will fit one of the smaller population sizes, and will be required to perform 100% QC – essentially revalidating their process – every month. Also, these establishments will likely not have the indicated additional number of products required to be counted in a QC period in the event of a QC failure, should one occur.
In addition, when applying for licensure, establishments are generally required to submit two months of quality control data. It is unclear how smaller establishments that wish to use the hypergeometric table will be able to submit two months of QC data if they do not collect enough product to fit one of the populations described in the table.
IV. Quality Assurance and Monitoring D. (2) – "Sample handling: Blood samples should be collected, processed, and tested within 48 hours (or per the manufacturer's recommendations for the methodology) of leukocyte reduction."
Recommendation – Section should be reworded: "Blood samples should be collected, processed, and tested within the timeline recommended in the manufacturer's recommendations for the methodology being used, or as validated by the establishment."
Supporting Information – A longer time should be acceptable if validation data are available demonstrating stability of the WBC for longer periods. This validation should include verification of the WBC counting method for older samples. Inability to complete testing in 48 hours could affect the availability of products. Some issues that small establishments face with the 48 hour requirement include:
- flow cytometry labs that may not be staffed full-time
- lack of available staff to perform manual counts, when needed
- loss of ability to collect some products on particular days because leukoreduction and tests for residual wbc content cannot be completed within the recommended window
AABB thanks the FDA for this opportunity to comment on this draft guidance. Should you have any questions or wish to discuss any of the comments further, please contact me at firstname.lastname@example.org.
M. Allene Carr-Greer, MT(ASCP)SBB
Director, Regulatory Affairs