Ask the FDA and CMS/CLIA
October 8, 2012
AABB 2012 Annual Meeting
- JAY EPSTEIN, MD – Director, Office of Blood Research and Review, (OBRR), Center for Biologics Evaluation and Research (CBER)
- PAUL MIED, PhD – Deputy Director, Division of Emerging and Transfusion Transmitted Diseases, OBRR
- JAROSLAV VOSTAL, MD, PhD – Chief, Laboratory of Cellular Hematology, Division of Hematology (DH), OBRR
- ELLEN LAZARUS, MD, CAPT, USPHS – Director, Division of Human Tissues, Office of Cellular, Tissue and Gene Therapies, CBER
- TERESITA MERCADO – Chief, Devices Review Branch (DRB), Division of Blood Applications, (DBA), OBRR
- SHARON O'CALLAGHAN, MT(ASCP) – Consumer Safety Officer (CSO), Office of Compliance and Biologics Quality, Division of Inspections and Surveillance, CBER
- JUDY CIARALDI, MT (ASCP)SBB – CSO, Blood and Plasma Branch (BPB), DBA, OBRR
- LORE FIELDS, MT(ASCP)SBB – CSO, BPB, DBA, OBRR
- JENNIFER JONES, MBA – CSO, BPB, DBA, OBRR
CMS (WRITTEN COMMUNICATION)
- PENELOPE MEYERS, MA, MT(ASCP)SBB – Division of Laboratory Services, Survey & Certification Group, Center for Medicaid & State Operations, Center for Medicare and Medicaid Services (CMS)
- DARALYN HASSAN, MS, MT(ASCP) – Division of Laboratory Services, Survey & Certification Group, Center for Medicaid & State Operations at CMS
- M. ALLENE CARR-GREER, MT(ASCP)SBB – Director, Regulatory Affairs, AABB
MODERATOR: Good afternoon. Welcome to the 2013 AABB Annual Meeting and this year's session of Ask the FDA and CMS/CLIA. I'm Allene Carr-Greer, director of regulatory affairs for AABB, and I thank you all for coming to this session and for submitting questions for the panelists. We are joined today by colleagues from the Food and Drug Administration. Representatives from CMS were not able to join us due to travel restrictions, but they have provided written communication so we can respond to the questions that were submitted to them. So again, I thank you, and Dr. Epstein has a few words he'd like to say.
DR. EPSTEIN: Well, really just to thank the audience for coming at the late hour of the day and to express our appreciation to you, Allene, for coordinating this session, as you've done now for several years running, and a special thanks to those of you who took the initiative to send questions to both CMS and the FDA. You know, it does cause us to think. I won't say that there are trick questions, but they're often hard questions, and we just hope that our responses can be helpful to you, and I want to draw attention that we really are representing three components here from the Center for Biologics Evaluation and Research at FDA, Office of Biologics Research and Review and then, also representing the Office of Cellular Tissue and Gene Therapies and then, from our sister center, CMS, representing the CLIA program. So, with that, I guess we'll just start with the first hard question.
MODERATOR: Thank you, Jay.
Question 1: I have historically tested four leukoreduced apheresis platelet products per month for residual WBC content and have acceptable results for this monthly testing. I now plan to implement a sampling plan with greater statistical significance. Since my current monthly Quality Control (QC) indicates that my process is in control and the only change would be to implement a different sampling plan (which would increase the number of products tested per month) – would FDA expect that I have validation data for implementing this new sampling plan or would it be acceptable to document a rationale for NOT having validation data for the sampling plan?
MS. FIELDS: Thanks, Allene. Establishments that have previously validated their process would not be expected to revalidate the system. So, if your processes are in control, there's no need to do the initial validation. However, what we would expect is that you would validate your new QC process. For example, this should include, but not be limited to, validation of new procedures, training, competency, and follow-up to ensure that your new sampling plan is working effectively.
MODERATOR: Thank you, Lore.
Question 2: Is FDA thinking of taking the statistical process control approach (21 CFR 211.160) for cellular therapy labs?
DR. LAZARUS: So this question is about one of the laboratory controls regulations in 21 CFR 211, which is the "Current Good Manufacturing Practice for Finished Pharmaceuticals", and specifically, the regulation describing the establishment of product specifications, standards, sampling plans, and other laboratory control mechanisms. As you may know, part 211 current good manufacturing practice, or CGMPs, apply to cell therapy products that are subject to licensure, or, in other words, those that are regulated as human cells and tissues and biological drug products. But those regulations do not apply to human cell and tissue products that we call HCT/Ps that are regulated solely under 361 and the regulations in 1271. I say that just to orient folks newer to the regulatory paradigm for human cells and tissues. So it's clear that the 211 regulations apply only to the cell and tissue products that are subject to licensure.
Now to the question. For an example of the agency's thinking on this particular regulation, 211.160, laboratory controls for cell therapy products, you can look at the core -- the licensure guidance, which states you should establish scientifically-sound and appropriate specifications, standards, sampling plans, and test procedures designed to ensure that components, drug product containers, and closures, in-process materials, labeling, and the final cord blood products, in this case, conform to appropriate standards of identity, strength, quality, and purity. So you will notice that this is not prescriptive, and it leaves it up to the sponsor to describe their laboratory controls and procedures in the Biologic License Application (BLA). And another useful reference for information on the related topic of process validation is in the guidance for industry entitled "Process Validation, General Principles and Practice" issued in January 2011.
MODERATOR: Thank you, Ellen.
Question 3: After reading the "Final Guidance for Industry: Pre-Storage Leukocyte Reduction of Whole Blood and Blood Components Intended for Transfusion" (September 2012) we have a few questions. We currently manufacture a leukocyte reduced red blood cell from whole blood using two different methods: in-line whole blood filtration (12,000 + units/month), or sterile-docked red blood cell filtration (50-75 units/month). The two processes use different filters, but the final product is labeled the same.
- When applying the two-stage binomial strategy for selecting products for quality control, are they considered the same product, or must they be considered separately?
- Is there a minimum sample size for using the two-stage binomial strategy described in the guidance document?
- How should a facility proceed if <60 units per month of a product are manufactured?
MS. FIELDS: Our final guidance did publish in September of 2012 for leukocyte reduction, and it does recommend that each filter should be considered separately when developing your sampling plans, and that's obviously because each filter needs to be QC'd because you're looking for manufacturing issues or anything like that. The minimum for the binomial plan is still 60 units/month, but you may also use the hypergeometric plan for quality control of these leukocyte-reduced products. We understand that there are issues for places who have low volume, but if you collect less than 60 units/month, you may want to investigate using the hypergeometric plan, which we developed for smaller centers. It may be more advantageous to your center. The other thing is we encourage you to develop your own scientifically-sound sampling plan and submit it to the FDA for review to determine if it would be an acceptable alternative. This could possibly include variables on the number of samples, the time period, those type of things, as long as it meets the 95/95 criteria [editor's note: 95% confidence that more than 95% of the components will meet the recommended results], and we will evaluate those on a case-by-case basis.
We are putting on a workshop on October 19th at the White Oak facility in Silver Spring, Maryland on the statistical process controls, and you may either attend in person or by webinar. If you would like to learn more about the statistical process controls that are going on at CBER and with quality control of blood products.
Editorial Note: The workshop materials are available at:
Question 4: Following the recommendations from the Blood Products Advisory Committee to the FDA that measures should be taken to address the residual risk of bacterially contaminated platelet components, and specific recommendations on secondary bacterial testing of apheresis platelets, what are the agency's current considerations of this issue? Would the agency see benefit in further public discussion at the Advisory Committee on Blood Safety and Availability prior to making its own recommendations?
DR. VOSTAL: Thank you, Allene. In the last four months, the FDA has participated in the public conference "Secondary Bacterial Screening of Platelet Components" organized by the AABB and also brought this issue to our Blood Products Advisory Committee. These two meetings are aimed at settling the scientific issues behind bacterial contamination and its detection in blood products. The Blood Products Advisory Committee made a range of recommendations to the FDA, the most significant of these being the message that FDA should take steps to further reduce the residual risk of transfusing a bacterially-contaminated platelet unit. There was a range of recommendations on how this could be achieved. All of these options are currently on the table and being considered by the FDA. These also include the option to take this issue to the Advisory Committee on Blood Safety and Availability committee, where the costs of the changes could be considered as well as the benefits. The FDA is aware of the potential impact of these options on the transfusion community, and we'll build into the final action a reasonable amount of time for implementation of any actions recommended.
MODERATOR: Thank you, Jaro.
Question 5: What Quality Control or proficiency testing is required for the Pall eBDS device which performs bacterial testing (moderate complexity / microbiology) on apheresis platelet components, and at what prescribed intervals must the testing be performed? There is further clarification that this test is categorized as moderate complexity in the microbiology subspecialty.
DR. VOSTAL: At this time, the FDA does not have specific instructions for validation of bacterial detection devices by the end user. It is the general expectation that the end users will validate these devices on their own, based on the manufacturer's instructions for use. The studies should be done according to good manufacturing practices.
MODERATOR: Thank you, Jaro, and, since there's a CLIA component to this –I will read the response provided by our CMS colleagues - this is from Penny Meyers. "As we usually do, we'll begin by stating that our answers today are based solely on CLIA regulations. Those laboratories that elect to receive CLIA certification by virtue of accreditation by CMS-approved accreditation organization such as the AABB must follow all requirements of their chosen accreditation organization, including those that are more stringent than CLIA." Penny also sends greetings from Baltimore, and she's very sorry they were not allowed to be here in person this year.
CMS: The manufacturer of the Pall eBDS system does not require any QC. Additionally, there appears to be no available control materials for this test system. Hence, 42 CFR 493.1256(h) of the CLIA regulations would apply. This regulation says, "If control materials are not available, the laboratory must have an alternative mechanism to detect immediate errors and monitor test system performance over time. The performance of alternative control procedures must be documented." Please note that the CLIA Interpretive Guidelines for 493.1256(h) are available from the following CMS Internet site: http://www.cms.gov/Regulations-and-Guidance/Legislation/CLIA/Downloads/apcsubk1.pdf.
The media used by the Pall eBDS system would not require the laboratory to perform quality control checks for sterility, growth, selectivity and/or inhibition and biochemical responses provided:
- The laboratory has documentation on the media label or brochure that the manufacturer's quality control practices conform to CLSI specifications; and
- The laboratory documents receipt and condition of each batch of media, and notifies the media manufacturer of any deterioration in the media.
Question 6: We were just informed by our blood supplier that they could no longer offer labeled antigen typed units based on historical data (computer confirmed) due to FDA communications. If we obtain these computer confirmed, antigen typed units for our sickle cell protocol, would we have to antigen type the units serologically for confirmation? Currently, we do not confirm the antigens unless the patient has the corresponding antibody (or history).
MS. CIARALDI: Thanks, Allene. I'm going to split up that paragraph in two and answer the first part and then, the second. The first part that discusses labeling units with the historical antigen typing -- FDA is currently looking into the issue of labeling units with the historical antigen typing results. We know this is very important to you. We expect to have further discussions on this, ongoing further discussions to see how it can be done. Now, to go on to the last part is that we don't have a policy for having you confirm the full phenotype on a unit that's been historically typed. However, we would expect that the appropriate antigen to correspond with the patient's antibody be confirmed serologically.
MODERATOR: Thank you, Judy.
Question 7: "Information for Blood Establishments: Unavailability of CHIRON® RIBA® HCV 3.0 SIA (RIBA)" was posted by FDA on October 5, 2012. This RIBA assay is the only supplemental assay licensed in the US that can be used for follow-up testing of antibody repeatedly reactive samples that also have HCV NAT nonreactive results. (Some NAT assays have limited supplemental claims and can be used to confirm the repeated reactive antibody results that are also NAT reactive.)
- 21 CFR 610.40(e) – Further testing. You must further test each donation, including autologous donations, found to be reactive by a screening test performed under paragraphs (a) and (b) of this section, whenever a supplemental (additional, more specific) test has been approved for such use by FDA, except: (there is no exception for "approved, but currently unavailable")
- 21 CFR 610.47 -- Hepatitis C virus (HCV) "lookback" requirements. (This section has a 45 day timeline but doesn't actually require a supplemental test, if it wasn't for 610.40(e)…? )
The notice posted by FDA described the process establishments can use to obtain an exception or alternative procedure to the requirements without stating whether it is necessary to obtain the exception/alternative procedure. Is it necessary for blood establishments to request an exception or alternative procedure in order to remain compliant with 21 CFR 610.40(e)?
The American Red Cross has an approved alternative procedure. Several establishments that have donor samples tested through ARC have asked if they must obtain their own "variance" or if it is sufficient to document the ARC variance?
DR. MIED: Thanks, Allene. Actually, I see two questions there, one in each of those paragraphs. I'd like to start by saying that we planned to update our Web posting as we learn more about how we can respond to this shortage. Let me address the RIBA test initially by saying that, as you know, the RIBA test is routinely used as an additional, more specific test for donations that are repeatedly reactive or in an anti-HCV screening test for purposes of donor counseling regarding the likelihood of infection with HCV and for notification of consignees and transfusion recipients when the RIBA is positive. Let me address donor notification and counseling first. We do not mean to request establishments to seek a variance to 21 CFR 610.40(e) simply because the unavailability of the RIBA test means that they're unable to perform a supplemental test when a donor is repeatedly reactive on an HCV antibody screening test and negative on the HCV NAT. Instead, until a supplemental test becomes available again for use in this setting, we would expect establishments to perform donor notification and counseling using the available information about the donor's test results, the HCV antibody screening test and the HCV NAT, and, of course, you may use the results of additional tests as additional information in your notification and counseling of the donor about the likelihood of infection with HCV. So the answer to the first question is no, it is not necessary for blood establishments to request an exception or alternative procedure in order to remain compliant with 21 CFR 610.40(e). However, if you don't obtain a variance to the more encompassing regulation 610.40(e) or to 610.47, the HCV lookback regulation, you will need to notify consignees and transfusion recipients, based on the repeatedly reactive screening test alone.
So let's talk about lookback. If a donor who is repeatedly reactive on an HCV antibody screening test but negative on the HCV NAT has donated previously, the regulations require blood establishments to take certain actions with respect to prior donations. Now, because of the relatively high rate of false-positives associated with the screening test results, supplemental test results, when they're available, have been used to determine whether an establishment is required to notify consignees and transfusion recipients of prior donations by that donor. The lookback regulations expressly state that, when supplemental testing is unavailable, the establishment is required to notify consignees and transfusion recipients of previous donations by this donor, based on the current repeatedly reactive HCV antibody test result. We recognize that this could lead to notification where the current repeatedly reactive test result is a false-positive. FDA regulations provide procedures for licensed and unlicensed blood establishments wishing to -- to obtain an exception or an alternative to the requirements in parts 600 to 680. Blood establishments seeking an exception or an alternative under 640.120 to the requirements to notify consignees and transfusion services solely on the basis of a repeatedly reactive HCV antibody test results may contact CBER.
The answer to the second question is that blood collecting establishments would need to obtain their own variance to avoid notifying consignees and transfusion recipients, based on the repeatedly reactive screening test alone. Any requests should include an alternative testing plan. For example, a modified algorithm that requires testing anti-HCV repeatedly reactive mini-pool or individual donation NAT, ID NAT negative specimens with another FDA- approved anti-HCV screening assay as a supplemental test in the absence of the RIBA HCV assay. Such an alternative procedure would enable blood establishments to use these test results in determining whether to notify consignees and transfusion recipients under the look-back regulations 610.47(a)(3) and (b)(3). If you wish to use an alternative procedure for consignee and recipient notification under the lookback regulations in 610.47, you may wait until you have identified an actual donor who has donated previously and is repeatedly reactive on an HCV antibody test and negative on HCV NAT. We hope that establishments will wait to request approval of an alternative procedure until the situation actually presents itself in their establishment, because FDA will then be able to address the alternative procedure requests in real time without facing immediate, upfront requests from all establishments seeking this approval. Under 640.120, FDA can approve requests made by telephone. However, such requests must be followed up in writing, and FDA must follow-up with a written approval. So, although these are prior approval supplements, we intend to respond very quickly to requests for variances.
DR. EPSTEIN: I just want to add one point, which is that the requirement to notify the consignee within 72 hours of the repeatedly reactive EIA or reactive NAT is still in place, regardless of any additional information. So consignees are notified rapidly to retrieve any in-date units from current or prior collection. What we're speaking about is the notification for purposes of recipient notification and counseling.
MODERATOR: Thank you, Paul and Jay. So that was a lot of information, and this transcript will not be available for some weeks. So can I ask if I've understood this correctly? a variance -- an alternative procedure -- does not need to be requested in order to remain compliant with 610.40(e), as long as the collection establishment makes the notifications, based on the repeatedly reactive antibody result?
DR. EPSTEIN: That is correct.
MODERATOR: Thank you. And the second question from those clients of the ARC, because ARC is testing using this alternative procedure, if those collection establishments are planning to make their notifications using those test results, then they must also have an approved alternative procedure that's pretty much in line with those results they're going to be using.
DR. MIED: Right…the regulation is directed at collecting establishments, so blood collecting establishments would need to obtain their own variance.
DR. EPSTEIN: That's also correct. However, if the collecting establishment makes clear that they intend to follow the same procedure for which a variance was already granted to the Red Cross, it can help us expedite the review and response, and just to remind you that there are 45 days from the time that the repeatedly reactive EIA was obtained to the time when you must notify. So there's a little time to sort it out.
MODERATOR: Yes. Thank you. I think that was very helpful.
Editorial Note: The FDA information webpage on HCV RIBA has been updated since this Q&A session. To view the latest information visit:
Question 8: Currently for HCT/P donors, HCV supplemental testing is suggested not required. Does the Office of Cellular, Tissue and Gene Therapies have any advice for HCT/P donor establishments who have been using the RIBA assay?
LAZARUS: According to the regulations, the tissue regulations, donor specimens must be tested for relevant communicable diseases, including HCV and others using FDA licensed, approved, or cleared donor screening tests with some exceptions. The tests that we recommend to meet this requirement are listed in the HCT/P donor eligibility guidance, and what we've listed there are an FDA-licensed screening test for anti-HCV and NAT tests for HCV or a combination NAT. The guidance also states that you should consider performing confirmatory tests when a positive or reactive screening test result is received for purposes such as donor counseling. However, that's not a requirement, and also, it's important to note that the results on the confirmatory test would not override the results of the donor screening test for the purpose of donor eligibility determination, except for syphilis.
MODERATOR: Thank you, Ellen.
Question 9. Please explain the rationale for the requirement for actual product volumes to be printed on the labels for Plasma, Apheresis Platelets and Apheresis Red Blood Cells but not for Red Blood Cells Leukocytes Reduced prepared from Whole Blood. The ISBT 128 label requirements and the CFR state the label should read "Derived from __ mL whole blood". Our hospital clients want this changed to the actual volume. If we wish to change this, must we submit the change as a Prior Approval Supplement (PAS)?
MS. JONES: Thank you. 21 CFR 606.121(e)(2)(i) applies to this question and states the type of anticoagulant and, if applicable, the volume of whole blood and type of additive solution with which the product was prepared, and I just wanted to clarify that this statement in quotations in the question isn't exactly the wording from the ISBT consensus standard. The question has "derived from _mL whole blood", and the ISBT 128 consensus standard actually uses "from _ml whole blood". In this situation, if the firm wanted to change to the actual volume, we would consider this additional labeling of the red cell volume, and we would consider the request, and we'd consider labeling to include both the container label and the tie tag. The firm should submit a request for an alternative procedure to 21 CFR 606.121(e)(2)(i) under the provisions of 21 CFR 640.120, and the submission should include an example of the proposed label, as well as Standard Operating Procedures (SOPs) describing how the firm will determine the red cell volume of the unit that would be documented in the label. If the firm proposes to change the content of the actual ISBT 128 container label, we recommend that they would contact ICCBBA for guidance. I want to clarify that the CFR labeling citations that I'm quoting in regards to labeling questions are from the new labeling rule that was released in July of 2012.
MODERATOR: Thank you, Jennifer.
Question 10: A blood center sends us an Apheresis Fresh Frozen Plasma labeled with ISBT product label E0902. The ISBT product code used requires that the volume is listed as 400-600 mL. However, the unit labels states "388 mL plasma in approximately 55 mL of ACD-A". We consider this to be an error in use of the product code E0902 as the volume of plasma is less than 400 mL. They have replied with the following: 1) 55 mL of ACD-A plus 388 mL plasma equals 443 mL and falls within the range listed on the label, and 2) 21 CFR 606 allows for a difference of +10% on the labeling of Fresh Frozen Plasma (FFP) products. So although the units in question were labeled as containing 388 mL of FFP, the labeling of the product was still within regulatory compliance.
- Can you tell us whether either or both are correct interpretations of FDA regulations for product labeling?
MS. JONES: We believe the ISBT product code should reflect the total volume, which would be the anticoagulant and plasma on a 400 to 600 mL label, and the applicable regulation would be 21 CFR 606.121(c)(5), which states, for whole blood, plasma, platelets, and partial units of red blood cells, the volume of the product accurate to within plus or minus 10 percent or, optionally for platelets, the volume or volume range within reasonable limits, and again, I just wanted to make a minor clarification to the statement in the question, which is 388 mL plasma and approximately 55 mL ACD-A is not exactly the language from the ISBT 128 consensus standard. The standard uses -- it's just a little bit different. It is "__mL containing approximately __mL" and then, you put in the anticoagulant. In the example provided 388 mL is the total volume and would not fall into the range of 400 to 600 mL, and we expect the volume to be the total volume. So, since 388 mL is below the expected volume for that product code E0902 (400 to 600 mL) we agree with the concern expressed in the question. The volume of 388 mL would be appropriate on a label with an expected volume of 200 to 400 mL. To clarify item two of this question, 21 CFR 606.121(c)(5) states that the total volume on the label must be within plus or minus 10 percent of the actual volume of the product.
MODERATOR: Thank you, Jennifer.
Question 11: Does the FDA foresee requiring hospitals to use bar code scanners to read cell therapy product ISBT labels in the future?
DR. LAZARUS: The labeling and tracking regulations for HCT/Ps, both those subject to licensure such as the unrelated allogeneic cord blood and also those that are not subject to licensure such as autologous cord blood and musculoskeletal tissues, apply to the product manufacturers, not the consignees. Consignees are, for example, the hospital or the dental office or the transplant physician. They have to have tracking systems and technologies that work for them, and those systems are beyond the scope of the HCT/P labeling and tracking regulations.
Question 12: Can you explain CBER's expectation of blood centers as it relates to the Medical Device Data System rule published earlier this year and blood centers' use of software / data transfers between medical devices and BECS? http://www.gpo.gov/fdsys/pkg/FR-2011-02-15/pdf/2011-3321.pdf
Specifically, does FDA consider that some establishments should be registered as a medical device manufacturer? What activities would require this registration? If a blood center has to register as a medical device manufacturer, what other elements of the Quality System Regulations (QSRs) will they have to comply with? http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/PostmarketRequirements/QualitySystemsRegulations/default.htm
MS. MERCADO: The blood center should determine if their system is a Medical Device Data Systems (MDDS). If it is determined that the system is an MDDS, the blood center should register as a device manufacturer, and in addition, they should list their device. The blood center should consider all the elements of the QSRs in the manufacture of their system.
MODERATOR: Thank you, Teresita.
Question 13: When whole blood units are drawn and are being transported back to the processing lab the requirement is that the units must be cooling towards 1-10 C if platelets are not being made. Upon arrival at the processing center the units should be placed at 1-6 C. Is there a maximum time for cooling towards 1-10 C?
MS. CIARALDI: If you don't mind, I'd like to go ahead for the transcript and read in the more complete regulation or at least paraphrase it. 21 CFR 640.4(h) is our storage regulation in the whole blood section. It said, "Whole blood must be placed in storage at 1 - 6 C immediately after collection, unless blood is made into another component or blood is transported from the donor center to the processing lab." In the second situation, if it's going to be transported, "blood must be placed in a temporary storage environment having the sufficient refrigeration capacity to cool the blood continuously to 1 - 10 C until it arrives at the processing lab. At the processing lab, blood must be stored at 1 - 6 C." There is a caveat in here. It says, "Blood from which a component is made must be held in an environment maintained at the temperature range specified for that component in the directions for use for the blood collecting, processing, and storage system approved for such use by CBER." So, in this case, this regulation is addressing all possible blood components, not just platelets.
So down to "Is there a maximum time for cooling towards1 - 10 C?" The regulations do not specify a maximum time to get down to 1 - 10 C. Cooling should be progressive and should be continuous. What's probably more important is when do the components have to be made? A maximum time before components are made and when they should be stored in their proper storage environment is specified in the package insert for the collection system, and it is specific for each component that is being made. Thank you.
MODERATOR: Thank you, Judy. So the overriding thing is looking toward the components that are going to be made from the whole blood.
Question 14: If red blood cells (RBCs) can sit at room temperature for up to eight hours during platelet production, why can't RBCs not intended for platelet production sit for the same amount of time before being placed into one to six degrees storage condition to simplify production?
MS. FIELDS: This is a great question, because it has both a historical and an educational component to it. So the regulation that Judy just read to you, 21 CFR 640.4(h) on storage also applies to this, and it discusses the temperature it should be. But the last sentence of that regulation says, "Blood from which a component is to be prepared must be held in an environment maintained at a temperature range specified for that component in the directions for use for blood collecting, processing, and storage systems approved for such use by the director of CBER."
In 1989, FDA started to approve package inserts for blood bags that allowed the whole blood to be made into components that may not include platelets that could be stored at room temperature for up to eight hours, and, on November 13th of that year, we actually did publish a memo notifying FDA staff, inspectors, and industry that manufacturers were granted the approval for the eight-hour room temperature hold time. Since that time, almost all blood bags manufactured for use in the U.S. do have that indication for use. However, it is in the package insert, and you will need to check your particular blood bags to determine what your room temperature storage time is. The little educational piece is, as new products are being developed and released, the package inserts become more important, because most of our regulations now that are specific will say statements like, "or as approved by the center director of CBER." So you want to check those package inserts very quickly, because sometimes they are very different from what you would have in your standard regulation.
MODERATOR: Thank you, Lore.
Question 15: The storage vs. transport temperature for RBCs stored in coolers issued to the operating room (OR) has been clarified in recent years. Is there a guideline for returning platelets to inventory? How do we document the room temperature for the OR for properly returning platelets?
MS. FIELDS: Our expectation would be that you would validate a process to ensure that the platelets would continue to be stored at 20 – 24 C in the OR for a validated time period like you would validate a shipping container or other such processes. Upon return to the blood bank, you should take measures to ensure that the product continues to be stored at the required temperature as described in 21 CFR 640.24(d)(1), which states that 20 – 24 C must be the storage temperature, or 1 – 6 C (not many people use that anymore). There are guidelines in the guidance document that was published in January 2011 on how to do validation, and it's titled, Guidance for Industry, "Process Validation, General Principles and Practice".
MODERATOR: Thank you.
Question 16: Blood is stored in refrigerators at temperatures between 1-6 C. Reagents should be stored between 2-8 C. Some facilities use the same refrigerator to store blood and reagents. Refrigerator alarms are usually preset by the manufacturer to sound at 1.5 C. Given these circumstances a reagent may be stored at a temperature 0.5 C lower than the recommended lower limits of 2 C. Can we acknowledge the difference in temperatures in our SOP's, or does the transfusion service need to file a variance with FDA?
MS. CIARALDI: Thank you very much. The regulation that applies to this one -- and this may not have been thought of by the inquirer -- is 21 CFR 606.65(e). It requires supplies and reagents to be used in a manner consistent with the manufacturer's instructions - the package insert- and the package inserts do contain storage requirements for the reagents. In the situation described below, the reagents are going to be exposed to 1.5 C , which is below the lower minimum required storage temperature for the reagents of 2 C, and if the reagents would be used for testing, then those reagents would be out of compliance with the package insert. It would be using a reagent that wasn't being applied in the manner consistent with the package insert. Both the blood and the reagents must be continuously stored at the required temperatures. If this particular facility, or any other facility, wants to store both products in the same storage device, the same refrigerator, they need to make sure that the storage environment satisfies the storage requirements for both.
Now, it's our understanding that the storage and alarm devices can be set to alert at a temperature that is specified by you, the user, and, to confirm this, I went down to the vendors and talked to them about this, the refrigerator and alarm vendors, and one of them gave me a flier that shows that they preset their refrigerator at 4 C. So not everybody sets it at 1 C. He says a lot of his competitors are the same; the user, the blood bank, can actually specify a different temperature to -- within which the alarm will alert. So it's our understanding that you can probably consider these other options. If you do want to use reagents that are exposed to temperatures outside of those required in the package inserts, then you must submit an alternative procedure, the variance that they're talking about, but you must include data to support this request. When the reagent manufacturer applied for licensure of the reagent, they submitted a lot of data to prove that, based on storage at those temperatures; the reagent was going to be effective, efficient and was able to do its job. So the burden would be on you to provide that same type of data to show when stored at a different temperature can still meet the requirements. So, in the end, you may want to consider looking more closely at your storage environment rather than putting the burden on you to provide that kind of data. Thank you.
MODERATOR: Thanks, Judy.
Question 17: This question relates to donor screening of unrelated umbilical cord donors under Investigational New Drug (IND) applications: On review of the completed donor screening questionnaire, staff realized the response to one question was not recorded and the information could not be obtained from the donor. Is the donor categorized as ineligible (as if they showed risk for this question) or can the donor be classified as eligible with an incomplete questionnaire?
DR. LAZARUS: Thanks, Allene. The answer to this question is nicely outlined in the unrelated allogeneic cord blood IND Guidance (June 2011) and I'll just make some comments here, but you can look at that later for some more recommendations and information about donor eligibility for cord blood under IND. In this situation, the donor eligibility determination cannot be completed according to the regulations, the donor eligibility rule does describe certain situations in which an HCT/P from a donor for whom the donor eligibility determination is not complete can be used, and those provisions are in 21 CFR 1271.60(d). Specifically, those would be under conditions of urgent medical need, as defined in the regulations. As I said, you can find information about this and other aspects of donor eligibility for unrelated allogeneic cord blood under IND in the specific guidance that you can find on our website.
MODERATOR: Thank you, Ellen.
Question 18: HCT/P donors are supposed to only be tested by FDA approved tests that are on the FDA list. http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/TissueSafety/ucm095440.htm If a test is not included on the list maintained on FDA's web page Testing HCT/P Donors for Relevant Communicable Disease Agents and Diseases, is it still okay to use the assay as long as the manufacturer can provide information that the test kit is approved for use with HCT/P donors? How often is the list of tests kits approved for testing HCT/P donors updated? For example: HTLV, new test by Avioq is not listed on this web page.
DR. LAZARUS: So the first sentence of this question is partly correct. The answer to the question is, yes, an assay can be used, as long as it is labeled for that use. And in this case, if the assay is labeled for use in testing samples from "other living donors", then the assay can be used for testing HCT/P donors for eligibility. So that's true, even if the periodic update of the website list isn't exactly keeping up with the pace of the test kit approvals.
MODERATOR: Thank you, Ellen. It did take me a while to catch on to the "other living donors" phrase - the significance of that in the package inserts.
Question 19: Two scenarios/questions related to registration for tissue activities:
- We are a transfusion service who stores and issues tissue allografts but we are not required to be registered with the FDA because we are not a tissue bank. An area hospital has an urgent case and needs to borrow a specific size allograft that we have in stock. Are we allowed to deviate from our SOPs to assist them without having to become a registered tissue bank?
- Our facility collects autologous tissue (bone flaps). We collect the tissue in the operating room, label the tissue and store the tissue in the blood bank for subsequent issue or distribution. Does our facility need to register with the FDA?
DR. LAZARUS: The first scenario is a situation of a transfusion service that has some tissues that are intended for use within their own establishment. Let's say they are simply receiving tissues for use in patients in their establishment. If that's all they do, then they are not required to register as an HCT/P manufacturing establishment with the FDA. However, if you are sending tissue to another hospital or another facility for use in patient care and that establishment is not your hospital or isn't part of your hospital system, then you are distributing HCT/Ps, and you are required to register, even if that is only an infrequent practice. In scenario b, we're talking specifically about autologous bone flaps where the tissue is recovered in the operating room and it is held in the blood bank, which is obviously acting as a tissue service, to some extent, until such time as the bone flap is needed for use, presumably, in that patient. If the follow-up surgical procedure is occurring at that same establishment and the tissue is going back to that patient, then the hospital blood bank is not required to register as an HCT/P manufacturing establishment, according to one of the exceptions in 21 CFR 1271.15. However, if the hospital is holding the bone flaps for some period of time and then, perhaps sending the bone flaps when patients are transferred to other establishments for their follow-up neurosurgical procedure, and those other facilities are not part of that hospital or hospital complex, then the blood bank/tissue service is functioning as a distributor and would have to register with the FDA as an HCT/P manufacturer, because distribution is a manufacturing step, according to the regulations.
MODERATOR: Ellen, can I ask for clarification on the first example? Because they said it was an urgent case, would they release this allograft and do the tissue registration subsequent to that? Must they stop and register before they release, in an urgent situation, an allograft?
DR. LAZARUS: In such a situation, you'd probably be advised to contact us, let us know what's going on. We want to enable the exchange of tissues to happen in a timely manner. So where there's a situation where you're pressed for time, it would be advisable to contact us and let us know what's going on.
MODERATOR: Thank you.
Editorial Note: For additional information on when to submit establishment registration, see 21 CFR 1271.21.
Question 20: Blood centers sometimes need to provide copies of external inspection reports to customers, insurance providers, etc. This includes 'proof' that a Form FDA-483 was not issued at the conclusion of an FDA inspection. Currently the Establishment Inspection Report (EIR) provides this information, but it is not included in the cover letter that accompanies the EIR. By having the information also included in the letter, it would allow the blood center to submit a copy of the letter to the requesting facility as proof of not receiving a Form FDA-483. Is this possible or is there another form that can be utilized for this purpose?
MS. O'CALLAGHAN: The cover letter that accompanies the EIR is a template that's used by the Office of Regulatory Affairs (ORA) for all of the product areas. It's not just a CBER-specific form. So we don't have the direct control over making adjustments to that form. However, we can pass this suggestion to ORA and see if there is -- reasonable effort that can be made to modify that form. So currently, the only place where the information about no 483 being issued would be in the EIR.
MODERATOR: Thank you, Sharon.
Question 21: We understand that EIRs should be provided to the establishment within 30 business days. Under what circumstances would FDA not send the EIR within the 30 business day timeline, and when this is the case would the establishment be notified of the reason for the delay?
MS. O'CALLAGHAN: Just to make sure you understand that the 30 days that the EIR would be provided is 30 days from the classification of the inspection. Not the end of the inspection, not when the investigator walks out your door. So, because that process may take some time, especially if there's some compliance actions that are being discussed between the district and the center, it may take longer than 30 days to get the EIR completed, and FDA does not notify you of any delay in getting the EIR to you, but that 30 days is from the classification of the inspection. Okay?
MODERATOR: Sharon, does the classification of the inspection result in a notification back to the establishment?
MS. O'CALLAGHAN: No, 30 days after that, that's when the EIR would be available. So there would be -- you know, depending on what the classification is, there may be communication with the firm. But there's not generally a notification that, okay, it's done.
MODERATOR: If an establishment becomes concerned because they're hearing nothing, they should call the district?
MS. O'CALLAGHAN: The district would be the first place to start, because they would be the ones responsible for the inspection to begin with.
MODERATOR: Thank you.
Question 22: I understand that FDA is promoting the use of a uniform consent for blood donation. Can you provide an update?
MS. FIELDS: Sure. Thank you. What FDA is proposing in our rule is a written statement of understanding that would include elements for all donors, so not just apheresis donors, but it would also include whole blood donors. Historically, in 2007, FDA did propose this new rule that includes a requirement for a written statement of understanding. The term "written statement of understanding" is being used as a general term to differentiate it from "informed consent", which is really a research thing for us, as defined in 21 CFR 50.25. So the blood establishments would be required to provide the written statement of understanding to all blood donors and ensure that the written statement of understanding is read and signed before each donation, is written in clear terminology, and does not include language that would waive any of the donor's legal rights. This was also discussed at BPAC in 2011, and we put several issues up for consideration by the panel. They included what would the content be, how to administer it, and when to administer it. So this is still under discussion at FDA. At this meeting, ABC did present a statement on the written statement of understanding, and ABC has also formed a working group with a mission to produce model education, informed consent, and parental guardian permission materials. It is our understanding that this group may be working on a uniform document for its members. In addition, Dr. Illoh, of the Division of Blood Applications, did do a presentation, a very complete presentation to update industry on the status of the statement of understanding, and this was discussed on Saturday. Her slides should be available through the AABB, or you can request, from your consumer safety officer, a copy of her presentation. It was very comprehensive, with everything that's going on.
MODERATOR: Thank you, Lore. And the ABC work product -- I think they're going to offer it to any facility that would like to use it and not just restrict it to ABC members.
Question 23: As establishments move to new computer systems, the ability to keep and access data from prior systems becomes problematic as data conversion and other records become unrecoverable. Many records are also kept on tape or other media which is also sometimes unrecoverable. What is the regulatory risk to an establishment if previous manufacturing records of the past 10 years are not recoverable as described above?
MS. CIARALDI: I took this to mean -- and I hope I interpreted it correctly -- that their records would not be accessible or available, including those records in the past ten years when converting to a different computer system. I hope that was right. I'm kind of wondering -- and I'm not taking names now, but I'm kind of wondering are there others -- could I see a show of hands where this is a problem for your facility?
MODERATOR: I think the raised hands are in the dark corner of the room.
MS. CIARALDI: Okay - we have one there. What I'm going to do is approach this, not so much from the regulatory risk, but more from the regulatory impact of not having the required records available, and I enjoyed looking this up. There was a ton of information for me to provide to you. First off, 21 CFR 606.160(d) requires records to be maintained no less than ten years beyond the expiration date of the blood component, and the reason for this is to facilitate reporting of unfavorable clinical responses. So, right away, that tells me it's important to have the records around. 21 CFR 610.48(b)(1)(ii) -- that is the HCV lookback historical record review requirement. It requires a lookback review for HCV to go back to January 1, 1988. Another regulation that applies is 21 CFR 606.160(b)(1)(viii), requires records to be available for those lookback activities, and one last thing, because I have no life, and I read these things. If anybody read the fine print on the 482 which is given to you by your investigators when they first show up at your center, it has excerpts from the Food Drug and Cosmetic Act. It says that FDA has the authority to access and review the required records. So, if you anticipate that when you change to a new recordkeeping system, whether it be electronic or a manual, you may lose some of the records, you should take precautions to prevent this from happening, to prevent losing the data that's in the required records, because, as you can see, you need it. Part of the way to ensure that this is done properly is to make sure that this is incorporated within your validation plan when you go to implement a new recordkeeping system.
MODERATOR: Thank you, Judy.
Question 24: Regarding licensed HPC, Cord Blood: Uniform product nomenclature and labeling of CT products has been encouraged. HPC, Cord Blood is the appropriate ISBT 128 product name. As cord bloods become licensed some have trade names, and some do not. What systems should a facility have in place - if any - to address the potential confusion that may result from having HPC cord blood products in inventory from multiple sources? Why are trade names used for these generic products – generic in the sense that they all have to meet pre-set criteria and have the same indications for use?
DR. LAZARUS: Let's start with the applicable regulations. The labeling regulations in 21 CFR 201 and in 610, Subpart G, apply to licensed biologics such as unrelated allogeneic cord blood, and, under those regulations, the manufacturers are permitted to apply a proprietary trade name for their product. Also according to another set of regulations in the tissue rules, each HCT/P must be labeled with a distinct identifier. These regulations apply to the manufacturers of the cord blood and other cell therapy products and HCT/Ps. As you know, for hematopoietic progenitor cell transplantation, there is a direct one-to-one correspondence; a relationship between the donor product and the recipient, and that's true regardless of the name of the product. The product has to have a distinct identifier such as an alphanumeric code. However, the regulations aren't prescriptive about what type of distinct identifier or system you use. It then becomes the responsibility, naturally, of the consignee to assure that the right product goes to the right patient. As I mentioned earlier, that's up to the consignee to implement systems that work for them for the types of product that they are administering to their patients, and administration is not a manufacturing step, so the labeling regulations do not apply to the consignee administering the products.
MODERATOR: So if they're using an ISBT product name, then they also should have that distinct identifier, the number. The alpha numeric you were just talking about is also part of that labeling system?
DR. LAZARUS: Well, the ISBT 128 is a distinct, unique identifier. It's just that our regulations don't prescribe the use of any particular identifier-- you just have to have one.
MODERATOR: Thank you, Ellen.
Question 25: It has always been "understood" that donors are identified several times throughout the donation process to confirm donor identity. Donors go through an identification process when they first present to donate, they are asked to confirm their name or another personal identifier when they begin the screening process and finally they are again asked their name or another personal identifier prior to venipuncture. Where in the CFR can I find documentation to support this practice?
MS. FIELDS: There are three major regulations that are applicable to this. In 21 CFR 606.160, which is the records section, (b)(1)(vii) -- records to relate the donor with the unit number of each previous donation from that donor, and 606.100, which is the standard operating procedures, in (b)(4), it says you need to have a method to accurately relate the products to the donor, and in 640.4, which is the collection of blood, in (e), under donor identification, it states each unit of blood shall be so marked or identified by a number or other symbol as related to the individual donor to be able to identify that donor and be in compliance with 640.3. So, although the regulations are general for identification, it is our expectation that identification of a donor to a unit is definite. Therefore, it is prudent to use measures to ensure identification through a reconfirmation process as the unit travels from step to step or process to process.
MODERATOR: Thank you, Lore.
Question 26: If a cellular therapy product is processed and stored by a bank for autologous use only without being associated to any particular indication, does the bank need to file an IND or BLA?
DR. LAZARUS: Good question. As I mentioned in my introduction to a previous response, HCT/Ps are regulated solely under section 361 of the Public Health Service Act, if all of the criteria listed in the 21 CFR 1271.10(a) are met. 1271 includes such requirements as registration and listing, donor eligibility requirements, and current good tissue practice requirements. Now, if the future use of the stored HCT/Ps will not meet all of those criteria in 1271.10(a) such as if the future use would be considered a non-homologous use or if there would be subsequent manufacturing that would entail more than minimum manipulation, then the product would be regulated as a biological drug. In such cases, submission of an IND or a BLA will be required before the HCT/P can be legally used in a clinical trial or distributed.
MODERATOR: Okay. And can it go into the bank now without an IND?
DR. LAZARUS: Well, you would just have to consider what you're doing. So that question really has to be specific for that product and for the way in which it's intended to be used in the future. So you just have to consider the products that you have and remember, or keep in mind, the regulations that will apply if the future use is one that would require an IND or BLA, meaning one that wouldn't meet all of those four criteria or that would entail manufacturing that again. You know, wouldn't meet the criteria.
MODERATOR: At some point in the future, the collection could have been quite important to an IND.
DR. LAZARUS: Right. And, the same thing could be true for donor eligibility. In the future, if you might want to consider doing the donor eligibility determination you're going to need that information because the use would be one that would be allogeneic use, for example.
MODERATOR: Thank you
Question 27: The CDC reports that 2012 has been one of the largest West Nile (WNV) outbreaks in the United States. As noted in FDA's Guidance for Industry: Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (August 2007) WNV screening, but not testing, is recommended for HCT/P donors. In 2008, FDA published a draft Guidance for Industry regarding the use of NAT testing to reduce the risk of transmission of WNV from whole blood and blood components intended for transfusion and donors of HCT/Ps, although the recommendations were never finalized for HCT/P donors. In light of the CDC report, how does FDA plan to address the risk of transfusion-transmitted WNV with respect to HCT/P donors?
DR. LAZARUS: Thank you. So, as this questioner notes, West Nile virus is considered a relevant communicable disease agent and in accordance with regulations we currently recommend screening for West Nile virus for HCT/P donors. As this inquirer notes, the guidance has not been finalized for HCT/P donors. We have received quite a few comments to that part of the draft guidance, and those comments are still currently under consideration.
MODERATOR: Thank you.
Question 28: These questions concern microbiology testing of HPC products under an IND. Does the laboratory that provides sterility, endotoxin and mycoplasma testing on genetically modified expanded HPC, apheresis products need to be registered with the FDA for the provision of microbial testing? Does the lab also need to be CLIA licensed for the sterility testing? A decision to treat or not treat the patient, with these cells, will be made based on the microbial tests.
MODERATOR: The CMS response to this question can be found in a policy memo on the website at http://www.cms.gov/Medicare/Provider-Enrollment-and-Certification/SurveyCertificationGenInfo/Policy-and-Memos-to-States-and-Regions-Items/CMS1243106.html. If donor notification policies are followed, then the sterility testing is subject to CLIA. So, if the result of this testing mean that donor notification policies will be followed, then the sterility testing is subject to CLIA, and the laboratory must obtain CLIA certification. If there are no donor notification policies, then the sterility testing is not subject to CLIA.
DR. LAZARUS: Regarding the microbial testing and the FDA regulations, the answer is that it depends. If the laboratory that's performing the testing, the microbial testing, is only performing that testing for products that are under IND, then the laboratory is not required to register as an HCT/P manufacturing establishment. However, I would think generally, in most cases, laboratories are performing this type of testing for a multiplicity of different types of products. If sterility testing is being performed for an HCT/P that's not under IND, the testing laboratory is required to register as an HCT/P manufacturer because microbial testing is considered a manufacturing step. Also, for licensed products, the test laboratories do have to register with the FDA. Again, the answer is that it depends. It depends on whether that's the only testing being performed, and again, if the testing is only being performed on products that are under IND, all of that information is encompassed in the IND, and the testing lab would not have to register separately as an HCT/P establishment, but, like I said, I think that's generally not the common scenario.
MODERATOR: Thank you.
Question 29: When is a transfusion service required to be FDA registered? Do the following processes require the facility to be registered? These examples were received from 4 different facilities.
- thaw plasma and split RBCs
- receive washed red cells from the blood supplier and then add plasma for an exchange transfusion
- divide red cell or platelet products for pediatric use
- re-label thawed fresh frozen plasma to thawed plasma
MS. CIARALDI: There's an easy answer, which is no, yes, no, no, but what I'd like to do is just take some time to explain why. The regulation that states who must or who is required to register is 21 CFR 607.20. It says specifically any establishment that manufactures a blood product must register, and there are some other criteria, but that's the main one that applies here. Additionally, there is a regulation 21 CFR 607.65(f), that lists some exceptions under which a transfusion service does not need to register, but that's a very limited and specific list. Now, to go on to the specific examples here, what I'd like to do is bunch bullets one, three, and four together. In those three situations, a transfusion service would not need to register. Thawing plasma to prepare it for a transfusion we don't consider the manufacturing of a product. So that is why that particular practice is exempt. In addition, splitting or dividing units for whatever reason, usually pediatric reason, is also not manufacturing a product. The end product is the same as the starting product. It's just smaller volumes. So that is the rationale behind why that would also not need registration. However, in the second bullet, washed red blood cells has plasma added to it, and the final product, which is sometimes called reconstituted whole blood or reconstituted red cells, is used for exchange transfusion. The answer to this is that, yes, registration is required, because the transfusion service is making a new product. The reconstituted whole blood is the new product. The final product, the whole blood product, is different from the two original starting products. So there is manufacturing of a product going on in this particular situation.
MODERATOR: Thank you, Judy.
Question 30: Scenario: An FDA registered hospital blood bank collects allogeneic and autologous whole blood and apheresis products and assigns a Donation Identification Number (DIN) containing the collection facility identifier. Blood samples for all donor required testing and the whole blood and apheresis units are physically sent to an FDA registered and licensed blood center located in the same state. The blood center, under contract with the hospital collection center, performs the required donor testing and manufacturing of the products and performs final labeling of the components which contain the collection facility DIN, name and FDA registration number. (The products do not contain a license number). The components are then returned to the collection facility.
According to the "United States Industry Consensus Standard for the Uniform Labeling of Blood and Blood Components using ISBT128", does the final product label need to include the information (name/FDA registration) for the facility performing the product manufacturing in addition to the information of the collecting facility, i.e., is this considered "joint manufacturing"?
MS. JONES: To answer this question, first of all, FDA doesn't use the term joint manufacturing, but we do have a guidance for industry, which is called Cooperative Manufacturing Arrangements for Licensed Biologics dated November 2008, and this guidance document covers shared and divided manufacturing, contract manufacturing, and short supply arrangements. So the scenario described in this question would fall into the category of contract manufacturing, and, in this situation, since the manufacturing steps described are performed under contract, the facility information of the manufacturer that is doing the testing and manufacturing steps would be found in the records, and it would not be necessary for the label of the final product to include the manufacturing facility information in the lower right-hand quadrant of the ISBT 128 label. However, if the blood center did choose to include the manufacturing facility information on the label, on the container label, it would be acceptable, because, with contract manufacturing, it is optional to have that information on the label. However, please note that the same guidance document does go into detail about both shared and divided manufacturing, which have different labeling requirements than contract manufacturing. So, if there are questions regarding shared and divided manufacturing, please contact your Consumer Safety Officer, if you have further questions.
MODERATOR: Thank you, Jennifer.
Question 31: Until such time as the electronic crossmatch guidance is updated will you accept variance requests for alternative procedures such as mechanical and/or electronic systems (pre- and postanalytic phases) in lieu of a second collection sample?
MS. CIARALDI: Thank you, Allene. We thought it might be useful at this time to go ahead and clarify what is in our current guidance document. The guidance document is entitled "Computer Cross-Match (Computerized Analysis of the Compatibility between the Donor's Cell Type and the Recipient's Serum or Plasma Type)" and it's dated April 2011. In section IV(B)(2), entitled, The Element of a Computer Cross-Match System, instructions are provided to determine the recipient's group and type. It goes on to say that this can be either performed or maintained in a second record, and the second test would confirm the original test. It goes on to say that the second test may be a record of a previous test or a repeat test done on a second tube that's been separately drawn. The guidance recommends against repeating the group and type on the same tube, because wrong blood in tube is a major cause of ABO errors. FDA, in its guidance document, said that it's preferable to perform the group and type on two separately drawn test tubes. The guidance document does recognize certain situations when only one sample is going to be available. The two examples it gives are emergencies and home transfusion situation. In this case, the guidance document says that it's acceptable to repeat the test on the same tube with, again, some caveats. The two tests should be performed by different technologists or using different reagents. If the inquirer or anybody else would like a procedure different than what's in the guidance document, they can always contact us and talk to us about it, but, as you can see, that there are certain situations where one sample may be all that's needed, especially on a patient for whom you have a history of a group and type. Thank you.
MODERATOR: Thank you, Judy.
Question 32: If I collect only double RBCs by apheresis from my donors, defer them for 16 weeks, and do not allow intervening donations of any type, do I have to document and track the donor's annual RBC and plasma loss?
MS. FIELDS: Yes, we do require that all apheresis procedures track both red blood cell loss and plasma loss. These values should be documented on a rolling 12-month window to ensure that the donors are not over-collected, and one of the reasons that we need to track apheresis procedures is that they not only have complete procedures, but they also have incomplete procedures, and these values need to be included in the total red blood cell loss. But, as always, as we discussed with 21 CFR 640.120, you may submit an alternate procedure to this practice, and we will review it at FDA. Thank you.
MODERATOR: Thank you, Lore. And again, thank you all for staying with us for the hour-and-a-half, for the questions that you submitted, and I thank our FDA panelists for their time. Thank you.
ADDITIONAL CMS/CLIA Q&A
Question 33: Does the CLIA Laboratory Director oversight include the equipment validation, QC, calibration and preventive maintenance procedures? Can these duties be delegated?
CMS Response: The laboratory director must ensure that testing systems developed and used for each of the tests performed in the laboratory provide quality laboratory services for all aspects of test performance, which includes the preanalytic, analytic, and postanalytic phases of testing [42 CFR 493.1445(e)]. In order to ensure quality laboratory services, the CLIA laboratory director responsibilities include oversight of equipment validation, QC, calibration, and preventive maintenance procedures which can be delegated to the technical supervisor. The laboratory director may reapportion specific responsibilities to the technical supervisor in writing. These responsibilities are identified in the Interpretive Guidelines to 493.1445(e) and in CLIA brochure #7 Laboratory Director Responsibilities. All of this information is available on the CLIA website at www.cms/gov/clia. There are links on the left for the CLIA brochures and for the Interpretive Guidelines for Laboratories. Personnel requirements are found in Subpart M of the Interpretive Guidelines.
Question 34: If I perform testing that does not have a proficiency testing program available, what are my options for meeting the CLIA regulation?
CMS Response: If no CMS-approved proficiency testing program is available for testing performed by the laboratory, the laboratory must verify the accuracy of that test or procedure at least twice annually [42 CFR 493.1236(c)(1)(2)]. CLIA Brochure #8, Proficiency Testing, is available on the CLIA website.
Question 35: If our transfusion service has a different Medical Director than the one listed on the CLIA license, can he/she sign the transfusion service policies, processes and procedures?
CMS Response: The current laboratory director named on the CLIA certificate must approve, sign, and date procedures and changes in procedures [42 CFR 493.1251(d)]. This requirement applies to all procedures subject to CLIA. For example, a procedure for performing antibody screening would require the signature of the laboratory director. On the other hand, a procedure for performing a therapeutic phlebotomy would not require the laboratory director's signature, because performing a therapeutic phlebotomy does not fall within the scope of CLIA oversight. CLIA does not prohibit laboratories from developing policies that require additional signatures, for example, the medical director of a blood bank. Also, many laboratories perform additional reviews that are not required by CLIA, such as an annual review of procedures. These reviews may be performed by the individual designated by laboratory policy or the requirements of the laboratory's chosen accreditation organization.
Question 36: According to CLIA regulations what is the rule for direct observation of employees - does it have to be done on all procedures for each employee, every year?
CMS Response: The direct observations of employees are part of the competency assessment requirements for all personnel performing tests or procedures that are subject to CLIA [42 CFR 493.1451(b)(8)]. Employees are evaluated for all procedures subject to CLIA at least semiannually during the first year and at least annually thereafter [42 CFR 493.1451(b)(9)]. The technical supervisor for high complexity testing is responsible for performing and documenting the competency assessments. This responsibility can be delegated, in writing, to a qualified general supervisor [42 CFR 493.1463(b) (1-4)].