Ask the FDA and Health Canada
Monday, October 6, 2008
AABB 2008 Annual Meeting
Montreal, Quebec, Canada
Jay Epstein, MD, Director, Office of Blood Research and Review, Center for Blood Evaluation and Research
Judy Ciaraldi, Consumer Safety Officer, Division of Blood Applications, OBRR, CBER
Sheryl Kochman, Chief, Device and Review Branch, DBA, OBRR, CBER
Jaroslav Vostal, MD, PhD, Chief, Laboratory of Cellular Hematology, Division of Hematology, OBRR, CBER
Paul Mied, PhD, Deputy Director, Division of Emerging and Transfusion Transmitted Diseases, OBRR, CBER
Sharon O’Callaghan, CSO, Division of Inspections and Surveillance, Office of Compliance and Biologics Quality
Ellen Lazarus, MD, Medical Officer, Division of Human Tissues, Office of Cellular, Tissue and Gene Therapy, CBER
Leslie Holness, MD, Chief, Blood and Plasma Branch, DBA, OBRR, CBER
Penelope Meyers, CLIA Program, Centers for Medicare and Medicaid Services
Peter Ganz, PhD, Director, Centre for Biologics Evaluation, Biologics & Genetic Therapies Directorate Health Canada
Francisca Agbanyo, PhD, Chief, Blood, Tissues, Organs, Xenografts Division Center for Biologics Evaluation
M. Allene Carr-Greer, director, Regulatory Affairs, AABB
THE MODERATOR: Good afternoon. I want to welcome you to this year's Ask the FDA and Health Canada session. We are very pleased this year that we were able to broaden the session to include questions for regulators in Canada and we are very pleased to have representatives from Health Canada with us. We will take a few minutes for Drs. Epstein and Ganz to make opening remarks and then we will begin with the questions that you submitted.
DR. EPSTEIN: Thank you very much, Allene, it is a pleasure to be here. I just want to extend a few words of thanks. First, to the AABB and also to yourself, personally, for organizing this ever-popular session. Also, I just want to note that we appreciate the format whereby questions were submitted electronically in advance. I think that this provides more opportunity for people to think over their issues and bring them to the session. It was harder for people to do that on the spot, I think. Then I just also want to note the novelty of this format, where the FDA and our sister agency representative from CMS are sitting together at the podium along with representatives from Health Canada. This reflects, I think, the spirit of the international meeting, the international AABB organization, which is also reflected in this non-U.S. venue, but I think from our perspective, it is also an emblem of the cooperation which exists amongst the regulatory agencies. Believe it or not, we do talk to each other and we even have confidential information sharing agreements and whereas our policies are not always the same, we are interested in the scientific foundations of any differences in policies. So I am thanking all our colleagues, both my own at FDA and our other colleagues at CMS and Health Canada. And then thirdly, I would like to thank you, the audience. On behalf of all of us, I know that we appreciate the opportunity to receive and try to answer your questions, as well as the opportunity to give a personal face to our organizations which otherwise, I am sure, to you, can seem like very remote, nameless, faceless non-caring bureaucracies. The truth of the matter is that we do care. Yes, we feel your pain, but perhaps most important is that we have an honest desire to be transparent and to give you answers to your important questions. Let me just say, in closing, that if there are unanswered questions, and I do not know that we are going to get through all forty-two questions that were brought to us last night, you are always free to contact our agency; please do so through the CSOs in our Division of Blood Applications. Again, it is a pleasure to be here and thank you all for coming.
DR. GANZ: Thanks, Jay. I would echo many of Jay's comments. I want to thank the AABB for their kind invitation to be part of this session and also thank FDA for allowing us to share the podium with them in this very popular session at AABB. By way of introductory remarks for Health Canada, certainly Jay has indicated FDA and Health Canada have a formalized Memorandum Of Understanding for exchanging information on a regular basis and, of course, even though systems are in place for exchanging regulatory information and the science behind policies, I think ultimately it comes down to people, not systems, and certainly the folks at FDA are always receptive to entering into dialogue concerning issues of commonality to North America and, indeed, globally. I would also remark that I think that just as blood banking is an international activity so too should be regulatory activities and I think through the number of venues that we have now to bring regulatory issues to the fore internationally, this is a very nice complement at AABB now, to be part of this particular session. I think that is really all I wanted to say other than a bit of a disclaimer, to say with our election here in Canada that Health Canada's remarks, in regard to answering many of your important questions, are really of a clarifying nature and Health Canada staff are really not here to announce any new policies or changes in direction. Thank you very much.
THE MODERATOR: Thank you. We will begin with our questions.
Question 1: Until recently the FDA requirement for lookback searches was 12 months prior to the last negative screening test or NAT test going back 5 years for HIV and 10 Years for HCV. It now seems to be 12 months prior to the last negative test going back 10 years for both HIV and HCV. Is this correct?
Is there a time frame for performing lookback for HTLV I/II antibody, hepatitis B surface antigen and hepatitis B core antibody?
What are the requirements in Canada?
DR. MIED: The answer to the first question is yes, that is correct. When the final rule for HCV lookback in 21 CFR 610.47 and 610.48 published, we also published a revision to 606.160(d) which changed from “the retention period shall be no less than five years” to “you must retain individual product records no less than ten years after the records or processing are completed...” We also revised 610.46(a)(1) in the HIV lookback regulation to state that within three calendar days after the donor tests reactive for evidence of HIV infection, you must review all records required under 606.160(d). That is, those records which are required to be maintained for ten years. For uniformity and consistency, the HIV lookback regulation in 610.46(a)(1) and the HCV lookback regulation in 610.47(a)(1) both refer to reviewing records required under 606.160(d) to be maintained for ten years. With regard to the second question, there are two parts to the lookback process: The identification and quarantine of blood and blood products from prior collections and secondly, the notification of transfusion recipients of products from those prior collections. The July 19th, 1996 FDA memorandum to blood and plasma establishments contained recommendations for the quarantine and disposition of units from prior collections from donors with repeatedly reactive screening tests for HBV, HCV and HTLV-1 stated that whenever a repeat donor has a repeatedly reactive screening test for HBsAg, anti-HBc, anti-HCV or anti-HTLV-1, blood establishments should identify and quarantine in date prior collections of whole blood and blood components in inventory extending back five years. But, of course, if there is a record of the last negative screening test then the quarantine to prior collections need only extend back twelve months before that test. FDA did not recommend that products which have already been pooled or further processed be quarantined. So the time frame for product retrieval is five years. Now, regarding the second part of lookback, recipient notification, in regard to products already transfused, FDA has not recommended tracing and notification of transfusion recipients of products from prior collections from a donor who is now positive or reactive for HTLV-I/II antibody, hepatitis B surface antigen or hepatitis B core antibody.
THE MODERATOR: Thank you, Paul. Peter, can you give us an overview of Health Canada regulations?
DR. GANZ: The way that our regulatory statutes are set up, we have an overarching Canadian Food and Drugs Act and regulations, and supporting those we have various directives and guidance documents that spell out or clarify our various regulatory requirements. In the last several years, we have actually created a group of national blood safety standards that have been accredited by the Canadian Standards Counsel and interestingly enough, AABB is a representative on that committee. You will hear us, throughout answering the questions here, refer to sections of those particular standards. With regard to this particular question, Health Canada has approved, in 2006, a six month only for the last negative test for HIV and HCV and, again, in this situation, it is assumed that there is a last negative result to go back to and if there is not, there is a requirement that you then go back five or ten years. For HTLV, it remains twelve months and for hepatitis B surface antigen and antibody to hepatitis B core, we basically adhere to our CSA standards requirement to perform a six month lookback. The reference for those standards is 19.3.1.
THE MODERATOR: Thank you.
Question 2: A patient was transfused with a unit of packed cells in 2006. He died during the same admission, within 48 hours of the transfusion. In 2008 the hospital received an HIV lookback notice stating that the donor of that unit now tests positive for HIV. To notify the family two years after the patient's death when there was no risk of transmission even if the unit had been infected will only cause distress to them and serve no useful purpose. Is there any way that the requirement to notify a deceased patient's family can be waived in such a situation?
DR. MIED: In 610.46(b)(3), the HIV lookback regulation says “when the supplemental test for HIV is positive, the consignee must notify transfusion recipients, or the recipient's physician of record, of the need for recipient HIV testing and counseling.” It also states “you must notify the recipient's physician of record or a legal representative or relative if the recipient is deceased.” So the consignee must notify the physician of record or a legal representative or a relative, in this case. We understand your concern about notifying the patient's family and causing distress to them in this situation, and the notification would appear to serve no useful purpose. The physician of record, at his or her medical discretion, may decline to notify the family in this case for the reasons that you have stated, and FDA would certainly grant a variance from the HIV lookback regulation in this situation.
THE MODERATOR: Thank you, Paul, that was helpful to hear you affirm that position.
Question 3: If you have a HIV (or HCV) lookback on a donor unit and find that the recipient was HIV (or HCV) positive prior to the transfusion, is it necessary to continue with notification to the patient's physician or patient?
DR. MIED: Yes, it is necessary to continue with the notification to the patient's physician or the patient. Now, you may have found out that the recipient was HIV or HCV positive prior to the transfusion, but the transfusion service or the physician of record may not be aware that the recipient was HIV or HCV positive prior to the transfusion because HIV or HCV testing of the recipient prior to a transfusion is not required. In this case, also, it would be left to the judgment and medical discretion of the physician of record whether to carry out the notification of the transfusion recipient.
THE MODERATOR: Thank you.
Question 4: There continues to be confusion at blood centers concerning what creates an incentive to donate and would result in the requirement to label the blood product as coming from a Paid Donor. We hear of programs to provide scholarships, gasoline, assistance with income taxes, etc. Please explain FDA’s current position regarding these issues.
The document we are aware of that can be used as a resource is Compliance Policy Guide, Guidance for FDA Staff and Industry – Sec. 230.150 Blood Donor Classification Statement, Paid or Volunteer Donor. We are interested to know if FDA has plans to issue a guidance document as this process would allow for public comment.
Does Health Canada have specific guidelines?
MS. O'CALLAGHAN: Incentives provided to volunteer donors are acceptable if they are not readily convertible to cash, nontransferable and there is no market for the product. The compliance policy guide that was referenced, originally issued in May of 2002 and updated in November of 2005, contains considerations for several specific incentives including scholarship programs, gift cards and event tickets. In addition, the compliance policy guide includes factors to consider that can be used to assess any possible incentive, and there are currently no plans to issue any further guidance on this issue.
THE MODERATOR: Peter, what does Health Canada do?
DR. GANZ: Canada has a one hundred percent voluntary blood donor system and we do not have specific regulations or guidance dealing with an allowance for provision of incentives for blood donation. CBS and Hema-Quebec, as licensed blood system operators in Canada, have not proposed to us invoking any kind of incentive system for blood donation.
THE MODERATOR: Do you even do T-shirts and coffee mugs?
DR. GANZ: Yes, in fact, when we hosted World Blood Donor Day a year or so ago in Ottawa, I think it was 2007, we did have an interesting T-shirt that was provided by both CBS and Hema-Quebec. It had one long sleeve and one short sleeve, which I thought was incredibly ingenious. Yes, there are coffee mugs and we do have programs at CBS and Hema-Quebec to honor long-term donors.
THE MODERATOR: Thank you. We do have other questions about donor incentives.
Question 5: In our ‘area’ juvenile delinquents can donate blood rather than perform community service. Would we need FDA approval to implement such a program?
MS. O'CALLAGHAN: Provided there were other options for this juvenile delinquent in performing community service, the person would be considered eligible to donate provided all routine donor eligibility requirements were met. FDA approval is not required to implement this kind of program.
THE MODERATOR: Sharon, that was based on the potential donor having an option of what to do and choosing to donate blood?
MS. O'CALLAGHAN: Yes, if that was the only option then we would not consider it to be acceptable. However, if there are other options provided to the juvenile delinquent, such as picking up trash on the highway, and they choose to donate blood, then it is up to the blood establishment to decide and make their determination whether they want to go ahead and accept this donor. We know that there are some issues around that of whether or not the donor is going to be reliable at that point but that is your decision to make, and as long as all the donor eligibility criteria are met, it is a perfectly acceptable donor.
Question 6: A local blood bank is giving out $40.00 gas cards to donors. Would we need FDA approval to implement this?
Is there a limit to the dollar amount and how can a pay-at-the-pump gas card be labeled with the donor name so that it is non-transferable?
MS. O'CALLAGHAN: FDA's approval is not required for donor incentives. A gift card is not necessarily considered a monetary payment but could be considered a monetary payment if it is readily convertible to cash - which, in some states in the United States, forty dollar gas card could be worth a whole lot more. However, if the incentives are nontransferable, nonredeemable for cash and bear the donor's name, such incentives would not be considered readily convertible to cash and the blood collected could be labeled with the volunteer donor label. There is no limit to the dollar amount of the gift card or gift certificate. A gift card offered without any limitation on transferability or redeemability would be transferable and possibly redeemable and therefore could be convertible to cash. If such a gift card is readily convertible to cash, meaning it could be easily and quickly sold, it may constitute monetary payment and blood donors receiving such a benefit would be considered paid donors. It is up to the blood establishment to determine how a gift card can be labeled with the donor's name. FDA does not have any policy on how to label gift cards.
THE MODERATOR: Sharon said earlier that there is not a plan to draft a guidance document but in conversation with her, I do know that this is a subject that comes to the Blood Safety Team with some degree of regularity; so there is conversation within the agency and people are calling and asking before setting up programs.
Question 7: 21CFR640.24(a) – Platelets must not be pooled during processing unless the platelets are pooled as specified in the directions for use for the blood collecting, processing, and storage system approved for such use by the Director, Center for Biologics Evaluation and Research.
Some CSOs are still recommending that firms submit for a variance during validation. Please clarify the current FDA requirements.
MS. CIARALDI: We acknowledge that there is some confusion about the submission requirements for the pre-storage pooling of whole blood platelets, but we corrected this in the direct final rule that became effective February 8, 2008 and this direct final rule is in the current CFR dated April 2008. The question correctly restates the current regulation. If a bag is used that has been cleared to store pooled platelets, then a variance is no longer needed because at this time you are following the manufacturer's package insert. Part of the confusion, on our part, is that our regulatory pathway - or review document - was developed before the rule became finalized and included the need for a request for a variance. My fellow CSOs and I reference our reviewed documents when we get requests or inquiries or we do the reviews. In this case, we may have referenced an older version of the regulatory path for reviewing pooled platelets. It is our responsibility to update our review documents and it is our responsibility to make sure that all of our CSOs are current with the updated documents, and we will make sure that this is done.
THE MODERATOR: Thank you, Judy.
Question 8: According to AABB standards for platelets 90% of the time the pH must be > 6.2. FDA requirements imply that 100% of the units must have a pH of >6.2. How can 100% be achieved?
DR. VOSTAL: Currently, there are two pH standards for platelet products. For whole-blood-derived platelets, the standard is listed in the regulations and states that all products must have a pH greater than 6.2. For apheresis products, the pH standard is listed in the platelet apheresis guidance and states that there should be ninety-five percent confidence that ninety-five percent of the products have a pH greater than 6.2. When the AABB and the FDA have different standards, the AABB standards defer to the FDA standards if these are more stringent. Now, we recognize the difficulties associated with meeting the one hundred percent requirement and will, in the future, consider adding statistical parameters around the whole-blood-derived platelet standard.
THE MODERATOR: In the meantime, if questions arise during inspections, what is the expectation for corrective action when the CFR requirement is not met?
DR. VOSTAL: We think that the pH of 6.2 is a pretty low standard, so we expect that it would be met at this time.
THE MODERATOR: Thank you, Jaro.
Question 9: We issue blood products to our surgical department in a validated cooler. The coolers are sometimes in the surgical suite for 6-8 hours.
Is it necessary to have someone open the cooler and record the thermometer display during this period of time?
Can we use temperature indicators that change color if temperature exceeds 6 C?
MS. CIARALDI: Storage containers, even those that are used for shipping and for temporary storage, must be qualified for their use. Usually this qualification includes determining the time frame at which the storage container can maintain the appropriate temperature. If the validation or qualification shows that the appropriate temperatures can be maintained for eight hours, then there is probably not a need to open the container periodically and take the temperatures. In fact, opening the container may affect the environment and the qualification. Regarding the use of indicators, the utility of this tool should be determined during the qualification process. If your qualification has shown that it is an effective tool in identifying proper storage, then certainly it can be used. One last statement, the use of a validated process does not exempt anybody from the required written procedures and required documentation, meaning that we have heard at FDA that because they are using a validated process they do not need an SOP for how they store the blood temporarily and they do not need to document that when it comes back out of that temporary storage or from the operating room, in this case, that it has its appropriate temperature.
THE MODERATOR: Judy, thank you for that clarification.
Question 10: When red cells are issued/transported to the OR in a validated cooler and then returned to the blood bank, at what temperature range should the products have been maintained in order to be suitable for reissue? It appears in 21 CFR 640.2(c) that blood can be kept at both 1 – 6 C and 1 – 10 C depending on how one defines the storage or transport mode. How should storage versus transport be defined? Will there be a forum to discuss the practical aspects of maintaining red cells at 6 C versus 10 C? Why are there two different standards for red cells?
MS. CIARALDI: Let's start with FDA's definition of storage and transport, and let's use red blood cells because that is the example in the question. Red blood cells are required to be stored at one to six degrees. This is in the regulation 640.11(a). We consider storage to be when blood is in inventory or at rest waiting to be transfused or waiting to be packed and shipped to another location. Once the blood is in movement or being moved from the storage situation to another site, then it meets the definition of transport. During shipment, red blood cells must be placed in an environment that maintains the temperature between one and ten degrees. This requirement is found in the CFR 600.15(a). Concerning evaluating blood that is returned back to the blood bank, in this case, the blood is going from a temporary storage environment to another storage environment within the blood bank. To be considered acceptable for reissue, the blood must have been stored continuously between one and six degrees. That is in the regulation cited in the question. It is against the one to six degree temperature range that the product has to be evaluated to be considered acceptable for reissue. If, however, the OR or the transfusion site is located offsite, like in a separate facility, and the blood has to be shipped out there and shipped back to the blood bank using your standard qualified shipping procedure, the red cells then must be evaluated according to their shipping temperature, which is one to ten degrees, therefore the blood must have been maintained no warmer than ten degrees in order to be considered acceptable for reissue.
THE MODERATOR: Judy, I think maybe the emphasis in this question, because we just heard again what the questioner posed, is that blood can come back to the transfusion service within the same hour from two different locations. One unit is acceptable at ten degrees, the other one is not. I think maybe the emphasis of the question is whether there is a forum to discuss these practical aspects of these different standards and maybe I would add to that, is there may be a plan to draft some change to the current regulations to address that?
MS. CIARALDI: Right now, there is no forum being developed to discuss the difference between storage and transport and the temperatures. The question asked, why are there two standards, why is it different? There is literature available; many, many in Transfusion, in fact, about the impact of temperature on storage lesions and in the interest of time, I would recommend that those articles be reviewed to see their content and their message on this. However, in a general sense, blood that is maintained at one to six degrees, red blood cells, shows that the storage lesions are at a much lower number. We understand that. We know that there is the confusion but right now there is not a forum set, but we are aware of the issue and are trying to make consistent definitions for transport and for storage, meaning temporary storage. I think the confusion exists because devices normally used to transport blood are now being used for the storage activity.
When the blood was stored in an OR refrigerator, things were very clear. The purpose of the validated igloos in the OR is to replace the blood bank refrigerators that were used in the OR. The igloos are performing the same activity as the OR refrigerators: They are holding (storing) blood until the OR patient needs it. Therefore the igloos must store the blood at the same temperatures as the BB refrigerators and blood returned to the blood bank should be judged in the same manner as if it was returned from the BB refrigerator in the OR.
DR. EPSTEIN: If this is becoming a significant practical issue to the blood community, we will certainly find a forum to address it. Whether we need a workshop or an advisory committee or if you convene a meeting we can come as a liaison, however we need to approach it. We are happy to do that if this has become a problem.
THE MODERATOR: Thank you, Judy and Jay, for that offer.
Question 11: When validating pneumatic tube systems for transport of red blood cell components to various parts of a hospital, is there a requirement to check for hemolysis in the transported component? In a previous validation we only checked for transport time and temperature of the transported component.
DR. VOSTAL: This is a very interesting question. So far, the FDA does not have specific instructions on how to validate pneumatic systems for delivery of blood products. However, if you plan to use such a delivery system, we recommend that you do validate it because there could be significant thermal and mechanical stresses encountered during delivery. Hemolysis could be used as one of the parameters in the validation and should be measured before and after transport to isolate the effects of the transport itself.
THE MODERATOR: So it sounds like it might be a useful thing to do?
DR. VOSTAL: Yes.
THE MODERATOR: Thank you.
Question 12: Which of the following is the acceptable pass rate for red cell recovery when performing leukoreduction quality control testing?
· 95% confidence that 95% of products tested meet the requirements that at least 85% of the red blood cells are recovered post leukoreduction
· 95% of products tested meet the requirements that at least 85% of the red blood cells are recovered post leukoreduction
· 100% of products tested meet the requirements that at least 85% of the red blood cells are recovered post leukoreduction
DR. VOSTAL: The 1996 leukoreduction guidance provides the eighty-five percent recovery standard without any statistical parameters. However, our current considerations, which are to be included in the draft leukoreduction guidance, are to have the ninety-five percent confidence that ninety-five percent of the products meet the requirements of at least eighty-five percent recovery.
THE MODERATOR: Thank you.
Question 13: Bacterial culturing systems such as BacT/Alert require that the Platelet Pheresis components first be leukoreduced. When a Platelet Pheresis component does not pass QC (residual leukocyte count) it is generally released as non-leukoreduced.
Can this product be considered leukoreduced for the purposes of the BacT/Alert package insert?
DR. VOSTAL: The short answer to this is no. The reason is that the residual leukocytes left in the product could actually have an effect on the sensitivity of the bacterial detection device.
THE MODERATOR: I did look at the package insert for the BacT/Alert and there is no recommendation of the actual leukoreduction level but there is the caution that failure to achieve adequate leukocyte reduction may result in false positive readings.
Question 14: If tissue is sent from one campus to another within the same hospital system but in different geographical locations is there a need to register with the FDA as a manufacturer/distributor?
While one campus is directly across the street, others are 10 miles away. Does it depend on the volume or incidence of tissue sent back and forth, i.e. occasionally or routinely? Does it matter if the hospitals have the same tax ID or not?
DR. LAZARUS: Okay. This is a question that is of fairly general interest to individuals who work in hospital tissue services, so I am glad this got asked. The answer is yes, an establishment that is shipping or sending tissue from one campus to another, even within the same hospital system, does have to register as a distributor. The different geographic locations are kind of a practical matter. The way this is understood, if the campus is directly across the street or the other building is directly across the street, that is generally considered the same geographic location but as this question is worded, the other campuses, that are miles away, would generally be considered different geographic locations. Therefore if the tissue is being sent from one such building to another building in another campus, some distance away, that is considered distribution even if the two establishments are within the same hospital system. I hope that is clear. This answer does not change even if the tissue is sent only occasionally. If this happens, even occasionally, then the establishment should register as a distributor. Same answer if the hospital has the same tax ID or zip code or whatever.
THE MODERATOR: Thank you, Ellen.
Question 15: If tissue has an expiration date with just a month and year, for example October 2008, would it expire October 1 or October 31 at midnight?
DR. LAZARUS: I think that you would want to ask the tissue bank what they meant by that expiration date, for one thing. It has to be understandable to you, the end user, and, of course, it has to be understandable to them for purposes of their inventory management. This gives me an opportunity to comment on expiration dating for tissue. I can remind you that in the HCT/P regulations 1271.260(c), the storage regulation, there is a statement that where appropriate, you must assign an expiration date to each HCT/P based on several factors and one of the issues is “where appropriate.” This refers to where such expiration dating is relevant for the purpose of preventing the spread of communicable disease or contamination with an infectious agent. Therefore, for purposes of the regulation, the expiration date should be meaningful for that purpose and I really cannot say. Generally, we would think it would be the end of the month, October 31, as opposed to October 1 but I would, again, recommend that you seek clarification on that point.
THE MODERATOR: Thank you.
Question 16: What is the forecast delivery date for the guidance document on the Cells, Tissues and Organs (CTOs) Regulations that became effective in December 2007? At a recent Stakeholder Consultation concerning Tissue & Organ Donation & Transplantation convened by Canadian Blood Services, there were indications that the Regulations are not well understood and that compliance is suffering as a result.
DR. AGBANYO: As some of you may be aware, we released a new set of CTOs, regulations for cells, tissues and organs, in June 2007, with an effective date of December 2007. At the same time, in June 2007, we did release a guidance document to help explain the regulatory requirements. Now, that guidance document was released for public consultation and we received several very useful comments, which we gave a great deal of consideration, and we are currently in the process of finalizing that guidance document to incorporate some of the comments that we have received. Hopefully, when that is done, the guidance will be clearer than the draft guidance that was issued and hopefully will help with compliance with the regulatory requirements.
THE MODERATOR: Thank you, Dr. Agbanyo.
Question 17: Could Health Canada clarify what they expect in terms of a physical examination by the attending physician/obstetrician at the time of collection of a cord blood sample for family banking and how they will enforce physician/obstetrician compliance?
DR. AGBANYO: As Peter had mentioned earlier, our CTO regulations do reference certain requirements in the Canadian Standards Association's safety requirements for cells, tissues and organs. These standards also have subsets for specific tissues, which include lymphohematopoietic cells. And in the lymphohematopoietic cell standard, specifically the section that was referenced in the Health Canada regulations, there is a requirement to conduct a physical examination of the donor. In the case of cord blood, Health Canada will accept a surrogate physical examination, meaning that the physical examination could be performed on the mother rather than the baby. The other thing that we have outlined in our guidance document is that in cases where there is already a physical examination done, there is no need to repeat it and that the physical
examination done on the mother, perhaps during pregnancy, could be reviewed and documented. With respect to compliance of physicians and obstetricians, that becomes a very difficult area for Health Canada to regulate, because we do not have a mandate to force a physician to participate in the cord blood donation process. Essentially, the onus is on the establishments that engage in the collection and storage of cord blood to put arrangements in place with a physician to assist with compliance. So you do need to really talk to the physicians involved and try to encourage them to provide the information that is required.
THE MODERATOR: Ellen, could you please speak to U.S. regulations?
DR. LAZARUS: This is an opportunity for me to point out some similarities between the Health Canada rules and recommendations, and the HCT/P donor eligibility rules and recommendations on this point. Specifically, the donor eligibility guidance that was published last year addresses screening donors less than or equal to one month of age where we say that the birth mother should be screened and a physical examination should be performed on the birth mother when practical. The general eligibility guidance also talks about, for living donors, how you, the establishment making the donor eligibility determination or obtaining the information necessary to make the determination, may examine only those parts of the body necessary to evaluate for relevant communicable diseases based on relevant donor history and you may rely on records of a recent report of a physical evaluation by other health care professionals. In that regard, our recommendations are quite similar.
THE MODERATOR: Thank you.
Question 18: Could Health Canada explain their rationale for requiring that maternal specimens for infectious disease testing for cord blood banking be drawn at the time of, or within 7 days following, collection of cord blood? This is a recent change for HC and is inconsistent with FDA regulations and other standards which allow specimens to be drawn within 7 days, before or after cord blood collection.
DR. AGBANYO: Health Canada recognizes that this requirement is different from that of the FDA and other standards. However, this was a requirement that was decided upon by the Canadian Standards Association Technical Committee that developed the lymphohematopoietic cell standards. One of the requirements that we generally put in place for products that can be stored for long periods of time is that you quarantine the products for a minimum period of six months and then retest the donor. In the case of cord blood, that particular requirement was waived so there is no requirement for that six-month quarantine. Therefore the idea was to try and narrow the window period as much as possible hence, the reason why the requirement was made on the day of donation or seven days post-donation. The only recommendation I can make is that the CSA process does involve consultation and they also encourage stakeholders to send them comments regarding the CSA standards. If there are any issues in the CSA standards that you would like to raise with them, it would be a very good idea to contact the Canadian Standards Association and direct your comments to them. We, at Health Canada, can also raise this as a comment that we have received from stakeholders, but it would be helpful if stakeholders themselves also send comments in to the CSA.
THE MODERATOR: Yes, Peter?
DR. GANZ: Just to add that this is a very good comment and Health Canada will be proposing that CSA make the change.
THE MODERATOR: Thank you.
Question 19: Public cord blood banks perform an initial HLA type on all cord blood samples to determine if the sample is of an HLA type they require in their bank or to register the HLA type into a searchable database so the sample can be made available to other banks. Could Health Canada explain the rationale for requiring that cord bloods collected for family banking must also have an initial HLA type performed?
DR. AGBANYO: The term family banking can, in fact, refer to two things with respect to cord blood donation. Health Canada does not regulate cord blood that is donated for autologous use. However, we do regulate cord blood that is intended for allogeneic use within the family. We do make a distinction between allogeneic use within the family or allogeneic use in general. In terms of the requirement for HLA typing, basically, the standards state that the HLA typing has to be done. I noticed the question focused primarily on the initial testing, because that is what is required to be entered into the database. However, our standards do not necessarily state when that HLA typing should be done. It just basically says that it needs to be done prior to using the product. I hope that does address the problem that the HLA testing needs to be done but not necessarily within a particular time frame, as long as it is before the product is used.
THE MODERATOR: And that would be if it is going to be used in an allogeneic situation?
DR. AGBANYO: Yes, if it is going to be used in an allogeneic situation. As I mentioned, we do not regulate autologous donations.
THE MODERATOR: Yes, Ellen, please?
DR. LAZARUS: Okay, so I can just comment for U.S. cord blood establishments’ purposes. As you know, our regulatory framework is slightly different in that the autologous and first and second degree related donor cord bloods are regulated as 361 HCT/Ps and there is a session tomorrow morning on that if you have questions about what that means. For 361 HCT/Ps, our regulations refer to prevention of spread of communicable disease so HLA typing is not in the regulations for 361 products.
THE MODERATOR: Thank you, Ellen.
Question 20: At the recent Somatic Cell Therapy symposium numerous FDA representatives very strongly encouraged attendance from the cell therapy community at the 17 November workshop on Structured Product Labeling. Please explain the relevance of SPL as many of us are very unfamiliar with it.
MS. CIARALDI: I am not taking Ellen's place in tissues, so I am here to try to share some information about structure product labeling and I will say I had to call a lifeline on this one back home. The initials SPL are the abbreviation for a structure product labeling and it is a relatively new initiative within CBER. CDER, the center for drugs, is also using it as well. It is a standard that is used for the exchange of drug establishment registration and drug listing information. It also makes possible the exchange of content of labeling and other product information. It will enable users to readily search and sort information about the product and again, it is rolling out for both pharmaceutical drugs as well as some biologic drugs. This is important as the health care community moves toward a fully automated health information system. FDA is running a pilot program right now to begin receiving drug information and drug establishment information. This pilot is expected to be completed in January 2009. In July 2008, we published a draft guidance document about SPL. It states that the SPL format applies to content of labeling, which is another name for saying a package insert, and it says that drug establishments that are registered under 207 -- 21 CFR 207 requirements, are the ones that would fit into this guidance, and right now that applies to the plasma derivative manufacturers. It also goes on to say that it does not apply to blood, tissue or device manufacturers who register under 607, 1271 and 807, respectively. We do still continue to encourage interested parties to attend the November 17th workshop. If you would like more information and believe me, there is a lot more information out there than what I am providing you, I would be happy to give you some contacts. The names of the people are Commander Vada Perkins and Lonnie Smith. For those that are interested, I will hold onto this and I will give you the phone numbers and the e-mail contacts for them.
THE MODERATOR: Ellen, please?
DR. LAZARUS: Thank you, Judy, so much. I can comment to put this in the context of what was conveyed at the somatic cell therapy meeting. At that meeting, the November 17 training session, it was discussed, and I believe it was recommended, that an ISCT representative attend the training but I just wanted to point out that this project would only be relevant for cell therapy manufacturers who were taking their products to licensure. Therefore, those of you who are in that position should pay close attention to this initiative.
THE MODERATOR: Thank you, Ellen and Judy. I think that was very helpful.
Question 21: With the implementation of ISBT what is the requirement for blood products labeled for transfusion that are shipped upon expiration to an entity for further manufacture? Do these units require re-labeling with a new ISBT product code or can the original label remain intact with a sticker applied to the container stating "for further manufacture, non-injectable use only"?
MS. CIARALDI: The expired unit must be relabeled with the new ISBT product code and the label must include the manufacturing caution statement that is referenced in the question. The U.S. Industry Consensus Standard for Uniform Labeling of Blood and Blood Components, using ISBT 128 - , this is version 2.0 dated November 2005 - helps us with this question. On page 54 -- I know you cannot see it but on page 54, there is an example of a label that is to be used for further manufacturing and on page 70 of the same consensus standard, it talked about the caution statement for further manufacturing use and it says that it is an attribute, and as you know with ISBT, attributes are a part of the product code. Therefore if you are relabeling a product for further manufacturing use, you would have to relabel it with the ISBT appropriate codes.
THE MODERATOR: Thank you, Judy.
Question 22: Do you have any idea when 21CFR Part 11 will be ready for publication? The draft version has been out for quite some time now.
MS. O'CALLAGHAN: In August 2003 FDA issued a guidance document which stated that we would exercise enforcement discretion in certain areas while we rewrite this regulation. The rule making changes are currently in progress, but I do not have a date of when they are going to be finished. The bottom line, though, with electronic records, is that you are to maintain electronic records in accordance with the underlying predicate rules. For example, with blood establishments it is 21 CFR 606.160, so you follow the predicate rules for all your records, including the electronic records.
THE MODERATOR: Thank you, Sharon.
Question 23: There are rumors that Health Canada is considering changing its policy of regulation of Computerized Blood Systems to mirror that of the U.S. FDA for Blood Establishment Computer Software (BECS) that is to require software developers to obtain Medical Devices Approval to sell their product in Canada. Is there truth to these rumors? If so, why does Health Canada consider the change to be necessary? What is the expected timing of the change?
DR. GANZ: We have heard this rumor as well. No, we are not considering changing our policy to regulate computerized blood systems to mirror those of the U.S. That is not to say that we do not regularly look at our policies and make some decisions about whether or not they need to be updated or not. We are looking at our policy and, in fact, we did have for many years, a guidance document that spells out regulatory requirements for blood establishment IT submissions which we are currently revising. That guidance document has been shared with our establishment license holders for comment and that process is ongoing. In the interpretation of this question, however, I wanted to remark that computerized blood systems is a catchall phrase, really, and that in Canada we do have quite a large variance in how we interpret that. The examples that I can provide for you are that for test kits for screening donors, for example, those are regarded are Class IV medical devices and are required to have a medical device license. There are other kinds of software or Information Management systems that are specific to blood establishments and in some cases, those are reviewed as part of a blood establishment amendment or a blood licensing amendment. I would encourage those in the audience who are interested in this area to come and speak with us so we can provide additional clarification if it is needed. And thanks for the question. It is a good one.
THE MODERATOR: Thank you.
Question 24: What do you see as regulatory obstacles to the use of Pathogen Inactivation processes in the US and Canada especially given the fact that some of these products are used in Europe?
DR. VOSTAL: Well, we do not really think of them as obstacles but there are regulatory requirements. For pathogen reduction processes, like any other improvement or change to the collection or storage system for blood products, they will need to meet regulatory requirements for devices and blood products. This includes a demonstration of the safety and efficacy of the pathogen reduced products. Now, the FDA is in communication with the manufacturers of the pathogen reduction processes to agree on the best approach to demonstrate safety and efficacy.
THE MODERATOR: Thank you, Jaro.
DR. GANZ: Certainly, public demand, I think, really drives the regulatory oversight in Canada and there are clearly very, very high standards that the public expects for the safety of systems in the blood area including pathogen inactivation kinds of technologies. Therefore, I think the standards that we have for demonstrating safety, efficacy and quality of these kinds of technologies is set high. However, certainly our expectation at Health Canada is that industry needs to come to Health Canada with a submission or have a dialogue with us in order for us to, in a prescriptive way, define what our requirements would be for clinical trials and the degree of data that we would need before approving these kinds of technologies.
THE MODERATOR: Thank you. So both agencies are ready to talk to manufacturers and discuss the processes if a manufacturer wants to do that, right?
DR. EPSTEIN: We are in ongoing dialogue with candidate manufacturers.
THE MODERATOR: Thank you, Jay.
Question 25: Regarding a medical device for platelet quality (functional integrity) testing:
What classification would a medical device have that is technically similar to a platelet lumi-aggregometer and analytically similar to a flow cytometer?
If there was a single-step test for platelet quality – following pathogen inactivation – what would be the requirements this technology would have to fulfill prior to approval?
Under what conditions would such a test be recommended or mandated by the FDA or Health Canada?
Dr. VOSTAL: So to answer the first part, the FDA classifies devices on the basis of the intended use and whether there is a predicate device already on the market. If there is a predicate device, then we need to determine if there are any technical differences between the two devices that would raise any new issues of safety and efficacy. If there are no issues then this device can be cleared by the 510(k) process. If there is a different intended use or there are new issues of safety and efficacy, then it would be approved through the premarket agreement or the PMA. Now for the second part, it is difficult to answer this question without really having more detail in terms of what the test is and what the device would be that would run the test. The regulatory pathway, and the requirements associated with this test, would depend on the intended use and the existence of a predicate device. Finally, to answer the last section, it is unlikely that a unique test would be required because we assume that the pathogen reduced products would meet the quality control requirements for current platelet products.
DR. GANZ: I think we have some harmonization in addressing this. Hypothetical questions for hypothetical devices, I think, are always difficult to try and answer but certainly we would require, at Health Canada, that data be provided that would support the claims of this particular quality test, or device, certainly, and that this would require premarket review to ensure that, in fact, there is data to support whatever stated claims that there would be.
Dr. VOSTAL: If I could just add a few comments here which is that there is a distinction to be made between the validation that a manufacturer must provide to be approved for the device to make a biologic end product versus the quality assurance testing that would need to be done in a blood establishment. They are not the same thing, and I think that we cannot delink the question of what the pathogen reduction technology does to the product from what testing might need to be done by the blood establishment. There is no way to define that without first knowing what the impact of that process is on the product. So I think the general answer here, which has been already stated, is that we cannot really answer that abstractly.
THE MODERATOR: Thank you for your consideration of the question.
Question 26: Hematology Analyzers – 42CFR493.1255 "Calibration and calibration verification procedures are required to substantiate the continued accuracy of the test system throughout the laboratory's reportable range of test results for the test system".
(b)(3) At least once every 6 months and whenever any of the following occur...
My understanding is that there is an exception to this requirement for automated cell counters – from the interpretive guidelines D5439 – “For automated cell counters, the calibration verification requirements are considered met if the laboratory follows the manufacturer instructions for instrument operation and tests 2 levels of control materials each day of testing provided the control results meet the laboratory’s criteria for acceptability.”
Whole blood controls do not span the linearity limits or reportable range of the instrument. Hemoglobin (Hgb) is not measured as a particle so in my interpretation, Hgb would not fall under this exception clause, and therefore WOULD require cal verification every 6 months. Also, manufacturer's hematology calibrators do not span a low-mid-high range across linearity limits (unlike chemistry analyzers), but rather focus on calibration target values for CBC parameters.
In summary, do hematology analyzers require cal verification every 6 months? Does only the hemoglobin portion require it? Would this be regarded as good lab practice (even though it may not be mandated) for hematology analyzers?
MS. MEYERS: Well, I will try to make the answer a little shorter than the question. The information in the interpretive guidelines applies to the hematology instrument as a whole. In other words, if the manufacturer's instructions are followed, two levels of quality control are tested each day, and the results are acceptable, then the requirement for calibration verification is considered to be met. The calibration verification for hemoglobin is not handled separately. However, each laboratory must also develop the protocol for calibration and calibration verification based on the performance specifications determined at the time the instrument was installed as well as ongoing quality control results. The lab may find it necessary to perform calibration and calibration verification more frequently or use additional calibrators, and the reference for this is 42 CFR 493.1253(b)(3). Finally, I will remind you that laboratories that obtain their CLIA certification by virtue of accreditation by a CMS approved accreditation organization are required to follow the standards of that organization, which may be more stringent than the CLIA requirements. I will also point out that the reference here to the interpretive guidelines D5439 is from the CLIA interpretive guidelines that can be found on the CLIA website.
THE MODERATOR: Thank you, Penny. I hope that is helpful to the person who supplied the question. If not, Penny Meyers could probably give you further help.
Question 27: Occasionally after submitting a BPD, there is a request for additional documentation. What type of BPD event or circumstance prompts the request for additional information?
MS. O'CALLAGHAN: We ask for additional information on reports that are not complete. For example, if the product information is not included in the report; we will ask for that information. Occasionally, we will need some clarification on the event in trying to figure out what the heck you are trying to report. Sometimes we get a big dissertation that we failed to quarantine the unit and go into all this detail about why you did not quarantine the unit and nowhere in the report does it say why the unit needed to quarantined to begin with, or same thing with the donor being deferred. You go through all this explanation about why you did not defer the donor but never say why the donor needed to be deferred to begin with. So that is the kind of information for which we would typically ask for additional information. In evaluating the BPD reports, we also determine if there is a potential recall situation, so we may need some additional information to make that cut.
THE MODERATOR: Thank you, Sharon.
Question 28: There has certainly been a lot of angst on US college campuses recently in regards to the MSM deferral policy. Does FDA have anything new on the table as far as moving from an indefinite deferral to something else?
What is Health Canada’s position on deferral for MSM?
DR. MIED: The MSM policy that is being referred to here is that men who have had sex with another man, at any time since 1977, which is the beginning of the U.S. AIDS epidemic, are currently not eligible to donate blood. Now, our primary concern, which is the reason for currently maintaining this deferral policy, is to keep blood safe by preventing the increase and the risk of transmission of HIV, and potentially other infectious organisms, through blood transfusion that is predicted to occur were this policy to be changed at the present time. Now, the question is would a change that we might consider, from an indefinite deferral, result in an increased risk of certain blood transmissible infectious agents to transfusion recipients? I want to emphasize that while FDA very much appreciates and values the desire and the willingness of individuals to donate, we would consider changes to this policy, as we would for any other blood safety policy, only if it is supported by strong scientific data showing that such changes would not present a safety risk. I should point out that this policy is not unique to MSM or to HIV prevention efforts. FDA has multiple similar deferral policies based solely on risk factors for infectious disease transmissions that affect donation by other groups as well. FDA continues to recommend the extra safeguard of risk-based donor deferrals. Deferral of persons at increased risk of transfusion transmissible infections lowers the potential for collection and mistaken use of a contaminated unit. In summary, we remain open to a scientific dialogue on this issue, and we are hopeful that the additional studies I have referred to will help us resolve these issues.
DR. GANZ: I would like to echo a couple of points. Within the Canadian context, certainly we want to make the point that we are deferring on the basis of risk behavior and not sexual orientation. As in the U.S. and many countries, our desire here really is focused on the safety of the recipient, in terms of this particular policy, which operationally, in Health Canada, amounts to an indefinite deferral for the MSM group. Similar to the U.S. position, and in other countries, Health Canada is very, very open to consider a scientific dialogue on the issue and that certainly we are welcoming of industry coming to Health Canada with either additional data or studies that would allow us to reconsider this particular policy.
THE MODERATOR: Thank you. Paul, I think the next two questions are both yours. They are about reentry. I am going to read them both and then perhaps you can give the response.
Question 29: What is the status of the guidance document for re-entry of donors previously deferred for 2 repeat reactives on the anti-HB Core test? I recognize it was issued as a draft status. Will it be finalized for implementation soon... or can we request a variance for re-entry using the algorithms presented in the document?
Question 30: We test our donors using a multiplex HIV NAT, HCV NAT, HBV NAT test. We've had 4 donors, including 2 long-time donors, who have tested positive with the multiplex test, but all discriminatory testing was negative.
I understand there is a draft guidance for HIV NAT and HCV NAT, but there is no guidance for HBV NAT.
Is it likely FDA would approve variances for these individual donors, what type of testing would you require, and would you consider a variance for a process as compared to individual donor variances?
DR. MIED: The FDA draft guidance for industry on reentry for anti-core was published as a draft, for comment purposes only, on May 20, 2008. The ninety-day comment period closed on August 19, 2008. However, we still welcome comments to the docket on this draft guidance. We have received several comments on this guidance and we are considering them. We want to emphasize that we recognize the importance of this guidance and we expect to finalize it. Issuing this guidance as final guidance is a high priority for FDA. This is evidenced by our update that Dr. Robin Biswas gave at the recent BPAC meeting, on September 11th, where he reviewed the FDA recommendations that are in the guidance and then summarized some of the comments that we have received. Regarding the question of whether you can request a variance for reentry using the algorithms presented in the document, 21 CFR 641(b) states “a deferred donor subsequently may be found to be suitable as a donor of blood or blood components by a requalification method or process found acceptable for such purposes by FDA.” The mechanism would not be to request a variance from a regulation, since there is no regulation involved here, but pending the issuance of the final guidance for reentry of donors by this algorithm, blood establishments can submit SOPs and test results to reenter individual donors on a case by case basis.
With regard to the second question about multiplex NAT, I would say that the issues you have raised here regarding deferral and reentry of donors who are reactive on a multiplex NAT, including a NAT for HBV and especially including the situation in which donors are reactive but they are negative on all the discriminatory tests, these are new issues for FDA and we recognize the importance of getting these issues addressed and we are right now in the process of developing policies in this area, but I must say that we are not really quite there yet.
THE MODERATOR: Thank you, Paul.
Question 31: Will Health Canada entertain the idea/process of reentering donors who have had "false positive" test results?
DR. GANZ: This is a very good question because we get many, many requests through the mail and electronic requests to Health Canada from donors who, in fact, have been deferred for false positive test results. This is a subject very dear to our heart at Health Canada. We have asked, informally, all blood establishments to approach us regarding their proposals for the development of donor reentry algorithms. In essence, we are very, very interested in receiving those kinds of proposals and have agreed to give them expedited and priority review.
THE MODERATOR: Thank you, Peter.
Question 32: When thawing FFP or Plasma Frozen within 24 hrs at what point can this product be labeled as Thawed Plasma? Is it considered misbranding if the thawed FFP or Plasma Frozen within 24 hrs is labeled as Thawed Plasma immediately after thawing? Does one have to wait 24 hrs after thawing to re-label the product as Thawed Plasma?
MS. CIARALDI: I am trying to look at my notes to get a shorter answer because of the time, but a lot of you already know that in order to store fresh-frozen plasma, thawed fresh-frozen plasma and thawed FP24 past the six hours before administration, you would need to have a variance approval for that. The requests that we have seen are extending that six-hour post-thaw expiration date up to twenty-four hours before administration. We are aware that some centers immediately relabel the thawed FFP or FP24 as Thawed Plasma or they wait until their six, or with an approval twenty-four, hour expiration date has passed and then they relabel it as Thawed Plasma. We also know that Thawed Plasma is mentioned in the Circular of Information. That said, the product, Thawed Plasma, has not been submitted to FDA for our review to evaluate its safety or efficacy, therefore we have not established any policies for this product. It is currently not recognized by FDA and is not a licensed product. If you elect to make this product, you must remove any license numbers from the label.
THE MODERATOR: Based on what you said, Judy, if a facility decides to immediately label it as Thawed Plasma, it is a non-licensed product and they could do so.
MS. CIARALDI: That is correct. Anything past the fresh-frozen plasma that has been stored, or FP24, that has been stored past the six hours, or with an approval past the twenty-four hours, no longer meets that standard for those products the way they are labeled and if they want to be used for something else, they definitely have to be relabeled. If somebody wants to not wait any longer, that is their decision to make. We, again, do not have any policy on Thawed Plasma.
DR. EPSTEIN: Let me just point out that it is a one-way street. Once it is relabeled as thawed plasma, you cannot decide well, it has really been less than twenty-four hours, we have our variance; let's switch back. No, it is a one-way street.
THE MODERATOR: Thank you, Judy and Jay.
Question 33: Why can’t I label my concurrent apheresis plasma as Recovered Plasma and ship it to my fractionator? I do not understand the FDA point of view that this plasma is different from the Recovered plasma this donor donated 8 weeks previously.
MS. CIARALDI: All right. This answer will take just a little bit of time. We are aware of the interest to convert apheresis plasma to Recovered Plasma prior to its outdating. This issue has been discussed in several venues, including BPAC meetings, and we are working on a policy but it will require rule making. The reason for this is in 640.60. It states that plasma collected by apheresis and intended for further manufacture is defined as Source Plasma, not Recovered Plasma. Source Plasma is a licensed product, therefore the product in the question cannot be labeled as Recovered Plasma. It is Source Plasma and a license is required in order for interstate shipment. What I do want to make you aware of is that you do have an option available and that is to apply for a Source Plasma license. If you are already a licensed facility and included within that license is approval for apheresis fresh-frozen plasma from infrequent donors and you want to make Source Plasma from these very same donors, especially at the same donation intervals, we had determined that you would not need an inspection. This would be a Prior Approval Supplement because you would be sending in SOPs, labels and informed consent. But you are already collecting infrequent plasma by apheresis, so we believe this fit is an easy fit for facilities in that situation. Also, unlicensed registered facilities that are currently collecting apheresis fresh-frozen plasma at infrequent intervals can do the same thing provided this process has been observed at or during FDA inspections. Again, a prelicense inspection would not be needed, but you would need to submit a new BLA, biologics license application, and include SOPs, labels and informed consents. Now, there are some manufacturing issues for Source Plasma that I wanted to make you aware of. First is the requirement for a minimum weight of 110 pounds, in 640.63. Also, the plasma must be frozen immediately after collection. This is in 640.69. And the informed consent must be administered by a physician, which is in 640.61. We have approved variances for the informed consent to be administered by other trained staff, known as physician substitutes, and there is a guidance document available, a memorandum, that will describe that and we will be glad to talk you through it. So, if you are interested in going this route - making Source Plasma from infrequent donors - please consult our guidance document. It is called Revisions of the FDA Memorandum of August 27, 1982, Requirements for Infrequent Plasma Donors. The guidance document is dated 3/10/95. It is on our memo Web site http://www.fda.gov/cber/bldmem/031095.pdf. Also refer to the regulations in 640.60 - 640.76 that discuss the other unique issues about Source Plasma that you may need to address in your SOPs.
THE MODERATOR: Judy, thank you. Jay?
DR. EPSTEIN: There is just one more dimension to this which is that we understand the desire of blood establishments to be able to sell plasma obtained by apheresis at the time of a blood component collection for further fractionation use, and that issue has been discussed with the Blood Products Advisory Committee. As Judy indicated, it would violate current regulations, which is why you still currently have to hold FFP for a year until it outdates but that the agency does have under consideration possible regulatory changes that would permit practices of that nature. Therefore I would just say stay tuned.
THE MODERATOR: Thank you, Jay and Judy. Judy, you mentioned one item that I would like to comment on. The requirement to immediately freeze the plasma has proven to be an issue due to the use of apheresis equipment at so many mobile collection sites and fixed locations that do not have quick access to the manufacturing freezer.
MS. CIARALDI: Right.
THE MODERATOR: There are some exemptions in the whole blood regulations about plasma, for example, expiry dates. Is there anything that a facility can apply for in an exemption category, or a variance to a regulation, that is currently of use with apheresis plasma?
MS. CIARALDI: Are you thinking of a specific variance? We do entertain requests for variances, especially if they are supported by data and there is a valid reason to deviate from the regulations. Again, it would apply to some of - most of the regulations - but not against the regulation for a licensure. There are no variances for being exempt for requiring a license for a product that we have identified as a licensed product. There may be, depending on the variances, approvals for certain and specific manufacturing steps to be done in an alternative manner but that would have to be brought forward to us on a case by case basis and for us to evaluate it based on the content of the submission.
THE MODERATOR: Thank you, Judy. I know that there is conversation between the Office of Blood and the Plasma Task Force on these issues.
DR. EPSTEIN: The short answer is not at this time – we have to establish a policy on plasma obtained concurrent with component for transfusion collection. Once we establish a plan for modifying regulations we would recognize variances to the existing source plasma regulation, pending the regulatory change itself.
THE MODERATOR: Thank you. I believe we need to stop now. I apologize for the questions that were submitted that we did not get to ask. I want to thank our colleagues from FDA, CMS and Health Canada for researching the answers to these questions and for sitting on today’s panel. I want to especially thank you, the AABB members who provide such good questions for our program.
Questions that were submitted but were not presented due to lack of time at the Annual Meeting session.
Question 34: According to recent proposals for donor eligibility and screening, intimate contact is defined as including the exchange of saliva. The exchange of saliva has not been implicated as a route of infection for any of the relevant communicable disease agents or disease. Why has the definition of intimate contact been modified to include exchange of saliva?
Our intention in modifying the definition of intimate contact to include exchange of saliva was to attempt to capture additional viruses that may be transmitted through saliva. We know that there are blood-transmissible disease agents that can be transmitted by saliva, such as EBV and CMV, for example, and perhaps also HHV-8 and HBV, but we just aren’t sure about those at this time. But I can tell you that we are still in the process of reviewing comments to the donor eligibility rule and, of course, your comments to the Docket for that rule are still welcome.
Question 35: Proposing an upper and lower limit for blood pressure and pulse and requiring the documentation of donor unexplained weight loss (greater than 10%) appears to go against FDA’s position of making decisions based on scientific evidence. How would these added criteria improve the safety of the blood supply?
The purpose of the revised donor eligibility regulations is to protect the donor’s health and ensure a safe product for the recipient. We proposed the new donor eligibility standards in a proposed rule and asked for comments.
21 CFR 600.100(b)(1) requires SOPs to include methods and measurements for performing donor eligibility testing, including minimum and maximum values for a test or procedure when it is used to determine acceptability.
Some of the donor eligibility criteria in our proposed rule (like vital sign ranges and unexplained weight loss) are still under discussion. We are currently reviewing the comments to the proposed rule. We would also like to receive data to support alternative donor eligibility criteria.
Question 36: Does antibody identification testing performed on a patient sample fall under CLIA regulations (42 CFRs) or blood product manufacturing (21 CFRs)? If CLIA, does it fall under CLIA only if no blood product is required and no crossmatch is ordered? The testing may be a part of pre-transfusion testing that requires selection of a suitable red cell product that has been tested to show lack of the corresponding RBC antigens.
There seems to be a conflict with regard to compatibility testing, since it is mentioned in both CFR series and we are concerned about the potential need for review by a second individual if 21 CFRs have oversight. CLIA regs do not require a review unless the testing tech is unlicensed.
Antibody identification does fall under CLIA regulations (42 CFR), regardless of whether it is performed for pretransfusion testing or for other purposes.
The questioner ended with the comment that CLIA regs do not require a review unless the testing tech is unlicensed. I would like to clarify that the review does not depend on licensing, but on the CLIA requirements for high complexity testing personnel. Those individuals who qualify as testing personnel by virtue of grandfathering require an additional level of oversight by the general supervisor, which may involve on-site supervision or review within 24 hours. More detail can be found in the CLIA regulations (42 CFR §493) under subpart M.
Question 37: I have a question regarding exchange transfusion. Can we issue AB plasma & RBCs in two separate bags that have been sterile docked together, but separated by use of a clamp so that the RNs can open the clamp and transfuse the product? Do we need FDA registration to do this?
If you sterile-dock plasma and RBC units together and issue it as a final product, you are performing a manufacturing step that is not covered by the exemption from registration in 21 CFR 607.65(f). You must register as a hospital blood bank.
If you combine all or part of a red cell unit and a plasma unit and issue it as a final product, this is also manufacturing not covered by the exemption from registration, so you must register as a hospital blood bank. If you issue separate red cell and plasma units, the administration of these products is a practice of medicine for which we would not require registration.
We encourage you to take a quality approach. Decide what process will minimize the risk and maximize the benefit to your patients, then determine the requirement for you to register with FDA.
Question 38: Can a laboratory have an FDA license for Donor testing independent of being affiliated with a Blood Center (collection facility)?
Background: FDA has eliminated establishment licenses. The current licensing paradigm (the BLA – Biologics License Application) is to license products that will be distributed in interstate commerce. The licensed product must be manufactured in facilities that meet establishment standards. The licensed products must bear the license number of the manufacturer who is responsible for the overall manufacture of the product; usually the “owner” of the product.
FDAMA (the Food and Drug Administration Modernization Act) passed in 1997 redefined the manufacturer and allowed manufacturing steps to be performed by contractors who are not owned or operated by the licensed manufacturer who owns the product and who themselves do own the product. They are independently owned and operated facilities that perform a manufacturing step on a licensed product.
These contractors must be registered under 21 CFR 607 because they are performing a manufacturing step. Because they are registered facilities, they will be inspected by FDA on a regular basis.
The use of contractors to perform donor testing is described in 21 CFR 610.40(f). This states that labs that perform the infectious disease tests required in the regulation, must be registered and either CLIA certified or meet CMS (formally HCFA) requirements. There is no requirement for the lab to be licensed.