Ask the FDA and CLIA
October 26, 2009
AABB 2009 Annual Meeting
New Orleans, Louisiana
· Jay S. Epstein, Director, Office of Blood Research and Review, CBER
· Alan E. Williams, Associate Director for Regulatory Affairs, Office of Blood Research and Review, CBER
· Ellen F. Lazarus, Director, Division of Human Tissues, Office of Cells, Tissue and Gene Therapy, CBER
· Paul A. Mied, Deputy Director, Division of Emerging and Transfusion Transmitted Diseases, Office of Blood Research & Review, CBER
· Sheryl Kochman – deputy director, Division of Blood Applications, Office of Blood Research & Review, CBER
· Judy E. Ciaraldi, Consumer Safety Officer, Division of Blood Applications, Office of Blood Research & Review, CBER
· Lore Fields, Consumer Safety Officer, Blood & Plasma Branch, Division of Blood Applications, Office of Blood Research & Review, CBER
· Sharon O'Callaghan, Program Surveillance Branch, Office of Compliance & Biologics Quality, CBER
· Daralyn Hassan, Division of Laboratory Services, Survey & Certification Group, Center for Medicaid & State Operations at CMS
· M. Allene Carr-Greer, Director, Regulatory Affairs, AABB
We want to welcome you all to this year's session of “Ask the FDA and CLIA,” I am Allene Carr-Greer, Director of Regulatory Affairs at AABB. We have a full agenda and may not get to all the questions, but we will move as quickly as we can. At this point, I will ask Dr. Epstein if he'd like to make a few remarks.
DR. EPSTEIN: Just a brief word of welcome to everyone. This is an ever-popular session at the AABB Annual Meeting; and just to say that from the standpoint of the FDA, we appreciate all the inquiries that we get. It keeps us on our toes, and it also reminds us how important it is that the users of regulatory requirements and guidance should have clarity. We hope that we can provide some of that in answering the specific questions that were provided for today's forum. I just also want to make mention that we have, of course, new hires at FDA continually, as times change. People come, people go; but there is one particularly important person who has joined the organization. Dr. Richard Davey -- perhaps you could stand so people can put a name to the face -- has come to us from Methodist Hospital in Houston, but is not a stranger to AABB and the world of blood, with his luminous career at NIH, Department of Transfusion Medicine, New York Blood Center, American Red Cross and so on -- many key appointments on your committees. We are very pleased to be here today and hope that we can edify you and perhaps entertain you at the same time. Thank you.
MODERATOR: Thank you, Dr. Epstein.
Question 1: While reviewing transfusion records, or conducting an audit, the Blood Bank staff sometimes identify what appears to be a transfusion reaction. In several instances the records note that the attending physician tells the nursing staff to continue the transfusion of a unit even when the recipient is experiencing symptoms, even a 3-4 degree temperature rise. What is the appropriate response for the blood bank staff to take at this point in time?
MS. HASSAN: Good afternoon. Today we will provide interpretation of the CLIA regulations to answer your questions. However, please remember that if your laboratory receives its CLIA certification by virtue of accreditation by a CMS-approved accreditation organization, your laboratory must follow all of the requirements of its selected accreditation organization, even those that are more stringent than the CLIA regulations.
That being said, to answer this question: Transfusion services are required to have policies and procedures in place to identify transfusion reactions, per 42 CFR 493.1103(d). It can be assumed that such policies would require a transfusion reaction investigation in cases where there is a three to four degree temperature rise. When blood bank staff identify such events during a retrospective record audit, they should bring it to the attention of the laboratory director who is ultimately responsible for the compliance with all CLIA regulations. 42 CFR 493.1271(e)(1) requires the laboratory to make recommendations to the medical staff regarding improvements in transfusion procedures. Thank you.
MODERATOR: Thank you Daralyn.
Question 2: My facility is excited to have the new cord blood licensure guidance available. Thank you. My question concerns the requirement to include all collection sites in the BLA. Once the BLA is approved what will be the process for adding collection sites to our license?
DR. LAZARUS: This question is referring to the CMC section of the newly finalized Guidance for Industry entitled Minimally Manipulated Unrelated Allogeneic Placental Umbilical Cord Blood Intended for Hematopoietic Reconstitution for Specified Indications; and I am only going to say that once and then I am going to abbreviate that. This final guidance was published last week and the CMC section of that guidance describes the manufacturer identification information that is to be included in the Biologics License Application. We say that this information should include all collection sites that act as agents of the cord bank, under contract agreement or other arrangement. Of course, it is not unusual for new collection sites to be added or for the collection sites to be changed for any given cord bank over time. This question is asking how to address this after the cord bank's BLA has been approved. This would fall into the category of changes to an approved application, which we refer to in the post-marketing activity section of the final HPC-C licensure guidance, where we refer to the regulation in 21 CFR 601.12, which is the provisions for reporting changes to your approved BLA. So, addition of a collection site would be one such change that you would inform FDA about. There are various different ways to do that. There are several different types of supplements to your license or some reporting can be done in the annual report. Questions you may have about which type of supplement or whether annual reporting only would be sufficient would be the types of issues that we could discuss during the licensure process. There may not be a one-size-fit-all approach for every cord bank; but this is a very common type of question that we work through during the BLA process.
MODERATOR: Thank you, Ellen.
Question 3: Concerning the new guidance documents on licensure of minimally manipulated, unrelated allogeneic cord bloods – it appears that the draft guidance on INDs makes provision not only for US products that may be of use for the ‘specified indications’ but for one reason or another do not meet the requirements of licensure, but also provides a pathway for use of products that are imported and therefore not licensed (whether they might meet the requirements or not). Is it true that my facility could apply for an IND that would allow us to continue using imported products that are not licensed?
DR. LAZARUS: The answer to that question is yes. This question is referring to -- I will read it one time -- the draft Guidance for Industry and FDA Staff entitled, “Investigational New Drug Applications (INDs) for Minimally Manipulated Unrelated Allogeneic Placental Umbilical Cord Blood Intended for Hematopoietic Reconstitution for Specified Indications,” HPC-C draft IND guidance, for short. The answer to this question is yes, and it sounds like the perspective of this questioner was from maybe a transplant center, because they say, “Could we apply for an IND that would allow us to continue to use imported products that are not licensed?" What you will see when you look at this draft guidance is that this option is one of several different possibilities for sponsorship for such an IND. There are other entities that could have an IND to cover this situation, for example, a cord bank or a registry or an individual sponsor, who would then be a sponsor investigator for the IND. I would also like to point out that this is a draft guidance published last week. We welcome your comments on this and other aspects of that draft guidance.
MODERATOR: Thank you.
Question 4: At our blood center, we perform platelet QC on one hematology instrument and qualify platelet donors using another hematology instrument (different methodology). The instrument on which we perform platelet QC is used as a backup for qualifying platelet donors when the primary instrument is down. What proficiency testing (PT) do we need to perform on these instruments?
MS. HASSAN: Per 42 CFR 493.801(b)(6) CMS-approved PT must be performed on the primary test system used for testing during the PT event. Twice a year, however, the laboratory must evaluate and define the relationship between test results using different instruments. This is per 42 CFR 493.1281(a). Thank you.
MODERATOR: Thank you, Daralyn. I think this next one might be for you.
Question 5: We perform platelet counts to qualify platelet donors at several of our fixed collection sites. Do I need to have a CLIA certificate for these sites?
MS. HASSAN: Yes. A CLIA certificate is required for every site in which testing is performed. However, such fixed collection sites may qualify for a multi-site exception if they perform a limited number of moderate complexity tests. The multi-site exception allows several sites to operate under one CLIA certificate. We recommend that you contact your state agency to determine if your facility qualifies for the multi-site exception. A list of state agency contacts may be found on the CLIA Web site, www.cms.hhs.gov/clia. Thank you.
MODERATOR: Staying on the subject of platelets but a different sort of question…
Question 6: The binomial sampling plan provided in the 2007 Platelet guidance is a problem for my institution. We are a small facility and do not always collect enough products to be able to follow this plan. What are we supposed to do?
DR. WILLIAMS: FDA has been encouraging movement toward a statistical-based process control for several years now, and really any statistically based method that you use is fine as long is it is a valid method. Of course, the challenge is that for some blood establishments the sampling frame is small, i.e. the volume of production is low, and some of the statistical approaches do not work. The binomial approach is considered to be a fairly straightforward approach that will work for a low to low-to-medium size center. There is actually an approach which will allow a little smaller sample size collection that is called a hypergeometric distribution -- you might want to look into that -- which allows a little lower sampling. If your institution is so small that this would not apply, perhaps you really need to consider 100 percent QC because a statistically based sampling plan just would not be appropriate.
MODERATOR: For a facility that is really struggling with this issue, is a phone call to the facility’s Consumer Safety Officer (CSO) appropriate?
DR. WILLIAMS: You could start there and we will either put you in touch with statisticians or suggest some approaches which might be appropriate for your institution.
MODERATOR: Okay, so FDA statisticians might be of help. Thank you, Alan.
Question 7: Apheresis monthly QC -- assume a sampling plan of 60 with one failure. What is expected of the facility with regards to retesting samples? For example, is it necessary to test an additional 91 samples using all collection equipment…?
MS. FIELDS: Yes, if you look on page 13 of the Guidance for Industry and FDA Staff, Collection of Platelets by Automated Methods (December 2007), the binomial statistical plan is laid out in a chart for you. Underneath the chart, there are several notes and it tells you what you need to do if you have a failure. So, if you select an N of sixty and you do get one failure, it does tell you that you need to do an additional ninety-one samples in order to be compliant with the 95-95 target that you have. Those ninety-one samples can be taken from the same sampling plan as your original sixty.
MODERATOR: Thank you Lore.
I want to go back just briefly to Alan’s last point that he was wrapping up pretty quickly and restate that he mentioned the hypergeometric plan for smaller facilities struggling with the binomial approach.
DR. WILLIAMS: Right, they are both for dichotomous variables. One is with replacement, one is without replacement. Hypergeometric is a well-established, published approach.
MODERATOR: Thank you. Our next question has to do with the new Circular. The August 2009 version of the Circular of Information for Use of Human Blood and Blood Components was announced as accepted by FDA last week with a guidance document that was published for immediate implementation. We thank the FDA for that guidance document being published and I wanted to say that the Circular is available for order through the AABB book store. Available on the AABB Web site now is what we call the educational or manuscript version, as well as the Chagas’ testing language. The West Nile Virus testing language was incorporated into this August 2009 Version.
Now, for the question that was submitted.
Question 8: The CFR says that transfusion of thawed cryoprecipitate should begin 6 hours after it is thawed or 4 hours after it is pooled, or spiked to begin the transfusion process. This regulation predates the guidance document on use of sterile connection devices. The August 2009 Circular seems to take into account the use of these devices. It states the transfusion should begin “within 6 hours if it is a single unit (from an individual donor, or pooled before freezing or administration using a FDA-cleared sterile connecting device), and within 4 hours after entering the container (e.g. to attach an administration set or to pool) without using a FDA-cleared sterile connecting device”. Did I interpret the information in the Circular correctly?
MS. CIARALDI: Yes. Let me go ahead and explain why. I also am going to include in my responses the CFR cites, like you heard from Daralyn. This is to get it in the transcript so it can be a good reference tool for you in the future.
The regulation that they are talking about in this question is 21 CFR 606.122(n)(5) and it does include the information that you have on this slide, so I am not going to repeat it. They are absolutely right in that we have recognized the new technologies in our review of the SOPs submitted with the products for licensure. Specifically, the SOPs that we have approved contain the following procedures. If a product has been entered, for instance, to attach an administration set or it is pooled before transfusion, not using a sterile connecting device, then it must be transfused within four hours. You are allowed to transfuse within six hours any product that was thawed and given as a single product, or if the cryo was pooled before freezing using a sterile connecting device. In other words, by the time it is thawed, it is still a single unit and meets the single unit requirements, or if you pool thawed cryo before transfusion using a sterile connecting device. All of those must be transfused within six hours. So, the answer is yes, we have recognized the new technologies when we review the SOPs for licensure of the product.
MODERATOR: Thank you, Judy. In recent years, we have had some difficulty correlating this information between our BBTS Standards, the Technical Manual and the Circular. We have alerted the Standards group of the newer interpretation that is now published in the Circular since the current Standards was published when the interpretation was that these pre-pooled products have a four-hour expiration.
Question 9: It is my understanding that FDA inspectors should not list previously reported BPDRs on the 483. Yet it occurs. Please explain how it really works and provide a reference/authority.
MS. O'CALLAGHAN: Field investigators are instructed by compliance program documents and Inspections of Licensed and Unlicensed Blood Banks, number 7342.001, which states that it is FDA's policy to only cite on the 483 as a deficiency associated with a previously reported BPD, if the blood establishment's investigation or corrective action was inadequate. If you have an event that you have reported and you continue to have that problem, it is very likely that you will be cited for an ineffective corrective action. Not for the fact that the event occurred; but that it continued to occur. Or, if you reported it but did not do a thorough investigation, you will be cited for that, but not for the fact that it happened. We also emphasize this in our training with our investigators and as always, with any citation, if you have a concern about what was put on a 483 or what investigators say that they are going to put on a 483, talk to them and find out exactly why they feel that they need to put that on the 483. It does not hurt to ask.
MODERATOR: Thank you, Sharon. I think that explanation is helpful.
Question 10: Regarding the addition of saline to pooled, cryoprecipitate prior to freezing: per 21 CFR 640.54(b)(2) diluent cannot be added to cryoprecipitated AHF prior to freezing. I have seen FDA-licensed, pre-pooled cryoprecipitated AHF frozen products where the label indicates saline has been added. The last time I checked the FDA web site for exceptions or alternate procedures I did not see this listed. Can this product be licensed?
MS. CIARALDI: The answer is yes. Now again, let me explain the reason behind this. The way that the question cites 21 CFR 640.54 is exactly correct. As it was with the previous situation, these regulations were put in place before the sterile connecting device was in practical use as an approved device for us to use. There is another regulation I want to make you aware of, and that is 606.122(n)(6). This one requires the Circular of Information to include a statement that says the preferred diluent is saline. Of course, these are pre-transfusion procedures. The license SOPS that we have approved for manufacturing pooled cryo contain procedures that use a diluent to rinse out the bags so that as much cryoprecipitate as possible could be placed into the pooled cryo bag before it is frozen. It is not a re-suspension step; it is just an aid in manufacturing the product. We have also seen in approved SOPs where the diluent is either saline or it can be compatible plasma. The new product was approved or licensed based on the submitted SOPs and on the quality control that came in with the submission.
MODERATOR: So, Judy, this is another recognition of the use of the sterile connecting device and the issuance of that guidance, subsequent to this regulation?
MS. CIARALDI: Right.
MODERATOR: Thank you. That is very helpful.
Question 11: At the recent workshop on licensure of whole blood and source plasma there was some discussion of licensure approvals where product QC has a 95% acceptance (rather than 100% as listed in the regulations) provided failure investigations and affected products were managed in a particular way. Please provide more information.
DR. WILLIAMS: This question really demonstrates one of the practical values of statistical based process control programs. Several product standards that have been in the regulations for some time just have absolute values rather than a statistically based requirement. When conducting quality control around that particular standard, if one has a single failure that creates a dilemma as to where to go next. FDA, in the past, has stated publicly that a ninety-five percent conformance in this situation is appropriate and would be acceptable to support licensure. This is not published, but it has been discussed publicly.
MODERATOR: Thank you, Alan.
Question 12: I work in a Blood Bank where we use photo ID's for donor identification, such as driver's license, passport, work ID, and voting card, but in many occasions, we receive donors that do not have a photo ID. We are thinking about creating the photo ID ourselves with the use of a digital camera. Would this be in compliance with FDA regulations?
MS. CIARALDI: I would like to give a little background information before I go to the simple answer. Again, a couple of regulatory citations for reference. 21 CFR 640.4(e) says that each unit of blood must be marked or identified by a number to relate it to the individual donor whose identity must be established to the extent necessary to show that that donor is in fact in compliance with the donor eligibility regulations. Some of you are applying for a licensure for source plasma and there is additional information in those regulations as well, and I will point out that these source plasma regs are a little bit newer than the blood regulations. The regulation is 21 CFR 640.65.b.3 and it says that a donor identification system shall be established that positively identifies each donor, and relates the donor to the unit, records and data. The system must include either a photo of each donor, which must be used at each visit to confirm the donor's identity, or some other method that provides “equal or greater than” assurance of positively identifying the donor.
So, I would like to ask a question first, for your consideration. If a donor presents without a photo ID how are you positively identifying a donor? While you mull over that, if you have a mechanism by which you can confirm the donor's identity then we have no objection to the blood bank taking the donor's picture.
MODERATOR: Thank you, Judy.
Question 13: Can an apheresis platelet product be collected between Whole Blood or automated RBC donations? In one place in the Platelet guidance it says this is OK. Later in the document where it talks about RBC loss it says that a loss of 200-300 mL RBC requires the donor to be deferred for 8 weeks. If a donor gives a 500 mL WB unit and has a 40% hematocrit, he will lose 200 mL of RBC in the WB donation plus the volume in the pre-donation samples. Since this is greater than 200 mL should this donor be deferred for 8 weeks or can he donate apheresis platelets if his pre-donation hematocrit is greater than 38% and the apheresis system used has an extracorporal volume of less than 100 mL?
Please explain when we should take into consideration the 200-300 mL RBC loss and when the donor should be deferred based on interval and frequency only.
MS. FIELDS: If we can start with the first question since that was pretty lengthy. Can an apheresis platelet product be collected between whole blood or automated RBC donations? The answer to that is yes. On page six of the Plateletpheresis Guidance, it does talk about how you can collect a platelet apheresis product -- as long as the extracorporeal volume is less than 100. The table that you are referring to in this question is for incomplete procedures, which is consistent with the apheresis red blood cell guidance document from 2001. As long as you do not have incomplete procedures, you just draw a normal red cell product, then you may collect a plateletpheresis during your eight week interval as long as the extracorporeal volume is less than 100 and you have not hit the maximums on any of your other red cell or plasma losses for the year.
MODERATOR: Thank you Lore. If anyone has questions after that explanation and looking at the guidance document, Lore would probably be happy to get your phone call.
MS. FIELDS: Just one more clarification. This does not apply to double-red cells. That is an automatic sixteen week deferral for all products.
MODERATOR: Thank you.
Question 14: At previous Ask the FDA sessions, the FDA has explained that combining Plasma and Red Blood Cells to create a "reconstituted" Whole Blood for neonatal exchange transfusion is considered manufacturing and requires FDA registration. Is there a threshhold frequency before registration is required (for this or other infrequent occurrences), e.g., if a procedure is only performed 1-4 times per year, is the facility required to register with the FDA for these infrequent activities?
MS. CIARALDI: FDA does require registration for this procedure because the reconstitution of red cells and plasma to make a third product, the Whole Blood, meets the general definition of manufacture in 21 CFR 607.3(d). There is no threshold frequency that is described in any of our guidance documents or regulations, but we feel, if you have established procedures for performing this process, you must register regardless of the frequency.
I would like to add a comment on top of that because it just came in right before I came to the meeting and it came in from a field investigator. There was a concern expressed and I do want to share that with you. If you are having staff members perform a procedure as infrequently as described in the example on the slide, how will you ensure their competency, consistent with our requirements in 21 CFR 606.20(b)? For procedures performed infrequently, there may be a GMP issue with making sure that staff are competent and experienced and knowledgeable about doing these procedures. It is just something to think about.
Question 15: In the near future there will be only one US licensed test to screen donors for HTLV-I/II. This is of great concern. What considerations/contingency plans does FDA have for blood to be released for transfusion if there is a time when this one test for some reason or other is not available for distribution to testing establishments? There are various issues that can cause a manufacturing failure or a failure to pass lot release at FDA.
DR. MIED: We understand that in the future there may be only one licensed donor screening test available for antibodies to reach HTLV-I and -II, and that it is possible that if problems arise in manufacturing or lot release or, for some other reason, even that test may not be available, at least temporarily. We recognize this as a problem, and we share your concern. The absence of an HTLV donor screening test would create a difficult situation and a problem that could threaten blood safety. We agree that there is a need for more licensed HTLV donor screening tests and we are working on several levels to address this issue. We are having a dialogue with AABB as part of the HTLV Task Force on this issue. We are encouraging manufacturers of unlicensed HTLV tests and manufacturers who are developing new HTLV tests to discuss approval criteria with FDA and to submit the test to FDA for licensure. At FDA, we will do all that we can to apply the least burdensome considerations in the clinical trials and the other approval criteria for a new test and to expedite the review of an application and the licensure of a new test to prevent this public health problem from developing.
MODERATOR: Thank you, Paul, and should the occasion arise, we will look to the agency for direction and leadership.
DR. MIED: We will be glad to provide that.
MODERATOR: Thank you. One thing Paul did say is that obviously everyone who has a thought or an avenue to explore on the issue is quite busy trying to track down a source for HTLV testing.
Question 16: Are there considerations for otherwise qualified donors that have blood diseases such as polycythemia that would allow them to give allogeneic donations? This would be similar to the process that is allowed for donors with hereditary hemochromatosis.
MS. CIARALDI: We currently do not have a position on this particular issue. But that is only because we have not been asked. We have not received any formal requests for this consideration and if you are interested please bring this to us and we will discuss it.
MODERATOR: Thank you.
Question 17: A recent notice published in the Federal Register addressed a 15 day response time for 483 observations. Are establishments expected to respond to inspection observations immediately after an inspection summary is provided at the closing summary, or should establishments wait for a written Establishment Inspection Report (EIR) prior to responding? Please discuss general recommended timelines to respond to observations. Are all observations considered "severe" or is there a different expected response timeline based on the specific observation cited?
MS. O'CALLAGHAN: The Federal Register notice stated the agency will not delay the issuance of a warning letter in order to review a response to a 483 that is received more than fifteen business days after the 483 was issued. If we receive a response within fifteen business days, we plan to conduct a detailed review of the response before determining whether to issue a warning letter. If the response is received more than fifteen business days after the 483 is issued, it will be evaluated along with other written material provided as the direct response to the warning letter.
It is certainly in your best interest to respond to all observations promptly after the 483 is issued, not when the EIR is completed. It is after the 483 is issued. The response time frame applies to all observations.
MODERATOR: Thank you, Sharon.
Question 18: Following a repeat reactive test for HBsAg, if the confirmatory test is "non-confirming" (cannot be interpreted as negative or positive based on the neutralization test), must that donor be kept on permanent deferral or can a reentry algorithm be used? This is usually due to a low O.D. value which is over the cutoff, but inadequate for neutralization to be definitive. If the donor returns after at least 8 weeks and is negative for both HBsAg and HBcAb would that be sufficient or must a NAT HBV also be run and be negative to allow reentry?
DR. MIED: The December 2, 1987 memorandum for blood establishments, “Recommendations for the Management of Donors and Units that are Initially Reactive for Hepatitis B Surface Antigen,” is actually still in effect. The recommendations in that memorandum state that if a sample from the donor is repeatedly reactive on a test for HBsAg, the unit should not be used and the sample should be tested using an HBsAg neutralization test. According to the criteria set forth in the neutralization test package inserts, a specimen is considered to be positive on the neutralization test if both of the following criteria are met: (1) the net absorbance for the specimen is greater than or equal to the assay cutoff; and (2) the reactivity of the specimen is reduced by a certain percentage, usually at least fifty percent depending on the assay. If the specimen meets the first criteria, the net absorbance is greater than or equal to the assay cutoff but is relatively low so that it is inadequate for the percent neutralization to be definitive, (the second criterion), that specimen should be considered non-confirming. The 1987 memorandum refers to a specimen that does not confirm as positive, by either of those criteria, as not neutralizable. If the donor specimen is also nonreactive for anti-hepatitis B core, the donor should be deferred, but may be eligible for reentry. After a waiting period of at least eight weeks, the donor may be re-entered if a subsequent donation is nonreactive for both anti-core and HBsAg.
Now, I should point out that although FDA has licensed several HBV NAT assays, currently they do not play a role in the HBsAg reentry algorithm. The reentry algorithm recommended in the 1987 memorandum is still in effect.
MODERATOR: Thank you, Paul.
Question 19: We are updating our pandemic flu preparedness plan. In the event of severe outbreak with shortages of donors and products, would the FDA consider a variance for 7 day platelets using the currently approved bacterial screening technologies?
DR. WILLIAMS: Planning for blood supply disruptions due to a pandemic or any other emergency is critical and we really do applaud the AABB and its task forces, the disaster task force and the pandemic flu task force, for the materials they have developed to help the membership prepare. We have had numerous discussions with the task force about potential interventions that may help to preserve the blood supply. To specifically answer the question, any establishment can submit a variance for consideration. However, in this particular situation we would encourage discussion with the FDA before doing so. The key issue is what is a trigger for implementing an intervention? We have had a lot of discussion about this and really have had great difficulty in defining a trigger that would be applicable nationwide for any change in policy to support response in the event of a disaster. With this in mind, FDA has not at this point promulgated policy in advance of an actual need, but we are prepared to act quickly if the situation warrants. And specific to platelets, again addressing the question, there is an increasing battery of bacterial tests available for platelets and they should be considered in the event that a situation like this arises. Basically, FDA will consider and publish policy if the situation warrants.
MODERATOR: Thank you, Alan.
Question 20: At a BPAC meeting earlier this year FDA presented a proposal for plasma for further manufacturing products that might be used in the place of Recovered Plasma so that plasma collected by automated platforms could also be sent for further manufacture. What is currently happening with this effort?
DR. WILLIAMS: As was mentioned, FDA did introduce the concept of two new plasma products at the Blood Products Advisory Committee (BPAC) meeting earlier this year. The two products were tentatively termed concurrent plasma, which is plasma collected in conjunction with the cellular product either by whole blood collection or by apheresis. The second product is component plasma, which is a plasma collected by apheresis as a sole product either for transfusion or for further manufacturing. We defined, for BPAC consideration, some key characteristics of the product which included: the ability to convert these transfusable plasmas to plasma for fractionation prior to their expiration date; and also a proposed consideration of labeling that would reflect conditions of collection and testing. The BPAC was supportive of the proposal made by FDA. They also had a fairly strong discussion related to the need for informed consent for collection of plasma as a sole component, and BPAC largely agreed with our proposal. We still largely agree with our proposal and we are having internal discussions to solidify this as it will involve some changes in regulations -- but as I think was mentioned earlier, as soon as we define a pathway, we would hope to proceed towards a rapid publication of guidance that would define the parameters for submitting exceptions under 21 CFR 640.120.
MODERATOR: Thank you. AABB has a task force that is looking at information provided to donors, not only on the issue of plasma but certainly looking carefully at donors from whom plasma is collected for further manufacture. Some of you in the audience may be participating in the task force and so we thank you for that.
Question 21: Can a single informed consent be used for multiple donations over a defined time period (12 months, for example) for acknowledging the risks of undergoing a plateletpheresis donation? We do not see a specific CFR requirement that this be repeated with each collection.
MS. FIELDS: The regulations only state that when collecting a plateletpheresis product, you must perform an informed consent. This is discussed in 21 CFR 640.21(c) . However, there are no regulations on how frequent this should be performed. We have, in the past, approved applications in support of licensure that contained varying options/periods. We do not have a recommendation though on what that period would be; so I do not really want to speak to that. There is a proposed regulation for donor eligibility under 630.10(i)(2) that discusses informed consent (written statement of understanding) for donation and if you do have any comments for this, you should submit those to the docket.
MODERATOR: So the comment period is closed, but the docket is still open, correct?
MS. FIELDS: Yes.
MODERATOR: Thank you.
Question 22: Syringes are being used for neonatal transfusions. Some companies are saying that the expiration date for a syringe red cell product is 24 hours (because it is an open system). I understood that syringes were not approved containers for blood products and should therefore have an expiration time of 6 hours from preparing. Can you clarify that?
MS. FIELDS: We understand that syringes are used for aliquotting blood for neonatal transfusion and we do consider those an open system. We do not have any requirements or recommendations on the expiration dates for these products. However the devices are not approved or cleared for the storage of red blood cells and you should, therefore, not be storing those blood products in the syringes.
MODERATOR: So, from the agency's viewpoint it is aliquotted for transfusion, not aliquotted for storage?
MS. FIELDS: Correct.
MODERATOR: Thank you. SOPs may need to be looked at to ensure that difference is clear.
Question 23: To what extent would FDA allow a Medical Director to vary from the regulated inter-donation blood collection intervals in a pandemic situation?
DR. WILLIAMS: Well, as I mentioned a couple of questions ago, FDA has been a liaison participant with the AABB Pandemic Flu Task Force and also has had numerous discussions with other segments of the blood community and several potential interventions have been discussed. One that would potentially make a big difference in the supply of red cells would be changes in the inter-donation interval and AABB, in fact, wrote to FDA with the suggestion as far as something to consider. But, as mentioned earlier, in the interest of maintaining uniform standards both for manufacturing and donor safety, one needs to consider again the question of triggers and FDA is prepared to act quickly if the situation warrants to help preserve the red cell supply.
MODERATOR: Thank you, Alan.
Question 24: Why is it still necessary to write open dates on reagents for ABO/Rh testing? CAP and AABB have dropped this requirement. I agree that if a vial is opened and the expiration date changes that the label must show the expiration date, but simply recording open dates does not make sense.
MS. KOCHMAN: There is, in fact, also no FDA requirement for writing the open dates on your reagents. The primary place that such a requirement would appear to come from would be the manufacturer's directions for use. The one scenario where I can think of where this would or may commonly be required is in cases where a reagent is placed on an automated blood grouping system instrument and the reagents stay on-board with that system. There may be an on-board reagent time, in which case the time that you opened the vial and placed it on the machine would be necessary so that you could track the on-board time. Otherwise, we are not aware of any requirement to do that.
MODERATOR: Thank you, Sheryl.
Question 25: At the recent licensure workshop it was emphasized that when SOPs are submitted with a BLA and accompanying form 356h the facility should report whether the SOP was originally developed by the facility or borrowed from another blood organization. I checked the 1999 guidance and this instruction is indeed contained in the guidance. I do not understand this recommendation. Is a reviewer going to interrupt the review of my application to go back to the other organization’s file and see if there is now a difference? We are not referencing a shared Master file.
MS. CIARALDI: Before I start, this is the second question that made a reference to the licensure workshop and I do want to speak for FDA and thank you for attending that workshop. Because of the questions that we are getting, we can call this Licensure Workshop Part 2. I do appreciate the opportunity to give a little more time to this topic, because it is important.
When the biologics license applications are submitted to FDA, they must include a description of the procedures that you will use to make your product. This is consistent with the requirements in 21 CFR 601.12 which specifically state that the BLA must include a full description of the manufacturing methods. There is a provision in 21 CFR 606.100(d)(3), that allows you to use SOPs of another organization as long as the procedures are consistent with or are stricter than the regulations. Just to give you an example of how this would work, if you are submitting a brand new BLA and you developed your own brand new procedures, then your BLA application would include your new procedures, and we would review them.
If you are a brand new applicant submitting a brand new BLA and you have gotten permission from another organization to use their SOPs and they have been previously approved by FDA, you would send us evidence of that permission and the reference number for the latest version that was approved. And take into consideration, if you are using another organization's SOP, you probably have some sort of manufacturing arrangement with them so that you have opened up this discussion and you can get the reference number or the submission tracking number.
If, however, you have decided to use this other organization's SOPs and they have not been previously approved by FDA, meaning they came, for instance, from a registered blood bank that is not licensed, then those SOPs would somehow need to be submitted to us. The same process would happen if you are already licensed and you are bringing in a supplement to your license.
The bottom line is that your licensed products need to be manufactured according to SOPs that we have reviewed and approved. If the SOPs for the original or subsequent submission have been previously approved by us and there is evidence of that with a submission tracking number and the approval letter that goes with it, you do not need to resubmit this. There is no need for FDA to review it again if it has already been reviewed. But we would like to have the submission tracking number included, so, if needed, we can go back and do that cross reference. We can pull out that other submission and look at the information so you will not have to do that.
MODERATOR: Judy, if the SOP was originally developed by another organization but my organization has modified it in any way, is it now my organization's SOP?
MS. CIARALDI: That is an excellent point. Thank you very much for clarifying that. Again, you would use the SOPs as is. If you change it in any way, then you are definitely no longer using the other organization's procedures. They are now yours because you have modified them. At that point, you might say the bet is off the table and we have to start out as if you have developed your own SOPs. Granted, you did not have to write it all the way from scratch. You took something and worked with it, even if it was an outline, but now you have added your own procedure, so it becomes your own SOP.
MODERATOR: Thank you.
Question 26: Regarding 21 CFR 211.25 and 42 CFR 493.1451. Please clarify timing of the requirement of assessment of competency of new employees moving from training to routine work. Also, do annual assessments have to be done on a rolling basis or can employees that have worked at the blood center for more than a year all do an annual competency in the same time period?
Ms. O’CALLAGHAN: 21 CFR 211.25 requires that training in current good manufacturing practice shall be conducted by qualified individuals on a continuing basis and with sufficient frequency to assure the employee remains familiar with CGMP requirements applicable to them. This regulation does not specify any time frames of when the assessments need to occur.
MS. HASSAN: Initially, the laboratory director is responsible for ensuring that personnel have received the appropriate training and have demonstrated that they can reliably perform all testing operations per 42 CFR 493.1445(e)(12). Subsequently, competency must be assessed semiannually during the first year and annually thereafter. It can be done either on a rolling basis or during one time period, as long as the requirement for semiannual or annual assessment is met for each employee. For example, if an employee is due for his or her annual evaluation in May and the facility evaluation period is normally in October it is not permissible to delay the evaluation. On the other hand, this employee can have his or her evaluation performed early, during the routine evaluation period in October of the preceding year and then annually thereafter.
MODERATOR: I hope this has been helpful to who ever it was that submitted the question, and if there are further questions, contact Daralyn or Penny Myers. They will help you.
Question 27: When a blood component is divided for neonatal use (using a sterile connection device) the aliquot is labeled with contents and volume. Must the parent (original) unit also be relabeled as divided, and the new volume recorded?
MS. CIARALDI: Yes, and again, let me give you some background information to help explain this. We found there is in the CFR a direct reference to part of this question. 21 CFR 606.121(c)(6) requires the labels of partial red cells to contain the product volume. What this means is that the volume of the parent unit must be revised to reflect the new content. We could not find, or I could not find any specific reference in the CFR that talks about the product name of divided units; but, it does say in 606.121(c)(1) that the proper product name must be on the label of the product. To help you comply with this, you may want to consult the ISBT labeling catalogue. In it, it states that the process of dividing products is encoded as part of the product description code, specifically data characteristics in the seventh and eighth position of the product code are reserved for information about divided products. They indicate when a division is done and the product no longer meets the volume that would translate to an adult dose volume. The bottom line is, yes, you would have to readjust, re-label for the name (the parent unit is now a divided unit) and you would have to re-label it with the new product volume.
MODERATOR: Thank you Judy.
Question 28: My facility is considering outsourcing the end user validation of our blood establishment software to our vendor. The validation will be performed in our environment, under our conditions. How does the FDA feel about vendors performing the end user validation of blood establishment software?
MS. KOCHMAN: Having the vendor perform the end user validation is not a violative situation, but it is certainly not the most ideal situation either. If you would refer to the “Draft Guidance for Industry Blood Establishment Computer System (BECS) Validation in the User's Facilities,” we specifically state there that validation should reflect and anticipate the system's actual use in your establishment. You should validate your system using your own personnel and your own test plans written for your specific intended use of the software. You may wish to retain a consultant for assistance and direction. In other words, it is unlikely that the vendor is going to know what your SOPs are going to say. They are not going to know how you have trained your staff. You need to be the one to take charge of the situation and make sure that you have covered all of the considerations in your facilities. There are lots of human factor issues that often come to light in the end user's environment. One example would be in a situation where the vendor staff normally enter a numeric value using the numeric keypad that is to the right of the keyboard, and then a user, for some reason, comes along and decides to use the numeric keypad that is across the top of the keyboard. We have actually seen cases where those two keyboards do different things, surprisingly. That is one of the reasons that you need to include your own staff in the validation because there may be something a left hander might do differently than a right hander, or something in your training did not convey the message properly and we feel pretty strongly that you can get help if you need it, but that you really need to do as much of this yourself as you possibly can.
The guidance also goes on to say…we also recognize that it is the common practice for the software manufacturer to provide test cases to blood establishments for use in system validation. We recommend that you carefully consider your own intended use of the software and your internal policies and procedures and add or change any test plans that they provide to you, as appropriate, to ensure that the software will accurately and repeatedly meet your requirements.
MODERATOR: I think Sheryl has given us a pretty good review of some of the situations that would arise that a facility would be more aware of than any vendor, but has also stated that to use the vendor to do this work would not be violative.
MS. KOCHMAN: That is correct.
MODERATOR: Thank you.
Question 29: If blood is transfused in an emergency situation, does the physician have to sign all emergency release forms if units were put on different forms and issued at different times (i.e. same physician) or is it acceptable to put all forms together with one signature?
MS. CIARALDI: I am familiar with this. I came from a large blood bank that had a shock trauma center and we ran into this an awful lot. But what I want to do is, of course, give you the FDA perspective. The regulation 21 CFR 606.151(e) requires procedures for the transfusion in emergency situations. It also requires that records be maintained of all incidents with complete documentation justifying the emergency action which must be signed by the physician. Also, 21 CFR 606.160(b)(3)(v) requires records maintained of the emergency release of blood that includes the signature of the requesting physician obtained either before or after release. If there is documentation that shows that all the emergency forms have been merged into one form, then we do not object to the physician signing only one of the forms. However, we do have one concern we want to bring to your attention. The question did not clarify how the forms would be put together. Depending on the method by which they are put together, forms could become separated; and if that happens, then you do have a form out there in your files that was not signed by the physician. So, once you go ahead and consider how you are going to merge the forms into one document, then it would be an acceptable practice, but please include this while you are developing your procedures.
MODERATOR: Thank you.
Question 30: Is there a requirement for the Blood Bank Medical Director to review records from platelet apheresis donors? This is mentioned in the AABB Technical Manual with a reference as to the CFR, but we cannot find such a requirement.
MS. FIELDS: We really cannot comment on anything that is in the AABB technical manual content. However, I did sneak down to the bookstore this morning and did check it out and this is in there. There is no regulation for this -- I believe this is a hold-over from the 1988 plateletpheresis guidance, which did have this recommendation in it. However, this 1998 guidance document was replaced in December of 2007 by the new platelepheresis guidance document. In the new guidance document, we do recommend that you should periodically review a donor's record to monitor the platelet counts. This is because there has been some data on transient decreases in platelet counts that have been reported in donors who undergo multiple collections on plateletpheresis; so, there really should be a medical professional or designee or who goes through and looks at the charts for the donors. In the new guidance document we do not identify who has to perform this function. It should probably be the medical director or someone that he can delegate this duty to. Additionally, there is no specific time period anymore and your firm should have an SOP, though, that describes the process, who the responsible parties are, and what your establishment considers an acceptable time period.
MODERATOR: Thank you, Lore. As the Technical Manual goes through its next review cycle, I guess we will see this updated as well.
Question 31: We received a Noteworthy Matter comment on our FDA inspection report because we perform a two-point (low, normal) QC check on our hematocrit measurement device rather than the three-point (low, normal, high) check that is recommended in the instruction manual. The general QC check range is on or about: 20-22% (low), 37.5-39.5% (normal), 50-51% (high). At our institution our acceptable range for allogeneic donors is 38-60%. What is the requirement for performing QC checks for hematocrit testing?
MS. KOCHMAN: The easy answer to this question is that you should always follow the directions in the manufacturer's instruction manual that come with the hematocrit device that you are using. We have been wondering if there is a little bit more to this question than that, since there is a reference to the general QC check range. So number one, the quick and easy answer is, clearly, if the user's manual for the microhematocrit measurement device says that you need to do a three-point QC check, then that is what you need to be doing. We get that through 21 CFR 606.65(e) which states that reagents and instruments must be used in accordance with their directions for use. Since there is this comment about QC check range, we were wondering if there was some confusion as to whether or not the directions in the QC reagents were at variance from the directions from the instrument's manual and if that case ever arises -- it is generally believed that the instrument's user manual supersedes any directions in the reagent instructions for use; or, if you really are confused, call one or both of the manufacturers. But, bottom line, the easy answer is, follow the directions for use.
MODERATOR: Thank you, Sheryl.
Question 32: Once the BECS validation is complete is it necessary to have ‘full validation’ records available at all sites or are summary reports suitable for alternate locations with the complete file available at the main facility?
MS. KOCHMAN: I think that there is an underlying question here that is a bigger question and that question is, “is it acceptable to validate your BECS at the main facility and not at each of other locations?” There was a point in time when we thought that that approach was probably acceptable, but we learn things as we grow and continue to be exposed to them. We now believe that it is probably not appropriate to validate at a main facility with little or no validation at your other facilities. In terms of where should the records be, the records need to be at each facility where you have done the validation and the validation should be done at each facility where the BECS is being used.
Again, this points back to the fact that while you may have exactly the same equipment at all of your locations, you certainly are unlikely to have the same personnel at all of those facilities. You may very likely have different utilities available to you, differing interferences -- like Blackberries buzzing in microphones -- available to you, and so we have learned that you really need to validate -- and you do not really validate software in a vacuum. You validate your software in conjunction with your whole computerized system, so you need to conduct those validations at each location and have the records available there.
MODERATOR: Sheryl, if the person with the question has in mind mobile operations, do you suppose that they are thinking that a summary report at their mobile locations is appropriate? This would not negate what you said about the other situations.
MS. KOCHMAN: I had not thought of mobile operations in that way. Can we get back to you on that?
MODERATOR: That would be great, thank you.
Question 33: FDA has committed to a periodic review of the deferral algorithms in place related to vCJD. Are there imminent changes that would result in reentry of the donors we lost due to time spent in Great Britain and Europe associated with vCJD?
DR. WILLIAMS: FDA does periodically review the deferral policy related to dietary BSE exposure. This is generally done through deliberations of the Transmissible Spongiform Encephalopathy Advisory Committee or TSEAC, and when these discussions occur, it is generally in the context of changing epidemiology or new scientific observations. The past two times policy has been reviewed, the committee has largely indicated that the current deferral policy is appropriate although transfusion in France was added at the last discussion. In response to what was known about the dietary exposure in the UK, the deferral was capped at 1996. That helped preserve some of the donors who spent time in the UK.
However, given the known transfusion transmissibility of variant CJD, and the as yet not well-defined incubation period which is known to be long, those who had dietary exposure to BSE during the peak of the epidemic in the UK (1980 to 1996) that exposure does not go away. Given the uncertainties about incubation period, it will be reviewed, I am sure, at some point in the future; but right now, the uncertainty persists.
MODERATOR: Thank you Alan.
And that concludes our question and answer session. Dr. Epstein has a few words.
DR. EPSTEIN: Well, really, just a few words of thanks. I want to thank Allene Carr-Greer for organizing this session on everyone's behalf, and thank the participants who submitted questions for discussion by the FDA staff members. We recognize that we do not have time in this session to answer every question that everyone may have submitted, but it is important for you to know that we do have a policy of transparency and that we do welcome your communications. You are encouraged to ask, particularly your CSOs for clarifications when you are dealing with emerging situations. Also, we have an office of communication and you can always call into 301-827-2000 and then your inquiry will be routed to the right place at the FDA. Again, we appreciate all the interest and attention that we get through this forum. Thank you.
MODERATOR: I add my thanks and appreciation to the panelists and to those of you with inquiring minds for submitting the questions.