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2010 Ask the FDA and CLIA Transcript

Ask the FDA and CMS/CLIA
October 11, 2010
AABB 2010 Annual Meeting
Baltimore, Maryland



  • Jay Epstein - Director, Office of Blood Research & Review, CBER
  • Ellen Lazarus - Director, Division of Human Tissues in the Office of Cells, Tissue and Gene Therapy, CBER
  • Hira Nakhasi - Director, Division of Emerging and Transfusion Transmitted Diseases, Office of Blood Research & Review, CBER
  • Paul Mied - Deputy Director, Division of Emerging and Transfusion Transmitted Diseases, Office of Blood Research & Review, CBER
  • Judy 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


  • Penelope Meyers - Division of Laboratory Services, Survey & Certification Group, Center for Medicaid & State Operations at CMS


  • M. Allene Carr-Greer, Director, Regulatory Affairs, AABB

MODERATOR: Welcome to Ask the FDA and CLIA. My name is Allene Carr-Greer and I am the Director of Regulatory Affairs for AABB. We provide this session each year at our annual meeting. It is a success each year because of the questions that are submitted to the panel by members of AABB, and because our panelists spend much of the past twenty-four hours poring over the questions, referencing regulations and guidance documents, and of course using all the knowledge they already have, to provide answers to the questions.

Question 1: The BPAC met November 2009 and agreed that, based on a risk-benefit assessment presented by FDA, it would be acceptable to allow blood collection, without deferral, from U.S. residents who have visited Quintana Roo. If my blood center submits a variance to FDA to accept blood donors who have visited Quintana Roo will FDA grant the variance prior to issuing a guidance document?

DR. NAKHASI: The policy for acceptance of donors from U.S. residents who have visited Quintana Roo, Mexico is still evolving. A blood center can submit a request for a variance; however, it is not clear at this time whether the FDA would approve such a variance, until we can at least publish a draft guidance on malaria. The short answer is that the policy is still evolving for accepting the donors from Quintana Roo. Blood centers can submit a variance, but most probably we will have to look at it and we may not be able to grant the variance until we can publish the guidance.

MODERATOR:, we wait for a guidance document.


Question 2: An auto HPC-A collected, processed and cryopreserved at facility #1 was transferred to facility #2 (with a positive culture) for infusion. All required and appropriate consents and approvals were in place. The recipient was given antibiotics, no adverse reaction was noted and engraftment occurred within expected range. Within 45 days post transplant of auto cells with known positive culture, the transplant facility (facility #2) submitted a BPD report to the FDA assuming 1271.350(b)(2) applied. The response from FDA was to reject the submitted BPD and said the manufacturing facility (not the transplant facility) should report it to the FDA. This came as a surprise to the transplant facility as although they did not contract facility #1 to manufacture the product, the transplant facility did contract with them to ship the HCT/P product. Please clarify the intent of 1271.350(b).

MS. O'CALLAGHAN: 1271.350(b) requires that you investigate all HCT/P deviations related to a distributed HCT/P for which you performed a manufacturing step and report such deviations related to the core GTPs if the HCT/P deivation occurred in your facility or in a facility that performed a manufacturing step for you under your contract. In this case, facility number 1 distributed a product in which there was a deviation, which was the positive culture, in a manufacturing step that facility number 1 performed. Therefore, facility number 1 is the one responsible for reporting. The statement about facility 2 contracted with facility 1 to ship the product is not considered manufacturing under contract. It is just basically where we have a contract with your facility to receive products from you. That is not part of manufacturing, per se. So facility 1 in this case would be the ones responsible for reporting.

Question 3: For 361 products, is it required to do microbial testing on each lot of DMSO? If yes, please cite what FDA regulation applies. Our facility obtains a certificate of analysis on each lot to verify sterility from the manufacturer and our facility then does microbial testing on each product after DMSO was added. What about for 351 products, does FDA require testing if each lot of DMSO prior to use? If yes, which regulation applies?

DR. LAZARUS: The answer is that, in some cases, it may be necessary for the HTC/P manufacturer to perform microbial testing on the cryoprotectant, but not always. I am going to walk you through the relevant regulations. I think it will be helpful. Starting with the so-called 361 HCT/Ps, those that are regulated solely under the tissue rules in 21 CFR part 1271, there is a regulation 1271.210 that addresses supplies and reagents, and in 1271.210(b), "Reagents used in processing and preservation of HCT/Ps must be sterile where appropriate." I think we would all agree that the cryoprotectant has to be sterile. Then I would look at 1271.210(a) which addresses verification of supplies and reagents saying, you must not use supplies and reagents until they have been verified to meet specifications to prevent introduction…etc. of communicable diseases. Verification may be accomplished by the establishment that uses the reagent or by the vendor. So in that case, perhaps, the certificate of analysis would be sufficient. However, for the so-called 351 HCT/Ps, the current good manufacturing practices would apply because those are regulated as human cells and tissues and also as biological products; and in this case, regarding the regulations for reagents, the CGMPs are more specific and would supersede the good tissue practices provisions that I just cited. So we would look at, first of all, the definition of a component in 21 CFR 210.3 which defines component as "any ingredient used in the manufacture of a drug product," and then 211.80 in the GMPs lists general requirements for control of components, and containers and closures, which is not relevant for this question; and then 211.84 addresses testing and approval or rejection of components, containers and closures.

Delving a little deeper into that regulation, which I think answers the question, 211.84(d) describes how component samples shall be tested and examined, with 211.84(d)(3) explaining that in lieu of testing by the product manufacturer, a certificate of testing may be accepted from the supplier, provided that at least a visual identification is conducted and provided that the manufacturer establishes the reliability of the component supplier test results through appropriate validation at appropriate intervals. So I think it does make a difference whether you are manufacturing a 361 or a 351 HCT/P regarding the types of verification or validation of the cryoprotectant you would follow.

MODERATOR: Thank you, Ellen, and thank you for providing the specific regulations.

Question 4: We perform all routine testing using gel technology. We also perform electronic crossmatches. For patients in whom clinically significant antibodies have been identified, is it sufficient to perform only a gel antiglobulin crossmatch? Does this satisfy the CLIA requirement to perform a test to detect ABO incompatibility?

MS. MEYERS: For this question, before I start, I would like to just make the comment that the answers that I will be giving to the questions today are based on the CLIA regulations. However, I would like to remind the audience that many laboratories choose to obtain their CLIA certification through a CMS-approved accreditation organization, of which there are six. One of which is AABB. These laboratories must follow all the requirements of their chosen accreditation organization which may be more stringent than the CLIA requirements.

Now back to the question. Actually, these CLIA requirements for crossmatching are based on the FDA requirements for crossmatching, and FDA and CMS have collaborated in preparing the answer to this question. The simple answer is that the IgG gel card does not fulfill the requirement to demonstrate ABO incompatibility. There are two issues involved here. First, the labeling clearly indicates that the IgG gel card is for direct and indirect antiglobulin tests. In other words, detection of cell-bound IgG antibodies. While the limitation section of the package insert states that some IgM antibodies may react, this limitation should not be interpreted to mean that the card is capable of detecting all IgM antibodies, particularly ABO antibodies. Secondly, the IgG gel card is a low ionic test system and there have been reports that ABO incompatibilities, due to IgM antibodies, can be missed when the antibodies are weak and the test is low ionic strength. While we acknowledge that there is continuing debate on this topic, but with the knowledge of these reports and in the absence of data from the reagent manufacturer to support the use of a low ionic strength system for detection of ABO incompatibility due to IgM antibodies, we believe it is not appropriate for users to omit some kind of test to detect these incompatibilities. And for eligible patients, an electronic crossmatch would fulfill the requirements. An immediate spin crossmatch, of course, is an acceptable method for all patients.

MODERATOR: Thank you, Penny. Can I ask, because I could not hear everything that you just said, but did you respond to the part about sufficient to perform only the gel antiglobulin crossmatch, that first part?

MS. MEYERS: No, it is not sufficient to perform only the gel antiglobulin crossmatch because that does not fulfill the requirement to detect ABO incompatibilities.

Question 5: For annual competency assessment, we distributed a written test to all our technologists. If they passed the test, they were considered competent. Does this meet the CLIA requirement for assessment of competency?

MS. MEYERS: No. The written test does not fully meet the requirement for competency assessment. 42 CFR 493.1451(B)(8) lists six elements that must be incorporated into the evaluation of competency of testing personnel. These include direct observation of routine patient test performance, monitoring the recording and reporting of test results, review of intermediate test results or worksheets, QC records, proficiency testing records, preventive maintenance records, direct observation of performance of instrument maintenance and function checks, assessment of test performance through previously tested specimens and an assessment of problem solving skills. Obviously, although a written test could assess some of these elements, it is not adequate to assess all six elements which must be incorporated into the assessment of competency for all testing personnel in order to comply with the CLIA regulations.

I would also like to note here that there are many blood banking activities that are not subject to CLIA regulations, which are for laboratory testing, so activities like operating an apheresis machine and irradiating blood components or checking a prospective donor's blood pressure do not fall under CLIA. While competency assessment for these activities is important and may be required by other regulatory or accreditation bodies, they do not fulfill the CLIA requirement for competency assessment of laboratory personnel.

Question 6: The medical director of our blood bank is not the laboratory director listed on our CLIA certificate. Will we be compliant with CLIA if the medical director reviews and signs off on the blood bank's SOPs?

MS. MEYERS: No, you will not be compliant. 42 CFR 493.1251(d) states, "Procedures and changes in procedures must be approved, signed and dated by the current laboratory director before use," and that means the laboratory director whose name is on the CLIA certificate. Now thereafter, any other reviews that are required by laboratory SOP, such as in an annual review, may be performed by other individuals according to the laboratory's policy.

MODERATOR: If the change in laboratory director happens in between issuance of certificates, is that handled just by a notification through the CLIA process (the assessment process)?

MS. MEYERS: If a laboratory director changes, then if it is an accredited lab, then the lab must notify the accreditation organization. If it is a laboratory that has a CLIA certificate of compliance, the laboratory would notify the state agency so that the change could be made in the CLIA database.

MODERATOR: Thank you. So, the banks just need to keep the certificates updated.

MS. MEYERS: Right.

Question 7: We are a busy transfusion service with 5 technologists performing blood bank testing on the day shift. Each technologist has his or her own rack of reagents. Quality control requirements under 21 CFR 606.65(c) state, "Representative samples of each lot of the following reagents or solutions shall be tested on a regularly scheduled basis by methods described in the Standard Operation Procedures Manual to determine their capacity to perform as required…" Are CLIA regulations consistent with the 21 CFR? That is, to be in compliance with CLIA regulations, must we perform QC on each rack of reagents daily, or can QC be rotated among the racks?

MS. MEYERS: Under CLIA the laboratory director is responsible for developing and implementing adequate quality control procedures to ensure the accuracy of testing performed in the laboratory. For laboratories using multiple racks of reagent typing sera and cells, laboratories must perform quality control on a representative sample of each lot of reagent in use on each day of testing. In addition, quality control needs to be performed on each new lot of reagent when first used. Also note that at a minimum, the manufacturers' recommendations for QC must always be followed.

Question 8: FDA recently posted updates to the list of deviation codes used to describe a reportable event related to blood and blood components. Could you please explain the changes to the deviation codes for tattoos, body piercing, needle sticks, and exposure to blood and body fluids?

MS. O'CALLAGHAN: In an effort to streamline both the recording process and our review process, we decided to combine events that had the same deferral criteria and the same risk; and that was the tattoos and piercings in particular. We also combined the other blood and body fluid exposure risks into another separate code. So there is one code for tattoos and piercings and then another code for any other blood exposure that would include things like occupational exposure, human or animal bites or accidental needle sticks, branding, scarification. Any of those would go under the other code. If it is a tattoo and something else, it goes under the tattoo and piercing code. We did this so that we can eliminate a lot of the back and forth that we had with some of the firms. Sometimes it was just a clerical mistake of entering the wrong code, but we would change the deviation code and then send the e-mail back to the reporter to let them know that we made the correction. So by using two codes instead of a total of five different codes, we hope to streamline that process.

This is also in an effort to look at not only the codes themselves, but look at the events that we have had reported in the past. Over the next couple years or so we are going to really start focusing on streamlining that whole process, so this is probably not going to be the last change we make. I also wanted to mention that when you are reporting donor screening, donor deferral or failure to quarantine events associated with donors who receive tattoos or piercings, if you know the date of the tattoo or piercing, please include that in the report. If you do not know, if there is no way you would know that, maybe there is a discrepancy in the information, so you do not know for sure when the donor actually had the tattoo, state that in the report as well. That is another area in which we are sending a lot of e-mails to get clarification on the reports. So that would be helpful to include that.

Question 9: 21 CFR 1271.15 allows for exemptions and alternative procedures to the requirements in Part C (Donor Eligibility) and Part D (Current Good Tissue Practices) of 21 Part 1271. Additional information about the process is found at Will OCTGT maintain a public listing of exemptions and alternative procedures that are granted, similar to the one maintained by OBRR?

DR. LAZARUS: No. There is not a public listing of exemptions and alternative procedures for HCT/Ps on the FDA website, and I can not speculate about what we might do in the future about that.

MODERATOR: I guess the person was wondering if any have been granted and the fact that there is no listing should not be taken as an indication that variances are not being granted. The process is available and if a firm wanted to request an exemption they can do so… ?

DR. LAZARUS: Absolutely. And the firms that have requested them know the answer. There is a mechanism to request through Freedom of Information Act…if other people want to obtain that information, that might be a possibility.

MODERATOR: Thank you.

Question 10: A sibling in a directed situation (it is expected that multiple transfusions will be necessary over the coming years) lets it be known after several donations /transfusions that he spent sufficient years living on military bases in Europe when he was a child to be an ineligible donor due to vCJD issues. Can the donor continue to be the directed donor to his sibling?

MS. CIARALDI: We believe that this falls under the practice of medicine and the blood bank medical director should decide whether this donor's blood can be used for his sibling. The medical director should weigh the benefits of using the sibling's blood against any possible risk to the patient and document the decision and the rationale. Of course, this documentation should be available for review at the next FDA inspections. In addition, if the units will be used, that is the decision that is made by the medical director. They should be appropriately labeled so they are not accidentally crossed over into the general allogeneic inventory; and we encourage the blood bank medical director to notify the patient's physician about the status of the donor and the units.

Question 11: The draft guidance on Trypanosoma cruzi for donors of whole blood and HCT/Ps issued March 2009 states "we are notifying you that we have determined T. cruzi to be a relevant communicable disease agent under 21 CFR 1271.3(r)(2), and are providing you with recommendations for testing and screening donors for antibodies to T. cruzi." The recommendations have not been finalized, therefore T. cruzi is not yet declared to be an RCDAD. Will OCTGT issue final recommendations in a guidance document specific for HCT/P donors and products, or will the recommendations be in a document that is also issued for whole blood donors?

MODERATOR: I guess the questioner is wondering about the timeline but did not want to ask you when it is going to be issued.

DR. LAZARUS: People have asked that question before and get the same answer every time. Our office, Office of Cell, Tissue and Gene Therapies has published two draft guidances jointly with the Office of Blood Research and Review, Dr. Epstein's office. One is the West Nile Virus draft guidance which has been finalized for blood donors but has not yet been finalized for HCT/P donors. The other is the guidance for Trypanosoma cruzi and that draft guidance has not yet been finalized for any type of donor, and I can not comment on the final form that guidance might take. Surely the intent is to finalize both completely for both sets of donors.

MODERATOR: So donors of HCT/Ps as far as we know are being screened, as if it is an RCDAD for the HCT/Ps, based on the draft recommendation right now.

Question 12: We have followed the guideline in the 16th edition Technical Manual pg. 294, "Cellular components stored in syringes have an expiration of 4 hours". However according to a company flyer from the manufacturer of a syringe set, "syringe blood aliquot (RBC, Plasma) must be administered to patient within 24 hours and syringe platelet aliquot within 4 hours". We have been assigning a 24-hour expiration date to RBC syringe aliquots. What is FDA's recommendation/regulation for this product?

MS. FIELDS: We actually have a regulation that is 21 CFR 606.65(e) that states, "Supplies and reagents shall be used in a manner consistent with the instructions provided by the manufacturer," and I think this goes back to what you alluded to.We are not sure if the company flyer is the package insert or just an advertisement that comes with the kit. So we do recommend or require you to follow the package insert that was cleared by the FDA (CDRH) with the device. Company flyers are probably not cleared and you should follow whatever the package insert is that comes with the device.

MODERATOR: So, a device that has been cleared by FDA would have a package insert with proper instructions and proper times.


DR. EPSTEIN: I would just add the comment that some syringes are filled in open systems and others are filled in closed systems; and certainly, if it is an open system-fill, then we would encourage you to follow four-hour outdating because of risk of bacterial contamination. The problem is that the labeling of the device may not specify the mechanism of filling of the syringe.

MODERATOR: That is an important caveat. Thank you, Jay.

Question 13: 21 CFR 600.15 states that during shipment Frozen Red Blood Cells (FRBCs) shall be maintained at -65C or colder. In contrast, AABB Reference Standard 5.1.8A states FRBCs must only "maintain frozen state" during transport. Has the FDA considered the same language used by AABB (maintain frozen state)? Getting an accurate temperature reading is difficult with FRBCs due to the rigidity of the product, i.e. can not wrap the product around a thermometer.

MS. CIARALDI: The requirement in 600.15 specifies the temperature of the environment in the container that the frozen cells are shipped in, and not the temperature of the product itself. We believe that there are several methods available to accurately measure the temperature of the shipping environment; therefore we are not currently considering broadening the wording of the regulation.

MODERATOR: I think that offers some clarification at assessment or inspection time, that it is the "environment" that the regulation refers to.


Question 14: When relabeling an ISBT labeled product with a new ISBT label, is it acceptable to overlay the original ABO/Rh label?

MS. FIELDS: Yes. We feel it is acceptable to overlay the original label if your current software has the capability to preserve the information from the original label. For example, you must have the ability to verify the old label and confirm the new label being applied to the unit. If the establishment's software or record-keeping system cannot record the information from the original label, then the firm modifying the product may not be able to overlay onto the unit.

MODERATOR: It is important that the system can maintain that information so that during the labeling process there can be a verification after the label is applied?

MS. FIELDS: Right.

MODERATOR: Thank you.

Question 15: We recently switched to using the ThermoSafe coolers that maintain the 1-6 C required for storage while the units are in the ER/OR. Are we required to "discard" any products returned that are over 6 C?

MS. CIARALDI: The regulations require red cells to be stored continuously between one and six degrees and we have consistently stated that we consider blood to be in storage when it is kept in the operating room or the emergency room. From the question, it was not clear to us when and where the excursion occurred, the maximum temperature reached, or how long the product was exposed to temperatures greater than six degrees. Using a continuing monitoring process would give you this information and help you better determine the status of the unit. That said, you should validate your storage containers for the temperature you want to be maintained and for how long you want that temperature to be maintained. If the units in this case were returned outside the validated time frame and outside the validated temperature, you should critically evaluate the acceptability of these units because now they have been kept in a storage container that failed its expected performance.

MODERATOR: Thank you, Judy. I think that gives some additional information that this person can consider.

Question 16: CLIA 493.1281(a) Standard: Comparison of test results. If a laboratory performs the same test using different methodologies or instruments, or performs the same test at multiple testing sites, the laboratory must have a system that twice a year evaluates and defines the relationship between test results using the different methodologies, instruments, or testing sites. Provide suggestions for an efficient way to meet the standard when a laboratory has multiple Ortho Summit Platform stations or Abbott Prisms that perform up to 4 assays each.

MS. MEYERS: While CLIA does not provide guidance on specific instruments, we can give some general guidelines on complying with this regulation. First, we do not expect that a major correlation study be performed since the laboratory has already verified the manufacturer's performance specifications when the instrument was first installed. This does not need to be repeated. The comparison can be as simple as evaluating and documenting something the laboratory is already doing, for example, comparing QC results from different instruments. It is up to the laboratory director to dictate the extent of the evaluation needed to meet this requirement based on the overall test performance and the clinical use of the test. If the laboratory is following its own policy, it will be determined to be in compliance.

Question 17: Currently, no standards exist to guide in the proper selection of administration sets for neonatal and pediatric transfusions. The Circular states, "All blood components must be transfused through a filter designed to remove clots and aggregates (generally a standard 170- 260 micron filter)."

Can you please give guidance to the proper selection of administration sets with applicable filter size for neonatal and pediatric patients? Several companies are making pedi-pack sets with inline 150-micron filters and claim that the blood can be filtered in the blood bank while preparing syringes for transfusion thus eliminating the bedside administration set.

- Is there a maximum time between filtering and transfusion?
- Are administration sets required at the bedside?
- Is the production of filtered syringes considered manufacturing and does it require registration?

MS. FIELDS: These products are currently cleared by CDRH and we were not familiar with the specific clearances of each of the devices. However, we do have some comments that we would like to make to each of the individual bullet points. We believe that you should review the package insert for the product to determine the maximum time between filtering and transfusion, and that, although we cannot require or recommend that you perform this step at the bedside, we feel that for scientific reasons, it would be prudent to filter the blood product at the time of administration. We would be concerned that additional potential changes including aggregates or clots could occur in the product during the storage time before a transfusion. Additionally, we do consider this part of manufacturing a step that would require you to register with the FDA.

Question 18: What are the requirements for vendors performing any or all aspects of validation of blood typing instruments in the transfusion service?

MS. O'CALLAGHAN: The vendor should be performing the installation qualifications and the transfusion service should perform the operational qualifications and the performance qualifications. Since the OQ and PQ are performed to assure the system works as expected under the conditions of use, that is, with the transfusion service's employees and their procedures, it is certainly in the best interest of the transfusion service to perform those qualifications themselves and not accept the vendor's validation for those.

MODERATOR: If vendors are offering to be on-site and guide facilities through all of these steps, is this acceptable?

MS. O'CALLAGHAN: Sure. That would be fine, but the transfusion service should be actively involved in that process. That is really the key, to make sure that the transfusion service understands what the vendor is doing and making sure that it is working the way that they would use it on a daily basis.

DR. EPSTEIN: I would just add that the accountability lies with the transfusion service and that whatever support you get from the vendor is fine, but it does not alleviate the responsibility of the transfusion service.

Question 19: We have continuing issues with our provider of ISBT 128 labeling software and hardware. Labeling is a critical part of blood banking. Can you confirm that these software and hardware products are required to be 510(k) cleared? What resources are available to blood banks to help us communicate to these providers that all changes must be controlled?

MS. FIELDS: Thank you. I think that we are sensitive to this issue and there are several phases here that I would like to discuss. The first is that the stand alone ISBT labeling devices, it was determined that they do not need 510(k) clearance. However, any system that was interfaced or is used in conjunction with the BECS (blood establishment computer software) does require 510(k) clearance. When these BECS do come in for clearance though, the labels are submitted to our device review branch and we have the blood and plasma branch do a review of these to determine that they are adequate. Additionally, as for how you handle the manufacturer, we do encourage communication with your vendors and we encourage all establishments to ensure before purchasing any software or hardware, for the purpose of manufacturing, that you outline what your expectations are as far as any regulatory or guidance requirements and how you want the vendor to respond to those. As far as reporting stuff to the FDA, with the stand alone system you really do need to work with your vendor to resolve these issues. If the device is 510(k) cleared and you are unable to resolve it in that manner, you may report to the district office any violative action.

MODERATOR: So the stand alone systems are just that. They are stand alone, they are not connected to 510(k) clearances?

MS. FIELDS: Right. The license facilities will still have to submit their labels for review for their products, and we will review those; but the unlicensed facilities will be responsible for ensuring their labeling is appropriate.

MODERATOR: When dealing with the 510(k) products, the district office is where the communication would be directed? Is that what you said?

MS. FIELDS: Yes, if something violative is going on and you would like to report it.

Question 20: The 1994 Malaria Memorandum and the June 2000 draft guidance recommend deferral of blood donors based on areas that are considered by CDC to be endemic for malaria. When determining if a donor has traveled to a malaria endemic area, our staff use the CDC malaria application. The map lists areas where there is "malaria everywhere", "malaria presence varies", and "no known malaria". If a donor traveled to an area that is listed as "malaria presence varies" or if only mosquito avoidance is recommended for prophylaxis, should this donor be deferred?

DR. NAKHASI: At this point, FDA does not make a distinction between "malaria everywhere" and "malaria presence varies". The reason being, it is very difficult to make that distinction. Either one is considered endemic at this time and hence the donor should not be accepted for whole blood or blood components prior to one year after departure from the endemic areas, i.e., continue to follow the 1994 memoranda and June 2000 draft guidance.

MODERATOR: So if CDC has the area marked as endemic on their map, then that qualifies as an area for which the donor should be deferred from the time of departure?

DR. NAKHASI: Yes, because, as the questions says, "malaria presence varies". It is very difficult to make that distinction in the same area - where malaria is and where it is not. Therefore people travel across and it is very difficult to remember what was going on. So at this point, it is recommended that the donor should be deferred for one year.

Question 21: If the manufacturer's package insert and/or Operator's Manual says to perform a maintenance or quality control function monthly - What is FDA's interpretation of monthly? There are various ways this could be interpreted.

MS. CIARALDI: FDA's interpretation of monthly is once a month and a minimum of twelve times a year. If a specific number, such as every thirty days, is not in the package insert, then your SOP should specify when QC will be performed. Additionally, you should refer to the package insert or operator's manual, as some may specify a time frame within which the testing must be done, for instance, plus or minus seven days of the test date that you have selected.

Question 22: In talking with colleagues at different institutions, I have learned that not all facilities that prepare, store and transfuse Thawed Plasma follow the same protocol to assign the expiration time/date to the product. For example, some institutions assign an expiration date for Thawed Plasma at midnight after 5 days following thawing, counting the day of thawing as day zero. Thus, in those institutions, Thawed Plasma might be stored for longer than 120 hours. Other institutions assign an expiration time/date for Thawed Plasma at 120 hours following the time of thawing (5 days x 24 h/d). Is either practice correct? If not, what is the correct (best) practice?

MS. CIARALDI: Thawed plasma is currently not an FDA-licensable product. There have been no data submitted for us to evaluate thawed plasma. For this reason, we have not set product standards for this product and have not approved any variances to extend the shelf life of thawed fresh frozen plasma or thawed PF24 to five days. Therefore, unfortunately, we can not advise you on how to calculate the expiration date of thawed plasma.

MODERATOR: There is a listing in the Circular of Information for thawed plasma and there are some instructions in the Circular of Information that could be your reference. Judy is correct. In the Circular of Information, there are a couple of products marked with an omega symbol to indicate that they are not licensed by the Food and Drug Administrative. Thawed plasma is one of those, as she just indicated.

Question 23: Many of the newer refrigerators have newer technology for performing alarm check. The newer systems will heat up the probes and will be able to initiate an audible alarm at the appropriate temperature. As this process is performed electronically, it is very quick and does not result in a "blip" on the recording chart to show that high or low temperature was reached. Do these new alarm checks qualify as appropriate controlled alarm checks or does the facility also have to perform the more time consuming process to slowly lower or raise the temperature so that a "blip" is recorded on the temperature chart?

MS. O'CALLAGHAN: The regulations do not require specific alarm checks to be performed. They only require that you store your products at an appropriate temperature and the temperature is monitored. It is up to you how you determine that the temperatures are being maintained appropriately which would include assuring that the alarms are functioning properly.

MODERATOR: So this, I think, has always been the attempt to show that the alarm will sound before the storage device reaches the out of range temperature. Thank you, Sharon.

Question 24: Please clarify FDA current consideration around the collection of concurrent plasma, more frequently than 28 days, when collected with PAS (platelet additive solution) platelets?

MS. FIELDS: We do not currently have any regulations or recommendations that would clarify this. I do want to clarify before I finish answering the question, though, that we do not consider this a concurrent plasma as we have been discussing at BPAC and other venues. Those products have not been approved yet. This plasma is a product that will be collected during the PAS platelet collection. It is the same amount of plasma that actually would have been collected and stored for the storage of the platelet during a normal collection as it occurs now. We have only cleared one device to do this and it is being done right now as only a fresh frozen plasma collection and blood centers, licensed and unlicensed, that are planning on manufacturing this plasma product must comply with the operator's manual. In the operator's manual we have listed several things that need to occur, and these include requesting an alternative procedure from FDA to 21 CFR 640.31(b), 640.32(b), 640.63, 640.65, and this can all be done under the provisions of 640.120 to manufacture this FFP more frequently than every twenty-eight days. The language that will be included in this approval will be that the donor must still meet all donor eligibility criteria as described in 21 CFR 640.3. The volume of plasma collected during the plateletpheresis procedure will not exceed that which would have been used for platelet storage or the total plasma volume allowed by the collection during the clearance of the device. You cannot exceed FDA's current guidelines on maximum plasma loss value within a rolling twelve month period, and your donor will not be able to participate in any other plasma program at another blood center or source plasma center. I would recommend that anyone who is interested in implementing this call their CSOs and we will provide all this to you in writing as well as references. Additionally, for the PAS platelets, there are other things that must be done and we can go over that with you.

MODERATOR: Thank you Lore. To additional plasma can be collected from the donor than what would be collected in a platelet collection, (non-PAS situation), there are several alternative procedure requests that must be filed and the plasma product will be a fresh frozen plasma.

MS. FIELDS: Correct.

Question 25: We would like clarification regarding the May 2010 FDA guidance document for NAT HIV and HCV. The draft guidance document specified a difference between a donor who had "persistent" vs. "intermittent" recurrence of HIV and HCV false positive tests. The final recommendations (May 2010 guidance) allow facilities to "try again" if a donor fails re-entry ("persistent" false positive), but they don't discuss an intermittent positive (a donor is deferred, but is successfully re-entered, but then has another positive that defers them). Are they permanently deferred if they have another false-positive event? Or can they start the re-entry algorithm again?

DR. MIED: For a donor that was deferred because of a reactive NAT or repeatedly reactive antibody test, the reentry algorithms for HIV and HCV are designed to determine whether the test result on the index donation was a false positive or if the donor is actually infected with HIV or HCV. After a waiting period of eight weeks for HIV or six months for HCV a sample from the donor is tested by ID NAT and an antibody test and both tests must be nonreactive for the donor to be reentered. A donor who meets all other eligibility criteria can be successfully reentered because it has been concluded that the reactive test result on the index donation was a false positive and that the donor is not infected and that it is safe to reenter that donor; and then of course, testing for all markers must be negative again for the donor's next donation to be used. If a donor has been successfully reentered and then has another NAT reactive result or another antibody repeatedly reactive result, that could also be a false positive test result; and in this case, the donor can again be indefinitely deferred. The new deferral can be treated as an independent event and the donor can be allowed to go through the reentry algorithm again; but, even though the guidance permits this, the blood center may not wish to allow repeated reentry for a donor whose donations are NAT false positive or antibody repeatedly reactive on multiple occasions. At any rate, I should point out that, of course, the unit is not used whenever there is a NAT reactive or an antibody repeatedly reactive result, even if it is a false positive.

MODERATOR: Thank you, Paul. Regarding your last comment - If you have a donor who is continually testing positive and the product's continually being discarded you might consider why you would keep putting them in the program..but it is allowed per regulations and guidance.

DR. MIED: That is correct.

MODERATOR: Thank you.

Question 26: 1271.85(a)(2) states "You must test a specimen from the donor of viable, leukocyte-rich cells or tissue for evidence of infection due to cytomegalovirus (CMV)". Is there a definition, in the regulations, of "leukocyte-rich cells or tissue" or any guidelines for determining if a cell or tissue is "leukocyte-rich"?

DR. LAZARUS: We do not define leukocyte-rich; we do not provide a description of how to determine whether an HCT/P would be considered viable and leukocyte-rich. However, we do give examples of leukocyte-rich HCT/Ps in the HCT/P donor eligibility guidance, which you can access on the CBER website and I will pull out just some information from that guidance for you here.

In that guidance, we state that examples of viable leukocyte-rich cells or tissues include but are not limited to hematapoietic stem progenitor cells and semen; and the guidance also recommends that you should consider cells and tissues to be viable and leukocyte-rich based on their status at the time of recovery or even if later processing might remove leukocytes.

MODERATOR: Thank you, Ellen. I think it is important what you just said. It is at the time of recovery, if they are considered leukocyte-rich.

Question 27: My medical director says Effient (Prasugrel hydrochloride) has the same effect on platelets as Plavix. How does FDA determine which drugs are cause for deferral?

MS. FIELDS: The FDA does agree with this question that Effient does have the same effect on platelets as Plavix; and the blood center should consider not collecting platelet products from these donors for a period of time as determined by your medical director. FDA has covered these issues by putting language in our guidance documents to allow the medical staff to have flexibility for new drugs. The current guidance, Guidance for Industry and FDA-Review Staff Collection of Platelets by Automated Methods, that was published in December of 2007 states in the introduction, "You should include additional deferral criteria for donors of plateletpheresis who have taken certain medications." And it further clarifies it in the guidance document to say, "You should not collect plateletpheresis from donors who have ingested platelet inhibitory drugs recently enough to adversely effect platelet function in the product or the safety of the donor. These recommendations include but may not be limited to," - and then we go on to describe the aspirin, Feldene platelets and Ticlid. So any time a new drug comes out that your medical staff is concerned about, the guidance document allows you to add that to your deferral list.

Question 28: Another question regarding the May 2010 NAT guidance - donations that are NAT HIV/HCV Duplex Reactive, but do not discriminate. According to the guidance the donor is eligible to donate after 6 months as long as all tests are negative with no separate reentry sample needed. Does use of the NAT Multiplex, which incorporates HBV NAT, confound this situation? The guidance states: "We have written this document in general form because other NAT may be approved in the future." My question, is if the sample does not discriminate, can the donor who was tested using the Multiplex test donate again in six months without a requalification sample?

DR. MIED: An individual donor sample that is reactive on a multiplex NAT which incorporates HBV, that is, a multiplex NAT for HIV, HCV and HBV, should be tested using the three discriminatory NATs for HIV, HCV and HBV. If the sample does not discriminate, that is, it is non-reactive on all three discriminatory NATs, our current consideration is that it would be consistent if we were to apply the same principle that is in the HIV/HCV NAT guidance for reentry of that donor. However, I want to emphasize that there is no current policy for reentering a donor whose multiplex ID NAT for HIV, HCV and HBV was reactive but whose sample was then nonreactive on all three discriminatory NATs. It is FDA's intention to address and clarify this situation in a future guidance.

MODERATOR: So with the current consideration being as you stated and guidance being in the future, should the situation occur, the blood center should contact FDA about the particular donor?

DR. MIED: At the present time, there is no reentry provision for that donor who is nondiscriminated on all three of those discriminatory tests.

DR. EPSTEIN: We do not have reentry yet for HBV NAT - period. If you did HBV NAT, regardless of additional testing, there is no recommendation through reentry. Stay tuned.

Question 29: Is tissue tracking software a "medical device software" like Blood Establishment Computer Software (BECS) or Laboratory Information System (LIS)? What are the FDA rules/guidance that apply to tissue tracking software?

DR. LAZARUS: The issue of whether tissue tracking software is to be regulated as a medical device is under consideration currently. There is some information about validation and verification of performance of computer software in the current Good Tissue Practices in 21 CFR 1271.160(d).

MODERATOR: So a facility who is using a BECS and processing their HCT/Ps using that same software, there are no issues with that.

DR. LAZARUS: They have to follow the regulations.We have some in the GTPs and also if you have 351 HCT/Ps, some additional regulations may apply. The the cord blood licensure guidance has a brief section on computer software that may be interesting for those of you that are manufacturing cord blood.

Question 30: How should a facility deal with hearsay information? We put the donor on a pending deferral list, do not call them for future donations but also we do not confront him/her with this information. If the donor donates again the unit is discarded. We also file a BPD for any units that may be involved from the past. Is this appropriate or is there a different way to approach this problem?

MS. O'CALLAGHAN: The medical director should determine how to handle hearsay information and that should be documented and be consistent. If the information may affect the safety, purity, potency of distributed product, then filing a BPD report on the previously collected units is appropriate. However, it does not make sense that if you decide a product quality may be affected that you would continue to allow the donor to donate and then discard the products. This really creates a potential for units to be released inappropriately. So, that is the only part that you might want to reconsider; but we do not have any policies per se, about hearsay information, so it is up to the medical director on determining that policy.

MODERATOR: Thank you, Sharon. I am assuming that the hearsay was something that was a permanent deferral type situation, not temporary.

Question 31: Please comment on the acceptability of issuing a donor a credit card. We plan on placing a dollar amount on it for each donation. It meets the criteria for acceptability: 1) Not transferable 2) Not refundable or redeemable for cash.

MS. O'CALLAGHAN: This is on the edge here. I do not think there is enough information here to really show that these units should not be labeled as paid - collected from a paid donor. The best thing to do would be to contact our donor incentive committee and provide all the specific details: the amount of how much money is going to be put on the card and how the card can be used. Stating that it is just not transferable is not quite enough. So I think this is something that is gong to be have to be followed up with our donor incentive committee.

MODERATOR: Sharon, could you just say a word about your donor incentive committee? We do not often hear about that.

MS. O'CALLAGHAN: It exists. We have a committee in CBER. Actually, I am not sure exactly how many people are on it right now. The Office of Communications will receive the questions about incentives and it is passed on to the committee, and the committee will evaluate the incentives that people are thinking about or have heard about or just hypothetically occur. They will discuss those and decide on which type of incentives are appropriate and which ones are not; so that is usually handled on a case-by-case basis.

Question 32: Regarding the May 2010 NAT guidance document - Section IV.C. (pgs. 20-22), RECOMMENDATIONS FOR NAT ALGORITHMS, specifically, Testing, Product Disposition, Donor Management, and Lookback for an Individual Donor Sample that is Reactive on a Multiplex NAT (ID-NAT) after Negative Antibody Screening Tests, states that if both Discriminatory NATs were reactive or if both Discriminatory NATs were non-reactive, notification of transfusion recipients should specify that the patient should be tested for both HIV-1 and HCV. The donor of the affected components is to be deferred for a period of 6 months and may be reentered after the 6-month period without testing a follow-up sample, and the FDA recommendation is to counsel the donor that the test result was likely a false positive result and that the donor is not infected.

Please clarify the thinking behind the messaging to patient, specific to discriminatory NATs that are non-reactive.

DR. MIED: When the donor's ID NAT is reactive, the current reg. 610.47(a)(1)(ii), requires that the blood establishment perform lookback, including notification of transfusion recipients or the physician of record of prior blood products from that donor. In the case you are describing, when you have a multiplex HIV HCV ID NAT reactive result, but both the discriminatory HIV NAT and the discriminatory HCV NAT are nonreactive, you do not know whether the NAT reactive could have been due to HIV or HCV. So the recipient notification message should mention the need for testing for both viruses. In this case, we recognized the inconsistency between how the donor is counseled and what the message is to the recipient of prior collections from that donor. Because of this, we would consider approving requests for variances to the regulation that requires a lookback for a multiplex ID NAT reactive when both discriminatory NATs for HIV and HCV are nonreactive.

Question 33: We have a donor who might be allergic to the "ChloraPrep one-Step" arm prep. Is green soap tincture swab following up with 70% isopropyl alcohol swab still an approved alternative arm scrub for donors who have iodine and/or chlorhexidine sensitivity?

MS. CIARALDI: 640.4(f) requires a phlebotomy site to be prepared thoroughly and carefully by a method that gives maximum assurance of a sterile container of blood. Data suggests that green soap has proven to be ineffective in meeting this standard. And I believe that it is out of the Standards, too. Green soap is not allowed by way of AABB Standards.

MODERATOR: That is right.

MS. CIARALDI: Okay. If you identify a donor who has a sensitivity or an allergy to chlorhexidine and no other methods are available, please call us. A couple of years back, we had a Blood Products Advisory Committee meeting where one of the topics was arm prep procedures and we would be glad to locate that transcript and the references will be included in that and hopefully provide some background information to help you determine what the best method is for this donor.

Question 34: The Circular of Information, for the Use of Human Blood and Blood Components, in the Instructions for Use section, item number 13 states: "Transfusion should be started before component expiration and (be) completed within 4 hours." What is the FDA's interpretation with regard to this instruction? For example, is it acceptable to start a component at 23:45 on the expiration date and allow the unit to be transfused for 4 hours (until 03:45 the next morning)?

MS. CIARALDI: Our regulations in 606.122 state that administration should start within four hours of entering the product. To us, this means that transfusion must be started within the shelf life of the unit. The length of time to hang a unit, specified in the Circular of Information, is four hours. We are aware that this may sometimes result in the transfusion ending after the unit has expired; however, we do not object to this practice.

MODERATOR: Thank you, Judy. And I know the Circular Task Force discussed this as they slightly tweaked the language this past time to try to be clear before this went to FDA for review.

Question 35: Some computer vendors offer a validation service to their clients as a final validation against the client's SOPs/database set up. Do you think this is a conflict of interest for the vendor to validate their own software?

MS. FIELDS: We actually published a draft guidance titled, "Guidance for Industry Blood Establishment Computer System Validation in the User's Facility". It states in that draft guidance that validation of your blood establishment computer system should reflect and anticipate the system's actual use in your establishment. When that draft guidance was published, our current consideration was that you should validate the system using your own personnel and your own test plans, written for your specific intended use of the software.

MODERATOR: And when was that published?

MS. FIELDS: 2007.

MODERATOR: Thank you, Lore.

Question 36: Can you provide information on the regulations regarding licensure of products collected by automated methods on blood mobile operations?

MS. FIELDS: This is a very complicated question. I would first advise anyone who has this question to contact your CSO at the FDA. Apheresis blood products are licensed by collection facility, so when you are collecting or manufacturing apheresis products on a mobile collection facility, we consider the facility that the mobile is returning to, to be the licensing location. In most cases, if this is a main facility, it is pretty clear cut that your licensure is attached to that facility. That is where the machines will be QC'd and maintenanced and the further manufacturing will happen on those products. If your mobiles do not return to a facility that performs collections, then you should call your CSO for more clarifying information.

MODERATOR: And then, in just a more general overview of the question, everything that applies to products collected in a fixed location would apply to products collected on a mobile?

MS. FIELDS: Yes, it would be the same regulations.

MODERATOR: It is just the peculiarities of where the product was collected. Thank you.

Question 37: The root cause of two BPDs was identified as an approved 510(k) transfusion service computer system not warning the operator of an expiration date of a modified product that is longer than the expiration date of an original unit when the input and output component type is different. The computer company sent a Client Notification letter to its user 2.5 years ago, indicating it knows about this problem and they have created a change request, and also responded that FDA is aware of the issue. With 510(k) products is there a timeline within which the change requests are supposed to be scheduled for future releases?

MS. O'CALLAGHAN: We do not have a required timeline for changes to be implemented and new release set out. Once the user becomes aware of a defect in the computer software, it is up to the user and it is the responsibility of the blood center or transfusion service to implement some type of work around to meet the requirements. We know that the software vendors will typically batch change requests so that they are not sending out new releases every other week. You know, two and a half years does seem like a long time. It might be worthwhile contacting the software manufacturer, saying when can we expect this change; but we do not have any specified time frames for that. It is still up to you as the blood establishment to make sure that your products are meeting all the requirements. So whatever you have to do to do that, which would include a work around, it is your responsibility.

MODERATOR: Thank you all again for an excellent assortment of questions. Dr. Epstein would like to take just a few minutes, please.

DR. EPSTEIN: Well, first I want to thank the AABB organizers for hosting this session. I know that many of you have questions that you want answered and I appreciate that perhaps not every question that was submitted was addressed in this forum; but we remain open to one-on-one discussions if you have further questions or if your question did not get asked and answered. Thank you for attending.