2007 Ask the FDA Transcript
AABB 2007 ANNUAL MEETING
ASK THE FDA
BALLROOM C
ANNAHEIM, CA
October 22, 2007
FDA Panel:
Jay Epstein, MD, Director, Office of Blood Research and Review (OBRR), CBER
Elizabeth Callaghan, MS, SBB(ASCP), Acting Director, Division of Blood Applications (DBA), OBRR, CBER
Sheryl Kochman, MT(ASCP), Supervisory Biologist, Division of Blood Applications, OBRR, CBER
Sharon O’Callaghan, MT(ASCP), Consumer Safety Officer, Office of Compliance and Biologics Quality
Ellen Lazarus, MD, CAPT USPHS, Director of Regulatory, Office of Cellular, Tissue and Gene Therapy, CBER
Ken Zemann, MS, MT(ASCP)SBB, Consumer Safety Officer, Division of Blood Applications, OBRR, CBER
Judy Ciaraldi, BS, MT(ASCP)SBB, CQA(ASQ), Consumer Safety Officer, DBA, OBRR, CBER
Paul Mied, Ph.D. Deputy Director, DETTD, OBRR, CBER
Jaroslav Vostal, MD, PhD, CBER, Chief Laboratory of Cellular Hematology
Leslie Holness, MD, Blood and Plasma Branch, OBRR, CBER
Moderator:
M. Allene Carr-Greer, MT(ASCP)SBB, Director, Regulatory Affairs
MODERATOR: Good afternoon and welcome to this year's session of “Ask the FDA.”
Dr. Epstein has some opening remarks and then we will begin with the questions.
DR. EPSTEIN: I just wanted to thank everyone for coming to this ever-popular session of “Ask the FDA.” I know you are here because you want to hear the answers to many pressing questions. And usually a question that someone asks is, more often then not, a question that is on your mind too. Also, it is an opportunity for us to be real people; real faces and I think that that connection is very important. I am impressed that so many people have turned out at a late hour in the day. I want you to know that this exercise is valuable not just to you but also to us. It matters to us what the concerns are of the blood organizations. The questions are also very thought provoking to us. If we cannot give you a complete answer to a question probably that is because there is a little bit more to it and we want to go back home and think about it. So with that one caveat, we are very happy to do our best to answer each and every question that has been submitted. Thank you.
MODERATOR: Thank you, Jay. We will now begin with the questions.
Question 1: My question concerns HCT/Ps imported into the US. Do these HCT/P donors have to be screened for WNV through either screening questions or testing?
DR. LAZARUS: The answer is simply, “yes.” West Nile Virus is considered a relevant communicable disease agent under the Human Cell and Tissue product regulations. Current FDA published guidance only recommends screening for West Nile Virus and does not include any recommendations for testing. Right now the recommendations are just for screening. What I want to emphasize is even those cell and tissue products that are imported into the U.S. still have to have donor eligibility determinations in accordance with the regulations. There is no distinction made between U.S. HCT/Ps and non-U.S. HCT/Ps that are imported into this country with regard to the donor eligibility rule. Any further recommendations that we might have about testing for West Nile Virus would appear in published guidance.
MODERATOR: Question 2: Concerning autologous mono-nuclear cells collected by a licensed/registered facility and shipped to a manufacturing facility for further processing (under IND) and then returned to the collecting facility for distribution: Is ID testing required? What labels are necessary? Does the answer change if the product crosses state lines?
DR. LAZARUS: I think I will just address the last part of that question because I think it makes the whole situation clearer. The answer does not change. The regulatory authority for the human cell and tissue product rules that we promulgated, which is Section 361 of the Public Health Service Act, does not make a distinction between HCT/Ps in interstate and intrastate commerce. So, I think, once you understand that, the answer to the question becomes very straight forward. Autologous HCT/Ps generally do not require a donor eligibility determination. So the question “is infectious disease testing required?” can be answered with a simple “no.”. The labeling that applies is explained in a specific regulation, 21 CFR 1271.90(b), which is the regulation that addresses exceptions for requirements for donor eligibility determination and also explains the labeling that has to be used for those products. So the labeling that would apply, if you had an autologous HCT/P and did not perform any infectious disease screening or testing, in accordance with the donor eligibility rule, would be “for autologous use” and the other statement is “not evaluated for infectious substances.”
MODERATOR: Question 3: The summary of records required by 21 CFR 1271.55(b)(2) includes “A listing and interpretation of the results of all communicable disease tests performed.” Does this require that each individual test performed and corresponding result be listed or is a summary statement about communicable disease testing acceptable (e.g. “Non-reactive for all FDA-required communicable disease tests” or “Positive for (xyz test) and non-reactive for all other FDA-required communicable disease tests”)?
DR. LAZARUS: The requirement is that each test performed and the corresponding results are to be listed in the summary of records and a summary statement would not be acceptable.
MODERATOR: Question 4: Our facility is considering taking part in clinical trials involving collection, storage and selection of autologous stem cells. There is also a trial that involves receipt and storage of frozen, allogeneic stem cells that are reconstituted on site for injection. We do not have a stem cell laboratory, or any other laboratory that complies with cGMP or cGTP standards. The researcher has stated that it is not necessary, since these are all clinical trials. Do we need to meet the cGMP/cGTP standards in order to conduct these types of clinical trials in our facility?
DR. LAZARUS: I think it is helpful to take this question in a step-wise fashion and go through an algorithm. So the first question is - are we dealing with an HCT/P? And the general answer would be “yes” - stem progenitor cells are regulated as HCT/Ps. So, as you all probably know, the first thing to determine is whether or not the particular HCT/P is regulated solely under Section 361 of the Public Health Service Act or if it is also regulated as a biological product under Section 351. So if we accept that these autologous stem cells are HCT/Ps, then we have to accept that they are manufactured in accordance with the HCT/P regulations, which include the current good tissue practices. So now we go to the next step, is this particular HCT/P that is to be manufactured in accordance with the good tissue practices also regulated as a biological product? And to answer that question you have to look at the criteria in Section 1271.10 and determine whether or not the particular products that are being used in the clinical trials are, as we say, “kicked up” and also regulated as biologics, thus manufactured in accordance with the GMPs. So whenever I hear about autologous stem cells, I consider whether the clinical use is homologous or non-homologous and is that what is being studied in the clinical trial. The question includes collection, storage and cell selection that is generally considered minimal manipulation. But if there is any more then minimal manipulation going on as part of the clinical study, then that would be, as we say in short hand, a kickup factor. The other criterion to consider would be, is the autologous stem cell product being combined with another article, other than water or crystalloid or sterilization or preservation or storage agent? And if it is combined with another drug or device, then it is kicked up as well. So if you go through that algorithm and you have a product that is regulated under both 361 and 351, then manufacture in conformance with the GTPs, good tissue practices, and also the cGMPs, the current good manufacturing practices. So then the final point I will mention for you is that if you want some information about how to comply with cGMPs, even in a very early stage of clinical development, you can look at a draft guidance for industry called, Draft Guidance for Industry INDs Approaches to Complying with cGMP during Phase 1. This draft guidance, published in January 2006, recognizes that the controls and the extent of controls differ between investigational and commercial manufacturing and also through the phases of clinical studies. It explains which GMPs have to be in place from the very beginning and which can be developed as you progress through your phases of study. So, that is a long answer but I hope I covered all the territory that this interesting question brings up.
MODERATOR: Well, I think it was a long question with a lot of steps in it. So thank you, Ellen. It was very helpful.
Question 5: Am I required to defer a potential donor due to sexual contact with another donor who has been deferred because of 2 reactive anti-hepatitis B core results (no other information suggests the donor has/had hepatitis B)?
DR. MIED: If a donor has been deferred because of two repeatedly reactive anti-core results and now they have a sexual contact who is a potential donor the answer is no. You are not required to defer the potential donor as long as the potential donor's sexual contact, the deferred donor, did not have symptomatic clinical hepatitis in the past year and the deferred donor has not tested HBsAg positive that is repeatedly reactive and confirmed by neutralization within the past year. As long as those things are not true, the potential donor is acceptable and may donate.
MODERATOR: Question 6: Am I required to defer a potential donor due to sexual contact with another donor who is deferred based on a verbal report of hepatitis after age 11 (current test results, including anti-HBc are non-reactive)?
DR. MIED: This is a similar situation. If the potential donor's sexual contact, the deferred donor, has not had symptomatic clinical hepatitis in the past year and has not tested positive for HBsAg in the past year, then the potential donor is acceptable and may donate.
MODERATOR: Question 7: What is the status of the final recommendations on HIV/HCV NAT? Draft “Guidance for Industry – Nucleic Acid Testing (NAT) for HIV and HCV: Testing, Product Disposition, and Donor Deferral and Reentry” was issued in 2005.
DR. MIED: This guidance was issued as a draft in July 2005 and we are now preparing a final guidance. There were many comments to the docket by various individuals and blood organizations. All of those comments and suggestions that we received have been and are being considered. The document is currently going through final comment and sign-off within FDA and we know that this is a guidance that is wanted and is needed. So it is a high priority for FDA and it is coming as soon as possible.
MODERATOR: Question 8: The Abbott PRISM HBsAg confirmatory assay sometimes produces the result Repeat Reactive Non-Confirming. Can you indicate whether a donor whose sample produces this result, and is non-reactive for Anti-HBc, is eligible for reentry consideration, or should this result permanently defer the donor?
DR. MIED: The donor with a repeatedly reactive, non-confirming HBsAg test and a non-reactive anti-core test is eligible for re-entry consideration according to the FDA memo to blood establishments of December 2, 1987. So it goes all the way back to the conditions in that memo.
MODERATOR: Question 9: We have blood donors who were indefinitely deferred due to their HIV antigen (p24) EIA results (indeterminate results on neutralization). The 1995 & 1996 FDA documents state that a donor with an indeterminate (or untested by) neutralization could be reinstated if all donor tests (including HIV antigen) are negative after a minimum of 8 weeks. We have not performed the HIV p24 test since June 2002. Is there an approved or recommended protocol for re-entry of these donors since the HIV antigen test is no longer available at our center?
DR. MIED: That draft guidance that we just mentioned on HIV and HCV NAT testing and donor deferral, and HIV and HCV re-entry was issued in 2005 and that draft guidance included consideration for re-entry of donors deferred because of a repeatedly reactive P24 EIA with either a positive or an indeterminate neutralization test. When we finalize the draft 2005 guidance it will supersede the 1995 and 1996 FDA memoranda on P24 testing, donor deferral and re-entry. The final HIV and HCV NAT guidance will address this issue.
MODERATOR: Question 10: Our donor HIV reentry program has been on hold for years. When I called FDA several years ago, I was told that a new FDA HIV-approved reentry program for blood donors would not be available until an HIV group O test was available. What is the status of the HIV donor reentry program for donors deferred for HIV Group O?
DR. MIED: For HIV in general, I would refer to the draft HIV and HCV NAT guidance that was issued in 2005. The draft guidance included consideration for reentry of donors because of HIV NAT and serologic test results. That draft guidance, as I mentioned, is being finalized. But it is also our intention to address the HIV group O issue through a separate guidance in the near future.
MODERATOR: Our next two questions are very closely related and I will ask both questions and Ellen will respond to both of them at once.
Question 11: My hospital has decided that the blood bank should monitor storage conditions for a new tissue freezer that is located in the operating room. Do we have to change our registration with FDA because of this freezer?
Question 12: The hospital’s Tissue Typing/HLA Lab does not have a 3rd shift to receive products into the hospital on the night shift. Our Transfusion Unit is staffed 24/7 and we have been asked to log-in the products, store them and issue to the surgical team during 3rd shift? Do we have to register with FDA if we agree to do this?
DR. LAZARUS: I thought that I could lump these two questions together because they are both variations of a very common theme that is becoming more and more common in blood banking, which is that the blood bank is taking on more and more responsibilities for tissue services within a hospital, sort of following the centralized model. There are several sessions during this annual meeting addressing the tissue hospital services activities. So these questions seem to fall into that scope of activity. For the first question, where the blood bank is monitoring storage conditions for a tissue freezer in the operating room, the answer is, it depends but ‘probably not’ with regard to registering as an HCT/P establishment because of the exceptions to the regulations listed in 21 CFR 1271.15. In particular, (d) states that you are not required to comply with the requirements in this part, which is the registration rule, if you are an establishment that does not recover, screen, test, process, label, package or distribute but only receives or stores HCT/Ps solely - basically - for use within your facility. So in the case where the tissue freezer that is now fallen within the purview of the blood bank, is only being used to hold tissue for use within that hospital, then the hospital would not be required to register as an HCT/P establishment. But if there were any of those other manufacturing activities occurring within that hospital, such as processing the tissue further, or distributing that tissue to other establishments, then the hospital would be required to register as an HCT/P establishment. With regard to the second question, I think the situation is that the transfusion unit logs in tissue products and stores them and issues them to a surgical team later in a limited period of time. I think this is a very similar scenario to the first one. The hospital tissue service is receiving the HCT/P and storing it for use within that same hospital. So I think the same exception in Section 1271.15(d) would apply.
MODERATOR: Question 13: Under what circumstances are establishments that perform compatibility testing only, required to register with the FDA? If they are not, could you please provide examples of what activity would result in a requirement to be registered with the FDA? For example, would mixing red cells and FFP for an exchange transfusion or performing electronic crossmatches, require than an establishment be registered?
MS. CALLAGHAN: We will take this in several parts. Under what circumstances would an establishment have to register? If all you are performing is compatibility testing, including electronic crossmatch, you do not have to register. If you are performing any other processes listed in the exemptions under 607.65, such as pooling platelets or packing red cells you do not have to register. However, if you are irradiating or washing red cells or you are mixing red cells and FFP for exchange transfusions, you do have to register with the FDA.
MODERATOR: Question 14: Why can’t a registered facility collect/ship blood products outside of the state they are registered in?
MS. CALLAGHAN: Congress deals with control of interstate commerce and they have written the statutes requiring that blood and blood components shipped in interstate commerce be from licensed facilities.
MODERATOR: Question 15: Manually monitored refrigerators, freezers and platelet rotators seem to have more than one thermometer in them (to monitor different areas with potentially different air flows). I have been told that only one sensor will be required if I switch to electronic temperature monitoring devices. Is this true?
MS. CIARALDI: FDA does not require storage devices to have more than one internal thermometer or sensor. It is acceptable to us for you to use a single validated or qualified sensor that will provide a meaningful reading. You will determine this whether or not you need one or two when you assess the process during your implementation validation. We talked a little bit about this last night, since we could not find in our own regulations where this practice may have come from. It is possible that it is a state or other accreditation body requirement - and may supersede the FDA requirements because it is more stringent - but FDA does not require more than one internal sensor or thermometer.
MODERATOR: And that internal sensor or thermometer should be giving, as you said, a meaningful response.
MS. CIARALDI: Right.
MODERATOR: This person indicates they might have different air flows within the storage compartment.
MS. CIARALDI: Right. And that is something they need to address and they may discover that through their validation that one will not give them an accurate reading of the entire storage environment then they may have to decide, again, as a process of their validation, that they need more than one. But it is not an FDA requirement – specifically.
MODERATOR: Question 16: What are the requirements for evaluating temperature of a unit of red cells returned (unopened) to the Transfusion Service? (Single units rather than units packed in a box for the operating room). Are they evaluated against storage temperatures (1-6° C) or transportation temperatures (1-10° C)?
MS. CIARALDI: What I would like to do is just start off with a little background, a little reminder of a policy that FDA has stated in the past. When red cells are stored outside the blood bank or the transfusion service, they must still be maintained at 1-6º C because they are in a storage activity. The storage usually takes place in a remote refrigerator, although this is happening less and less, a cooler or a shipping box that is qualified to maintain blood at 1-6º C for the maximum possible storage period. So immediately before, or being in a wait state before transfusion, we consider that activity to be storage and the temperature should be 1-6º C. Now in this case here, a single unit is being issued to the floor for immediate transfusion and it does not have the benefit of being transported to the floor within a cooler or a storage container or stored on the floor in a validated or qualified refrigerator. So it is issued from the blood bank or the transfusion service with the intent that it will be administered but it is not. It lays out somewhere on a nurse's stand or receptionist desk and they decide, for some reason, not to give it and it is returned to the blood bank. In this case here, the blood, while it is waiting to be transfused, is still in a storage space and it is not maintained at the required 1-6º C. So when the blood comes back down you would be evaluating whether or not it was properly stored and that would be using the 1-6º C temperature range. Now, looking into the requirements for determining the conditions under which blood can be reissued, we have a regulation, 21 CFR 640.2(c). It also says, in addition to the requirement of being maintained at the proper storage temperature any blood that has been removed from a controlled storage environment may only be reissued if the container has remained sealed, the segments are properly attached and the blood has been inspected or observed for abnormal color, physical appearance or any indication of bacterial contamination. If any of these conditions are not met, the blood should not be transfused. We also have in our CFR the requirement to have SOPs and records for this process and the records should include evidence of the inspection and the results of that inspection.
MODERATOR: Question 17: I would like to know the requirements computer vendors are held to when developing computer crossmatch programs. Is there a list of minimal functions that the software is required to support?
MS. KOCHMAN: This is one of the areas that does cause quite a bit of confusion for users. The fact of the matter is that blood establishment computer software, whether it has a computer crossmatch program or not, is regulated under the 510(k) mechanism. All that a manufacturer is required to do is to prove that their software product is substantially equivalent to a predicate device or a software product that was either on the market prior to the medical device amendments act or has been cleared and allowed to come to the market. So, it simply has to be similar to something that is already on the market. We have not had or developed any minimal functions that the software is required to do. That is why it is incumbent upon the user, to decide what it is that the software needs to do in your facility and get a very good description of what the vendor says the software will do and see if that software is going to meet your needs. Just because a software product has been cleared for marketing does not mean it is going to meet everyone's needs in every situation. It is incumbent on you to do your homework and figure out what you need and what is available when making these decisions.
MODERATOR: So if the person who wants to use the software is looking for a vendor with software to capture a particular piece of information – to meet the facility’s predetermined specifications - the software vendor may or may not provide it, but there is no FDA requirement specifically listing fields that must be available for data entry?
MS. KOCHMAN: That is correct. I should mention one other point, and that is in some cases there are functions that would be very reasonable for a user to expect software to do, based on some of the other functions. They might draw a conclusion that if it can do these three things, it probably should be able to do this fourth thing also. In the case where that does seem to be a logical conclusion but in fact the software does not do that fourth thing, it is required that the manufacturer state that in their limitations. That while you may expect that our software can do this thing, in fact it cannot.
MODERATOR: Question 18: I work in a Transfusion Service and we perform electronic crossmatches. I am concerned by a recommendation in the draft guidance document recently published. “You should determine if the donor has clinically significant atypical RBC antibodies or a history of clinically significant atypical RBC antibodies. If the donor has atypical RBC antibodies or a history of clinically significant atypical RBC antibodies, you should not rely on a computer crossmatch.” A transfusion service does not have access to the donor’s historical information. How can I comply with this recommendation?
MS. CALLAGHAN: 21 CFR 606.121 requires that if you have an atypical antibody in a blood component that the blood or blood component be labeled with that atypical antibody. If you receive a unit of plasma in your facility and you plan on transfusing it and it does have an atypical antibody label on it, we suggest that you do a serological crossmatch not a computer crossmatch.
MODERATOR: That would be the current product and it looks like they are interpreting the guidance document to speak of a historical antibody from an earlier donation --
MS. CALLAGHAN: The blood center that is collecting the product would have the history, not the transfusion center. So they [the blood collector] should label appropriately.
DR. EPSTEIN: The point is - the situation should not arise. The collector should have appropriately labeled the unit.
MODERATOR: So if the donor has a history of clinically significant antibodies, what we are hearing is that the collecting facility should be labeling that product with that information.
Question 19: We are in the process of evaluating what processes would change if we implemented the use of a positive patient ID system for phlebotomy and for blood transfusions. Currently, we require that 2 licensed practitioners verify the information on the patient’s arm band, the unit, and the transfusion tag. If using a hand held bar code reader to verify this information, is it necessary to have the second person check?
MS. KOCHMAN: There are a couple points of interest in this question. Number one, we are aware that manufacturers of these positive patient ID systems will often state that their system reduces the amount of staff required to do these kinds of things. One of the things you need to take into consideration is whether or not there is some state requirement, or other requirement, to have a certain number of checks when performing these tests. There is, in fact, no FDA requirement on this. We are silent on the requirement for the number of people that are performing the check and we suggest that you follow the manufacturer's instructions or, if necessary, evaluate against other state or local standards.
MODERATOR: Question 20: We receive our blood components from another facility and only collect on an emergency basis. We do not currently have, or have plans to purchase, bar code readers for the patient bedside. Does the bar code rule apply to us?
MS. CALLAGHAN: “Yes” and “no.” For the units you collect under emergency, “yes” you do have to label them appropriately, including the appropriate bar codes. However, FDA has no requirement that you use bar code readers at the patient's bedside. So you do not have to purchase them because we are telling you to.
MODERATOR: We had several related questions that we tried to roll into one set of examples.
Question 21: I work in a transfusion service that does pooling, aliquotting, and washing of components. I send components to the medical school next door when they need to be irradiated. Please explain which facility(ies) should be identified in the machine readable information on the following products: pooled platelets or cryoprecipitate from one or more suppliers; an aliquot of irradiated red cells; washed, deglyced red cells; an irradiated apheresis platelet component. On occasion I am asked to send one of these products to another hospital in my city. Does that change any of the responses? Please explain.
MS. CALLAGHAN: First of all, I would like to, sort of, go back to the other question I answered about “do you have to register.” If you are washing cells or irradiating, you have to register with the FDA. If you send the units to a medical center or medical school to be irradiated, they are a contract manufacturer so their information does not have to be on the label, your identifying information does. Even if you send it to another hospital, only your information has to be on there. However, you do have to keep records so that the traceability of all the processes being performed on your components can be traced.
MODERATOR: It looks like some of the situations were set up such that the product has been moved into a bag different from the collection bag. Would the original blood collector still be identified on this bag, or is it only the ID of the facility that did the pooling or the washing?
MS. CALLAGHAN: Yes. But remember, you have to keep records so that everything can be tracked.
MS. MODERATOR: Question 22: Regarding FDA review of ISBT 128 label submissions – I have heard that it takes 6-months for the review – is this a typical timeline? Can the review time be shortened?
MR. ZEMANN: A submission of ISBT labels are considered, under 21 CFR 601.12 to be a major change to your biologic license. Our maximum internal review time, allowed for label review when submitted as a prior approval supplement is six months. Label reviews normally take less than six months. However, we strongly recommend you do not wait until the last minute to submit your labels.
MS. CALLAGHAN: Yes, please get them in before April 15th.
MODERATOR: Concerning “can the review time be shortened” question, careful attention to putting the submission together is important. We have recently posted on the AABB Web site a list of ISBT labels that would be required to be submitted. The idea is that additional labels would not be required if you already have your CodaBar labels approved. So if you look on the AABB Web site there is a listing of ISBT labels that would be required, more than that are not required. A careful submission preparation, would be helpful is what we have been hearing as we have asked some questions and heard experiences back from some of you.
Question 23: I have heard that I can submit a “press proof” of my ISBT 128 labels for review – rather than a fully converted, top coated, die cut adhesive label. Is this true? Can I do this for any label besides the door identification number (DIN)? Is there additional follow through required when I receive my final labels?
MR. ZEMANN: We are currently scanning all ISBT labels that are submitted to CBER. You may submit proofs, but please verify before submitting that the label bar codes are all scanable.
MODERATOR: Is there an additional requirement when this facility then gets their final label from the vendor?
MR. ZEMANN: You do not need to submit final labels as long as you verify that your final printed label is exactly the same as the approved label you originally submitted.
MODERATOR: Can a press proof be submitted for labels other than the Donor Identification Number (DIN)?
MR. ZEMANN: Yes that is fine.
MODERATOR: Question 24: We frequently have triple plateletpheresis products – A, B, and C – in our inventory (same donor unit number but different product codes – A, B, C). A & B are each split into 4 portions for pediatric transfusion, and irradiated. Will we have to submit ISBT 128 product labels for review that reflect divided A1, A2, A3, A4, B1, B2, B3, B4 or will we just need divided, irradiated 1, 2, 3, 4.
MR. ZEMANN: You only need to submit one label example of one of the divided unit labels and one example of an irradiated blood label. I also want to note, that if you only submit partial labels and not the full face 4 x 4 label, you must submit at least one example of each of the four label quadrants for review, that is where we see all the caution statements and all.
MODERATOR: Okay. So one divided non-irradiated product and one divided irradiated product is what you would want to see in this case?
MR. ZEMANN: Right.
MODERATOR: Question 25: The Donor Identification Number (DIN) on product labels has an easy to read format with spaces after the facility ID and after the year. Also, in most examples the final 6 characters have a larger font. I asked my LIS vendor for a similar format on the crossmatch form and compatibility tag because the Nursing units do not have barcode scan capabilities and trying to compare 13 characters in an unbroken line is going to be prone to error. The vendor replied the FDA does not allow them to change the format from the 13 unbroken characters. Is this correct?
MR. ZEMANN: The donor identification number (DIN), should have the same print size and font. Spaces between numbers are allowed, only as noted on the label illustration as noted on page 43 of the United States Industry Consensus Standard for the uniform labeling of blood and blood components using ISBT version 2. You can have spaces but it should be as it is in the illustration.
MODERATOR: Question 26: When the platelet count for an apheresis platelet unit does not meet the 3.0 x 10(11) requirement, can the unit be labeled to be the equivalent of a lesser number of random units? For example, if the count is equal to a 5 pack or 4 pack, can the unit be labeled as such with notification to the end user of this?
MS. CALLAGHAN: If your unit does not contain the appropriate amount, number of platelets, you must label the unit with the actual platelet count.
MODERATOR: So not to generalize it as a four pack or a five pack but the actual count.
MS. CALLAGHAN: Right. The actual count.
MODERATOR: Question 27: If I perform viral marker testing on AUTO HPC (HPC-A) products that are collected at my facility, but do not ask health history screening questions, do I need to apply the “NOT EVALUTED FOR INFECTIOUS SUBSTANCES” label specified in 21 CFR 1271.90(b)(2)? How should we label the Auto HPC if we do not perform health history screen or perform viral marker testing?
DR. LAZARUS: As you know, the donor eligibility determination does not have to be performed on autologous HCT/Ps, but we are aware that establishments do perform testing and some also perform screening. So in the case where you are only performing the viral marker testing on your autologous products, you still have to affix the statement “not evaluated for infectious substances.” You would only not have to apply that statement if you did both screening and testing in accordance with the donor eligibility rule. So the second part of this question, is the part that I already addressed. How should we label the autologous HPCs if we do not perform health history screening or perform viral marker testing? You would label the autologous HPCs in accordance with 21 CFR 1271.90(b), exceptions from requirements for donor eligibility determination and also labeling information. In that case, you affix the statement “not evaluated for infectious substances” and “for autologous use only.”
MODERATOR: Question 28: An FDA rule states that “A total serum or plasma protein determination and a quantitative determination of IgG and IgM or serum protein electrophoresis must be determined at 4-month intervals for donors undergoing large-volume plasma collection, if the total annual volume of plasma collected exceeds 12 liters (14.4 L for donors weighing more than 175 pounds) or if the donor is a frequent plasma donor.” Does this apply to plateletpheresis donations as well?
MS. CALLAGHAN: This probably does not apply to plateletpheresis collections because the donor does not undergo more than twenty-four collections a year and should not reach the 12 liter cutoff. However, if you are collecting plasma and you are collecting more than twelve liters (more than 14.4 if the donor weighs more than 175 pounds), not only will this four month SPE requirement kick in but you also have to do total proteins at every donation and you have to do an annual physical. So it is a little more complicated then just a test every few months.
MODERATOR: Question 29: As I understand it, regulations limit donor red cell loss (tracked on a rolling 12 month calendar) to the amount that would be lost if a person donated whole blood every 8 weeks (21 CFR 640.3(b)). However, calculating this loss is quite complex – 450 and 500 ml collection bags are used, 7 donations can be made in a 12 month cycle, double red cell donations may occur, there is red cell loss in the apheresis process for platelet and plasma donations, and samples for required tests are collected. What is the maximal red cell loss in milliliters that can be collected from a donor in a rolling 12 month calendar and still be compliant with 21 CFR 640.3(b)?
MS. CIARALDI: 21 CFR 640.3(b) states that a person may not donate whole blood more than once in every eight weeks. We interpret this to mean that a donor should not lose more red cells by any means than what is allowed for whole blood donations that would occur every eight weeks. As the question states, this is a very complex issue and we certainly agree with that assessment. FDA does not have a recommended maximum value for an acceptable red cell loss in a rolling or a stable twelve month period. If you decide to set such a value, and make that calculation, you should base that calculation on the collection practices at your establishment. We would recommend that you include in your calculation the absolute red cell loss from any and all donations, sample tubes, red cell loss to kits, incomplete procedures and the process of rinse-back or no rinse-back. As I mentioned, we agree with you this is a very complex issue. This is a case where we urge you to contact your CSO and talk about it with them to get more information.
MODERATOR: Question 30: Can a hospital that currently uses a ‘bar code drug dispense’ system use the same pharmacy system for positive patient identification prior to infusing blood components? At the bedside (after issue from the lab) the nursing staff would scan the Group and Type from the blood component and then scan the patient armband and get an “OK” or “Match” from the bar code reader. Would the computer system be subject to the same regulations as blood establishment computer software?
MS. KOCHMAN: In order to answer this question we had to make some assumptions. The question states that it is a bar code drug dispense system, so we have to assume that that is the intended use the manufacturer has affixed to it. If that is the case, “yes”, a hospital can make a decision to employ one of these pharmacy systems in their blood bank if they believe that they can adapt it for that use. They take on the burden of validating the new intended use for the device and it could be quite a bit of evaluation that they need to do. Generally, a pharmacy system would not have built into it the feature of group and type and getting an “OK” when you scan a blood bag and compare it to the wrist band. As far as would the software system be subject to the same regulations as blood establishment computer software, that depends on who is making the decision or making the claim that this pharmacy system can be used in a blood transfusion environment. If the manufacturer of the software has made that claim, even if it is a verbal claim that is an intended use that they are assigning to their device, they need to submit a 510(K) for it. If the hospital, on the other hand, is choosing to apply this intended use based on their validation studies, and they are presumably using it in-house only, there would be no 510(K) required.
MODERATOR: As long as it is an in-house product.
MS. KOCHMAN: Right.
MODERATOR: Question 31: Our facility wants to use an electronic form of the transfusion tag and believe the component blood type and expiration date should be carried through to the patient’s medical record. This information is commonly found within the laboratory blood bank computer system, but is not readily available on the patient’s electronic medical record. We have been told by our software vendor that this is not required. Is this true?
MS. KOCHMAN: It is true. There is no FDA or CMS requirement for that record to become part of the patient electronic medical record.
MODERATOR: Question 32: Are medical device software manufacturers held to a higher level of scrutiny than independent consultants when it comes to writing customized reports for end-users of the software? For example, if a blood center wants a custom report (based on data extracted from the BECS) and an independent consultant can develop the report, is it expected that the consultants should follow Design Controls? Would the consultant be subject to FDA inspection? Does the intended use of the report affect the answer?
MS. KOCHMAN: There is not enough information about how the consultant is preparing these customized reports. So with that in mind, we would prefer to just speak with whoever has this question directly. You are welcome to see me after the meeting or e-mail me at some point in time. We are willing to get you the answer you need but we need to understand what you are asking for.
MODERATOR: Question 33: When do you think the storage life for apheresis platelets will be extended to 7 days? What about the 5 day pre-pooled platelet component?
DR. VOSTAL: So, seven day apheresis platelets are actually available currently, as long as you are willing to use a specific manufacturer’s bag and willing to participate in the Passport study that is to validate the bacterial detection device that is associated with seven day platelets. For the five day pre-pooled platelet component – that is available currently. If the question was addressing whether we are going to have a seven day pre-pooled component, that will depend on when we get an application from the manufacturer to validate the storage bag and also a study to validate the bacterial detection device.
MODERATOR: Question 34: BPD reporting currently requires firms to submit reports of false bacterial culture results from testing performed on plateletpheresis donations. Since bacterial detection (cultures) is not an FDA requirement, why are the reports required?
MS. O’CALLAHAN: The report is required because the product has been distributed at the time you obtained the positive test result. That information is something that may affect the safety, purity or potency of the product, regardless of whether you determine in the end that it was a false positive. If you have that positive test and the product has been distributed, it is reportable.
Additional note from Ms. O’Callahan: I wanted to let you know that this morning we posted on our Web site, an updated list of deviation codes for fiscal year 2008. There are two statements to which I wanted to draw your attention. In particular, I wanted to bring your attention to one of the statements that is in front of the list of the deviation codes –there is an excerpt here that says, "Following review by our blood safety team, CBER determined that BPD reports are not required for distributed products collected from a donor who either had a history of cancer or was diagnosed with cancer after donating. We found no evidence that the safety, purity or potency of these products may be affected." So because of that, we deleted about six or eight codes that specifically refer to the donors having a history of cancer or post-donation diagnosis of cancer. You no longer have to report those. Another statement that I wanted to draw your attention to, specific to transfusion services since we have had some issues with some transfusion services selecting the appropriate codes, we included a statement that says that if you are a transfusion service only, the deviation codes you should select from are component preparation, routine testing, labeling, quality control and distribution. So if you are a transfusion service trying to use a post donation code or a donor screening code or donor deferral code you are probably not the facility that needs to report that. I just wanted to point those two items out and these codes are effective for any reports that have been submitted on or after October 1st.
MODERATOR: Question 35: The College of American Pathologists allows for Fresh Frozen Plasma or Plasma Frozen within 24 Hours After Phlebotomy, that is thawed at 30-37°C and maintained at 1-6°C, to be labeled as “Thawed Plasma” and be given an expiration date of 5 days from the date of thawing. Can a license be obtained from FDA for Thawed Plasma?
DR. VOSTAL: So as the question correctly points out, this is not a licensed product. We would be happy to review a license application but it should be accompanied with data and the data would depend on the indication for the product.
MODERATOR: Question 36: Is it permissible to convert Recovered Plasma to Plasma Frozen within 24 hours After Phlebotomy, so long as the original product was frozen within the 24 hours? We are attempting to use male only plasma for transfusion (as mitigation for TRALI) and on occasion male plasma is incorrectly labeled as Recovered Plasma.
MS. CALLAGHAN: Once you have labeled a product as recovered plasma for further manufacture, it is not permissible to re-label it as plasma for transfusion. That said, if a problem does arise and you have incorrectly labeled units, I suggest you call your CSO to discuss this because each situation will be looked at on a case-by-case basis.
MODERATOR: Question 37: In 2002 FDA verified that it is permissible to convert whole blood-derived FFP to Recovered Plasma at any time during the storage period or at outdate. Is this still allowed?
MS. CALLAGHAN: This is an easy one, yes. You may convert whole blood derived FFP to recovered plasma at any time.
MODERATOR: Whole blood derived FFP?
MS. CALLAGHAN: Yes.
MODERATOR: Question 38: We use NIST traceable certified thermometers for our blood product storage units that have a manufacturer’s lifetime guarantee for the calibration. We wanted to check calibration annually, but found that removing the thermometer from the packaging to perform the check would void the guarantee. Can we accept such a guarantee in place of checking the calibration? Or do we still need to check the calibration, and if so how often?
MS. CIARALDI: The simple answer is “no.” It does not replace any required calibration, standardization or quality control. If a blood establishment feels it is a conflict or is a burden with their thermometer setup, they are allowed, under 21 CFR 641.20 to submit an alternative procedure to us - their request to deviate from the regulations. Include in that submission, if a submission is to be made, the rationale for deviating from the regulations and all the information necessary to support your request. This would be a prior approval submission.
MODERATOR: Question 39: Do wireless central temperature monitoring systems require 510(k) clearance?
MS. KOCHMAN: Temperature monitoring systems have consistently been reviewed in the same category as blood bank refrigerators and freezers, as accessories to those devices. Since those devices are now exempt from 510(K), the temperature monitoring systems are also exempt from 510(K). I would caution, however, that anyone who is contemplating implementing a wireless system make sure you do all the appropriate validation of the wireless environment to look for electromagnetic compatibility and electromagnetic interference in the environment that it is being installed.
MODERATOR: Question 40: 2% chlorhexidine gluconate/ 70% isopropyl alcohol is often used as an alternative prep for donors that are sensitive to Iodine. Can a firm use this product on all donors as a primary method of arm preparation?
MS. CALLAGHAN: “Yes,” you can. Howsoever, as many of you might have heard earlier this week, there is some emerging infectious disease data that not all arm prep methods are equal. So you should use whatever is the best in your facility. Keep tune to whatever is going on and whatever information is coming out so that you are using the most appropriate method when collecting blood.
MODERATOR: Question 41: FDA states in the October 1996 Guide to Inspections of Infectious Disease Marker Testing Facilities: Quality Control of each lot of incoming reagents should be performed as described in the firms SOP which should follow the manufacturer’s insert. Each shipment (even if the same lot number has been sent and previously tested) of test kits should be checked with positive and negative control before use with donor or patient samples to ensure that the reagents perform as expected. We have employed a reagent qualification process that meets the requirements stated above (running a batch containing a positive and negative control before use with donor samples), but have not identified a single unacceptable shipment in the past 10 years. We see no value in performing this qualification, and wonder if FDA would reconsider this requirement?
MS. KOCHMAN: Well, I am not usually the one answering questions about infectious disease testing, but the response to this is actually a much broader issue than just infectious disease testing. You need to remember or understand why it is that FDA believes that it is appropriate to do QC on all of your incoming reagents, particularly biological reagents. The product has left the control of the reagent manufacturer. It is now in the hands of shippers who may not handle it appropriately. It may sit somewhere for extended periods of time. It may be subject to extremes of environmental conditions that may affect the way that the product performs. So we continue to believe that it is appropriate and necessary to do an incoming quality control check on these products, to make sure that shipping has not affected it in any way. We are becoming more and more aware of counterfeit products available in the marketplace and we worry about tampering of product in the marketplace. So it is something we think, while we realize and hope that the results will generally reflect that the product is fine, the number of cases where the results indicate that the product should not be used will be very low. We still believe it is valuable and it is something that needs to be done.
MODERATOR: And so this hinges on the fact that the product is out of the control of the manufacturers.
MS. KOCHMAN: Yes.
MODERATOR: We now have a long list of miscellaneous questions.
Question 42: Does the FDA maintain a comprehensive list of drugs and solutions that can be added to blood or components during the infusion? If so, is the list publicly available?
DR. HOLNESS: The answer to the question is “yes.” CBER's office training and manufacturer's assistance, OCTMA, maintains a short list. If you contact them they will give it to you.
MODERATOR: Question 43: Is it permissible to post the current Circular of Information (COI) on a Web site for access by customers in lieu of including one in each shipment based on the wording noted in 21 CFR 606.122? “An instruction circular shall be available for distribution if the product is available for transfusion.” NOTE: Each CBER Guidance document includes the statement “You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations.
MS. CALLAGHAN: Unfortunately, you probably know the answer to this already. CFR 606.122 requires that you have the Circular available for distribution when you ship products. So yes, you must. If you look at your note appended to the question, you are talking about guidances and guidances are not binding, however, regulations are. So yes, you must have the Circular available.
MODERATOR: Question 44: When dealing with potential donors who do not speak English, what is considered acceptable to obtain confidential answers to health history questions? Our facility does not have a bilingual employee.
MS. CIARALDI: FDA does not prohibit donation from potential donors who do not speak English. That said, the way that we have reviewed this or addressed this issue is through our review of SOPs for a licensed blood establishment. What I will do is share with you the kinds of things that we look for in the SOP and the kinds of things we have seen. We evaluate the SOPs to see if they have a mechanism to insure that the donor comprehends the questions and answers it truthfully and completely. And that the donor will be in an environment that will allow him or her to answer freely. So those are the two main things that we try to evaluate based on the SOP. What we have seen in the SOP is that maintaining this general objective has required the blood centers to obtain a translator. In some cases, it is an employee within the whole facility, not necessarily the blood bank but within the whole facility, who is bilingual who understands the terminology and can share that with the donor. In some rarer cases, the translator has been obtained from an outside translating service. One of the things that we do see consistently within the SOPs is that they elect not to use a family member or a person who is known to the donor because of the concern that in that environment the donor may not share that very sensitive information. So in an effort to try to maintain that private environment, to be screened and to get truthful and complete answers, they provide translators that are separate from the inner circle of the donor.
MODERATOR: Question 45: When a request for exchange transfusion is received, is it acceptable for the laboratory to issue separately the packed cells and the frozen plasma to the nursing unit and have them reconstitute the blood in the ward before transfusing the product? The laboratory would calculate the volume of the plasma needed in order to obtain a 50% hematocrit and would give this information to nursing, and would provide the necessary training for the nursing staff.
MS. CALLAGHAN: If you are performing reconstitution, you have to register. Regardless of where the reconstitution is taking place, it is still being reconstituted and yes, you would have to register and you would have to make sure it is being done appropriately.
MODERATOR: So it sounds like this facility could choose to do that and this facility would still need to be registered.
MS. CALLAGHAN: That is correct. The blood bank does not have to be confined to one little box in the basement where we usually are.
MODERATOR: Question 46: What are the regulatory implications for an establishment that provides blood products, storage equipment (and monitors the equipment) to an outpatient surgical facility that is not a part of our hospital system?
MS. CALLAGHAN: All of the equipment and the storage of the products are subject to all the regulations that we require if they were in the transfusion service. So we must make sure that all the appropriate GMPs and temperatures, etc., are being taken care of.
MODERATOR: So the responsibilities are the same as if it was in their own establishment.
Question 47: My facility identifies particular components that can not be manufactured if the draw time for the whole blood collection exceeds a certain limit. I can not find an FDA regulation to support this. Is there such a reference?
MS. CALLAGHAN: Exactly. You cannot find a reference because we really do not have one. That being said, maybe considering this question we should look into this topic and come up with some sort of a reference of standard. But right now there is no FDA requirement.
MODERATOR: There are some good industry standards already in practice and perhaps FDA would not need to address this. The AABB Technical Manual addresses the issue.
Question 48: What are the requirements for tracking lot number, expiration date and manufacturer of the blood administration sets that we use? (I am reviewing the processes in place at my transfusion service that would be relevant to a recall notice we might receive from a supplier.)
MS. CALLAGHAN: 21 CFR 606.160(a)(2) says that you must have records of all the reagents and all the supplies and it must be available so that they can be reviewed in case we need them. So “yes,” you do have to record them all.
MODERATOR: And you can not recall them without a record.
MS. CALLAGHAN: Unless you have a good memory.
MS. MODERATOR: Question 49: I work in a 250-bed hospital. We have a small transfusion service where we perform crossmatches and antibody identification. We also pool platelets and cryo and thaw FFP. We have no donor service. On occasion, we perform a therapeutic phlebotomy and discard the blood. We are not inspected by FDA. Do we need to follow CFR regulations and if so, what parts?
MS. CALLAGHAN: Yes, all the parts of the CFR that are applicable to good manufacturing practices as well as transfusion, storage and records, etc. There are a lot of them but yes, you are required to follow many of the GMP requirements.
MODERATOR: Question 50: We are about to go live on a new computer system and I would like to go “paperless.” Currently we have a hard copy of the order from the HIS and we attach the “tail” of the Typenex band to this hard copy. With the new system we will not have the hard copy of the order – is it OK to affix the tail of the Typenex band to the patient specimen for storage?
MS. KOCHMAN: There are a couple of parts to this. Number one, you need to make sure that by attaching the tail of the Typenex to the specimen tube you are not putting yourself out of compliance or you are remaining in compliance with 606.151 regarding sample labeling. The other point is, surely there are directions for use of the Typenex and what to do with the various stickers and the tail. I believe that it actually does recommend that the tail be attached to the specimen bag. So you need to double check with either the package insert or with the supplier of the Typenex tags.
MODERATOR: Question 51: Concerning manufacturing and distribution of pre-pooled (e.g. 5 units), frozen cryoprecipitate – can saline be added prior to freezing?
MS. CALLAGHAN: This is another easy one. Number 640.54(b)(2) specifically says that diluent cannot be added to cryo prior to freezing.
MODERATOR: So they can be pre-pooled and frozen but without the additional saline.
MS. CALLAGHAN: Yes, but without the saline addition.
MODERATOR: Question 52: My facility uses the Olympus PK 7200 and I am concerned about the potential for not having a validated source of Anti-D reagent if the new Olympus monoclonal reagent is not cleared for marketing prior to exhaustion of the current supply of Immucor polyclonal reagent. We have another reagent that we want to validate for use on the Olympus. How do we update our files with FDA when we make this change?
MS. KOCHMAN: Such a change would be a prior approval supplement and I would like to point out that it would also, therefore, require a compliance check before we can approve the change. It is something that has to be submitted because you would not be following manufacturer's directions for use for this reagent. We are acutely aware of the situation; at least we believe we have a good understanding of the situation. We are still very hopeful that a replacement reagent will be available before the current supply is exhausted. If you believe your supply is due to run out within the next few months, I would appreciate having that information relayed to us so that we can get a handle on the state of the inventory right now. I also would mention that FDA did meet with the major blood industry representatives to discuss this problem and worked with Olympus in developing some plans that would allow the reagent to last a bit longer on the shelves. Anyone who is an Olympus PK 7200 customer should have received a letter describing those alternatives that they can use. We are very hopeful that those alternatives will alleviate any shortage.
MODERATOR: Thank you to the panelists for entertaining all of our questions. Thank you to the audience for the questions you submitted to us.