Members of the Blood Products Advisory Committee to the Food and Drug Administration gathered in Gaithersburg, Md., for their 100th
meeting on April 28-29 to consider several topics of interest.
Use of Plasma From Whole Blood Donors for Further Manufacturing
FDA provided an
overview of current pathways used to manufacture fractionated plasma products – Source Plasma and Recovered Plasma – and explained the similarities and differences between the two pathways. Regulatory oversight exists for donor eligibility in both pathways, and products for transfusion that are later shipped under short supply agreement as Recovered Plasma are covered by regulations. However, product standards for the unlicensed Recovered Plasma product are handled primarily through contracts between the fractionator and the establishment. In contrast, Source Plasma is a licensed product, and product standards are regulated. FDA reiterated that current products in use – Recovered Plasma, and the finished product or products that are the result of the further manufacturing process – are suitable and safe, but the blood community and FDA are in agreement that licensure of the plasma product obtained from whole blood donors for further manufacturing is desirable. The issue was previously reviewed by BPAC in April 2009, at which time the committee endorsed the concept that FDA previewed but recommended simplification of the proposed labeling scheme.
FDA representatives (Alan Williams, PhD, and Mark Weinstein, PhD) presented current considerations for two licensed products that would be used for further manufacturing into fractionated plasma products. FDA did not propose any changes to existing licensed products for transfusion.
Concurrent Plasma, or CCP, was defined as a new licensed plasma product intended for further manufacturing obtained from 1) licensed Whole Blood, or WB, collected manually, 2) licensed plasma collected concurrently with cellular components by apheresis, or 3) conversion at any time from licensed Fresh Frozen Plasma, or FFP, or WB-Plasma Frozen Within 24 Hours After Phlebotomy, also known as PF24, collected concurrently with a cellular product. FDA further noted that the CCP definition reflects the concept that blood obtained from community whole blood donors is intended primarily to serve transfusion needs. Licensed products for transfusion could be converted to CCP at any time, but CCP, once labeled, could not be re-labeled as a transfusible product. CCP shelf-life would be three years from the date of collection.
Component Plasma, or CMP, was defined as a new licensed plasma product intended for further manufacturing obtained by relabeling of expired licensed FFP collected under whole blood standards as a stand-alone plasmapheresis product. CMP shelf-life would be three years from the date of collection.
Under FDA's proposal, CCP and CMP would be suitable for manufacture of injectable end products (subject to certain additional restrictions) but also could be made into non-injectable end products. Plasma products not meeting the standards of CCP or CMP would not be subject to licensure requirements and could continue to be distributed as Recovered Plasma under short supply agreements, but only for use to make non-injectable end products.
During the open public hearing, the AABB Interorganizational Plasma Task Force provided a
statement in support of the proposal for a licensed plasma product for further manufacturing and suggested further discussion of several items that would benefit from additional discussion and/or would facilitate implementation of the new regulatory pathway. The task force agreed with FDA's understanding that unidirectional labeling of plasma for transfusion to plasma for further manufacturing was the predominant direction labeling would take but asked for consideration of circumstances where a deficit of transfusible product could arise and bidirectional labeling, if not prohibited by regulation, could fill the need. The task force noted that the proposal to license two products for further manufacturing does not have a scientific or biologic basis and creates a good manufacturing practice, or GMP, error-prone process when apheresis Fresh Frozen Plasma products need to be relabeled for further manufacturing. Considerations for Factor VIII testing as process validation and possibly also quality control testing under GMP were noted by the task force to be a concern as the text quoted does not reflect mandatory requirements of the European Pharmacopoeia and U.S. blood establishments do not perform FVIII levels on FFP or PF24. The proposal to freeze plasma products at -20 C would require modifications at some establishments, and FDA was requested to be mindful of those issues when establishing implementation dates for any new requirements. Task force membership includes representatives from AABB; the American Red Cross; America's Blood Centers; Blood Centers of America; Blood Systems, Inc.; the U.S. Department of Defense; Hema-Quebec; Plasma Protein Therapeutics Association; and manufacturers' representatives from Baxter BioScience, Octapharma and CSL Plasma.
The results of a survey administered by America's Blood Centers, the Blood Group Alliance and Blood Centers of America were presented by Gay Wehrli, MD, of Virginia Blood Services. The survey was designed to respond to questions raised by FDA about the impact of the proposals for the licensed plasma products for further manufacturing. ABC centers were surveyed, with a response rate of approximately 50 percent; all respondents reported that they prepare plasma for further manufacturing. Most of the responses indicated an ability to meet the requirements of the proposals, and the number one advantage of the new structure would be an increased flexibility in managing inventory. The responses demonstrate support for FDA's consideration of including cryo-poor plasma (thawed and refrozen during the production of Cryoprecipitated AHF) in the listing of products deemed acceptable for use in injectable products.
Celso Bianco, MD, the non-voting industry representative to BPAC, reiterated the support for the new structure and acknowledged the items for discussion that the Plasma Task Force had presented. He also noted that the industry was encouraged by the current considerations that FDA had brought to BPAC.
Questions for the Committee:
Question 1 – Please comment on FDA's current considerations on standards for CCP.
- Labile products made only from plasma held at ≤24 hours from collection to placement in freezer.
- Average FVIII level ≥70 IU/100 ml for plasma used to make labile products as Quality Control testing under GMP where appropriate (process validation).
- Non-labile products made from plasma held at ≤72 hours from collection to placement in freezer.
- Replacing ≤-20°C for ≤-18°C for all conditions of freezing, shipping and storage
- Allowable shipping and storage temperature deviation can exceed - 20°C ≤72 hours total, never greater than -5°C (never refrozen).
- Storage up to 3 years.
- Plasma that has been thawed and refrozen would not be used for injectable products (with the possible exception of cryo-poor plasma).
With regard to a) it was noted that the proposal would support a quality plasma product; there was no "downside." In response to questions about temperature deviations described in e), FDA staff noted that this is current practice for Source Plasma and Recovered Plasma. The important issue is that temperature conditions are monitored and documented. At -5 C, the products are still frozen. With regard to g) it was explained that current practice is to include cryo-poor plasma, as the thaw and refreezing cycle occurs under controlled circumstances during the manufacture of Cryoprecipitated AHF.
Question 2 – Does the Committee agree with FDA's current considerations on labeling categories for CCP?
Placement in ≤20°C freezer
avg FVIII ≥70 IU/100 ml*
avg FVIII <70 IU/100 ml*
|≤72 hr || ||x||x|
|>72 hr|| || ||x|
*process validation and possibly also Quality Control testing under GMP
During committee discussion of the proposal for FVIII testing, several members noted that validation processes would suffice, but FDA indicated that QC might also be necessary due to the many processes that would be involved. However, they were aware of the concerns expressed regarding the burdensome nature of the proposal.
The committee voted in unanimous agreement with the labeling categories as described by FDA.
Question 3 – Does the Committee agree with FDA's current considerations on labeling categories for CMP?
|Placement in ≤20°C freezer||Labile||Non Labile||Non Injectable|
|Future products?*|| || || |
*FVIII process validation and possibly also Quality Control testing under GMP
Several members noted the comments presented by the Plasma Task Force regarding the necessity for differentiating the two apheresis plasma products. In response to a question, it was explained that FDA will leave a pathway for future products to be included.
The committee voted in unanimous agreement with the labeling categories as described by FDA.
Whole Blood Donor Written Statement of Understanding
Orieji Illoh, MD, provided the FDA
overview. Although FDA has regulations requiring informed consent for Source Plasma, plateletpheresis and plasmapheresis donors, FDA has not required that blood establishments inform Whole Blood donors about the blood donation procedure. In a 2007 proposed rule on human blood and blood components for transfusion and further manufacturing use, FDA included a proposed requirement for blood establishments to provide all donors with a written statement of understanding. This proposal would create new requirements for providing information to Whole Blood donors in part to ensure blood safety while protecting the health of the donor. FDA explained that the choice of "written statement of understanding" rather than "informed consent" is an effort to differentiate the donation process from the informed consent process that is required for research. The committee was provided with an excellent overview of informed consent by Christine Grady, MSN, PhD from the National Institutes of Health. She noted that there are many factors that might affect what the donor understands, and also the difficulties for the interviewer in knowing what the donor understood. An important task should be determining
the essential information that needs to be communicated. Acknowledgement of understanding can occur in many ways.
Beth Shaz, MD, New York Blood Center reviewed the evaluation of informed consent forms for adults and minors for whole blood donation used by U.S. blood centers (Transfusion, June 2009) that concluded with a recommendation for a task force to consider development of standardized information for use with whole blood donors.
Ronald E. Domen, MD, of Penn State Milton S. Hershey Medical Center, reviewed the results of a donor survey, "Informed Consent for Blood Donation," performed at his facility. Domen concluded the following:
- A large proportion of donors were incorrect in their comprehension of the risks and eligibility requirements of whole blood donation.
- Donors were perhaps more aware of some of the immediate risks but not as aware of some of the more consequential/long-term risks.
- HIV/AIDS transmission comprehension was good and was mentioned or discussed in several formats suggesting that there is probably some strength in repetition.
He believes the study raises questions about how well donors are informed about donation risks and the donation process in general. It would be beneficial to have "best practices" defined and disseminated.
statement presented during the open public hearing emphasized the requirements of AABB Standards for Blood Banks and Transfusion Services that provide the framework for educational material, consents and notification policies that must be developed and implemented by member blood establishments. The requirements parallel the elements that FDA proposed for inclusion in the written statement of understanding. AABB voiced support for the development of an evidence-based statement by the community to be used with locally developed materials to explain the risks and hazards of Whole Blood donation to the donor, rather than a standardized statement developed through guidance or rulemaking. AABB standards allow electronic acknowledgements for issues such as a statement of understanding, and it was noted that some FDA-cleared computer systems for donor screening do not require actual or electronic donor signatures. AABB Standards require that the steps referred to in the written statement of understanding be performed at each donation, prior to collection. AABB believes the decision of when to administer the statement of understanding on the day of donation should be left to the establishment as donor flow through facilities, and particularly at mobile sites, is not uniform and is often dictated by location constraints, as well as the specific medium used to administer educational materials.
Gay Wehrli, MD, Virginia Blood Services, presented an overview of a project to create model donor education and informed consent documents. An ABC working group plans to expand on the two elements not related to transfusion-transmitted infections that FDA proposed for inclusion in the donor written statement of understanding – risks and hazards of the donation process, and the opportunity to ask questions and withdraw consent. The working group plans to address potential donor questions from recruitment and donation preparation through potential post-donation adverse events, test result reporting, and deferrals. Funding has been secured to study, develop and test new materials and their impact on donors. FDA was requested to allow this to proceed as a development from industry rather than being disseminated through guidance or regulation.
*Questions for the Committee:
Question 1 – Please comment on the seven proposed elements of the written statement of understanding as listed in FDA's 2007 proposed donor eligibility rule.
- The donor has received and reviewed the educational material.
- The donor agrees not to donate if the donation could result in a potential risk to the safety, purity, or potency of the blood supply.
- A sample of the donor's blood will be tested for specified relevant transfusion-transmitted infections and for syphilis.
- If any of the tests are reactive, the sample of blood will be tested further.
- If the donation is determined to be not suitable or if the donor is deferred from donation, the donor's record must identify the donor as ineligible to donate and the donor must be notified.
- The hazards and risks of the donation procedure are explained.
- The donor has the opportunity to ask questions and withdraw consent at any time.
Various committee members noted the following:
- Inclusion of terminology such as "safety, purity, potency" is not appropriate when speaking to the donor.
- The information noted in d) is too detailed and should be covered in c) with the ultimate goal that the donor should be informed of the results of the testing and should never be surprised by a communication from local or state public health authorities.
- Hazards and risks should incorporate relevant information related to donor hemoglobin/iron levels.
- Withdrawal of consent "at any time" was supported and reflects current practice of withdrawing already distributed products based on receipt of post donation information.
- Incorporating unnecessary details into regulations will not be helpful.
- Staff presenting the material should feel they are educating the donor rather than "mirandizing" the donor.
Question 2 – Does the Committee agree that the data support a need for minimum standards for the explanation of the risks and hazards of Whole Blood donation to the donor?
Committee comments included a caution that "minimum" standards might be at the expense of educating the donor, and any attempt to standardize the process that will be used will likely inhibit communication with the donor.
The committee gave unanimous support to development of minimum standards.
Question 3 – Please comment on what methods are acceptable for presenting the written statement of understanding to the donor, and how the donor should acknowledge receipt of this statement.
Committee members noted that there are many methods/media known to be acceptable and it is important that establishments be able to select from the available options what will work best for their own donor populations. Validation of donor comprehension is important. There was widespread agreement that electronic acknowledgements are acceptable.
Question 4 – Please comment on when blood establishments should administer the written statement of understanding.
- Before donor questions?
- Before physical examination?
- Before phlebotomy?
During the committee's discussion, the importance of notifying donors of the donor deferral list prior to administering the questionnaire – that might result in a donor being placed on the deferral list – was noted. Otherwise, the committee discussion reflected the importance of allowing flexibility in the process used to administer the statement of understanding so as to maximize available tools and methods for communicating with the donor.
Question 5 – Please comment on how often blood establishments should administer the written statement of understanding to Whole Blood donors.
The committee briefly discussed possible benefits of a shortened process for repeat donors.
*All speakers and Committee members agreed that adolescent donors likely need special consideration in each of these issues.
Testing Source Plasma for Hepatitis B Virus by Nucleic Acid Testing
Source Plasma collections in the U.S. are tested for hepatitis B surface antigen as required by the Code of Federal Regulations, and most (possibly all) are tested voluntarily for HBV DNA by NAT due to requirements of the Plasma Protein Therapeutics Association QSeal (Quality Standards of Excellence, Assurance and Leadership) Standard according to presentations by Susan Zullo, PhD, of the CBER Office of Blood Research and Review, Division of Emerging and Transfusion-Transmitted Diseases, and Joshua Penrod, Vice President of the Source Division of PPTA. Following several presentations from industry representatives, specific to the testing being used, and other speakers during an open public hearing, the committee discussed the questions posed by FDA before voting.
Questions for the Committee:
Several committee members noted that Source Plasma is collected from qualified eligible donors, the pools undergo further testing, the product is fractionated, pathogen reduction technology is applied to the process, and there has been no disease transmission in the past several decades. The question was then asked, Why is FDA asking the committee to discuss HBV NAT, especially since it is already being performed on a voluntary basis? FDA representatives explained that if the committee felt the test was important, perhaps reliance on a voluntary standard was not enough.
Question 1 – Do the available scientific data support the concept that testing of Source Plasma donations by HBV NAT increases the safety margin of plasma derivatives?
Ten members voted Yes. The chair abstained, noting current data would not appear to show an improvement in safety of an already safe product.
Question 2 – If so, is a sensitivity of at least 500 IU/mL for the individual Source Plasma collection suitable for HBV NAT when testing minipools of Source Plasma?
Nine members voted Yes. Two members abstained.
Question 3 – Please comment on whether detection of HBV infection in Source Plasma donors by HBV NAT adds benefit to public health compared with testing only for HBsAg.
One member noted that public health benefits would be slightly greater than the benefit to the recipient – which would likely be zero. Other members noted that there were no data presented on current follow-up with donors, and this information would likely have been informative.
AABB did not present a statement on this topic.