ASK THE FDA AND CMS/CLIA
October 24, 2011
AABB 2011 Annual Meeting
San Diego, California
- ALAN WILLIAMS, PhD – Associate Director for Regulatory Affairs, Office of Blood Research & Review (OBRR), CBER
- ELLEN F. LAZARUS, MD, CAPT, USPHS – Director, Division of Human Tissues, Office of Cells, Tissue, Gene Therapy, CBER
- ORIEJI ILLOH, MD – Medical Officer, Division of Blood Application (DBA), OBRR
- LESLIE HOLNESS, MD – Chief, Blood and Plasma Branch (BPB), DBA
- JUDY CIARALDI, MT (ASCP)SBB – Consumer Safety Officer, DBA
- LORE FIELDS, MT(ASCP)SBB – Consumer Safety Officer, BPB
- PAUL MIED, PhD – Deputy Director, Division of Emerging and Transfusion Transmitted Diseases, Office of Blood Research & Review, CBER
- 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)
- M. ALLENE CARR-GREER, Director, Regulatory Affairs, AABB
MODERATOR: I want to welcome everyone to today's session, "Ask the FDA and CLIA (Clinical Laboratory Improvement Act)". I am Allene Carr-Greer, the Director of Regulatory Affairs for AABB. I want to thank our panelists for coming this year and for some of them, year after year, to join me here, and also to thank those of you who have submitted questions for this session. Alan wanted a few minutes before we get started with our list of questions. So, I'll turn it over to Alan Williams.
DR. WILLIAMS: Thanks Allene. It is always gratifying to see the large turnout for this session. We do have a lot of interaction through the years, and it's always good to see so much interest and the quality of the questions that come to us for consideration. So, thank you for those, as well. One thing that has been under active development in large part within our office is the eSubmitter program which provides the software to allow electronic submissions from those of you who are submitting regulatory applications from blood establishments and other manufacturing facilities. This is a Turbo Tax-modeled program which allows submitting facilities to work through the software, answer questions, receive hyperlinks related to guidances and other prompts such as Standard Operating Procedures (SOPs) that are needed for a regulatory submission, and it really walks one through the process resulting not only ultimately in a faster submission, but a higher quality, more complete submission which helps at this end and ultimately should help to improve turnaround time for the review. This is a longstanding program now. eSubmitter is in use in most of the FDA centers now for everything from adverse event reporting to registration. We are now developing a template for Investigational New Drugs (INDs). It's a stable program and it was described in a session yesterday. Although there are some developmental things still to be worked out – some details, the ultimate conclusion was eSubmitters saved a lot of time, particularly with the replica type applications. So, I do encourage you to look into it and begin using it, and our staff here is very familiar with it and would be happy to help you.
MODERATOR: Thank you, Alan. There was one other thing that I just wanted to mention. On the FDA webpage today there is a Federal Register notice announcing a draft guidance document that is now available for comment on FDA's thinking on the abbreviated Donor History Questionnaire (aDHQ) that one of the AABB task forces has been working on for a number of years with the liaisons from FDA. That is available now for comment and for you all to have a look at the aDHQ so you can comment on the guidance document as well as the questionnaire documents. And Judy, who is our liaison from FDA has some information about those materials.
MS. CIARALDI: Thank you, Allene. I wanted to say that this is very exciting that it came out at this time. The title of the document is "Implementation of Acceptable Abbreviated Donor History Questionnaire and Accompanying Materials for Use in Screening Frequent Donors of Blood and Blood Components". And, this is a draft guidance document. As Allene said, this is a draft guidance document for comment only. The aDHQ is not yet recognized by FDA. It won't be until the final guidance is out. I've been approached by some blood establishments asking if they could implement what is in the draft guidance document. The draft guidance document is not directly for implementation, and the reason for this is that information within the guidance and possibly the aDHQ could be revised, edited or changed based on the incoming comments that we get. So, it's kind of a buyer beware. If you elect to do that, there is a chance you may have to revise it in the future. If you do have questions for the licensed blood establishments about using this, please call your Consumer Safety Officer (CSO). You will have to submit it as a prior approval supplement until it comes out as an accepted document in the final guidance. Thank you.
MODERATOR: Okay, we will start with our list of questions
Question 1: As a Cell Therapy Lab we participate in proficiency testing surveys that are not designated CMS approved PT (Proficiency Testing) Programs, including CAP Stem Cell Processing Survey, Charles River endotoxin proficiency testing, and STEMCELL Technology CFU proficiency testing. Is it okay to share the samples from these PT providers with other staff members provided that the initial PT results have been submitted to the provider or do we need to wait for the results to return before sharing?
MS. MEYERS: Before answering the first question today, I would like to remind the audience that many laboratories obtain their CLIA certification by virtue of accreditation by a CMS-approved accreditation organization. For those laboratories, you must follow the requirements of your accreditation organization which may be more stringent than the CLIA regulations. Back to the first question: I could have made this answer very complicated or very simple, so I'm going to give you the simple answer today. For the analytes in subpart I, of the CLIA regulations, CMS-approved proficiency testing is required. For those analytes, laboratories must not use the PT specimens for any other purpose until after the cutoff date for returning the results to the proficiency testing provider. However, for laboratory testing that is not subject to CLIA regulation, these requirements do not apply. There is a document on the CMS website that provides CLIA applicability determinations for many commonly performed laboratory tests that are related to blood and cellular therapy products and also organ testing. And we do receive a lot of questions about this type of testing and whether CLIA applies or not. This document can be found on the CLIA website at:
MODERATOR: Thank you, Penny.
Question 2: What is the Blood Bank Medical Director's responsibility for oversight of off-label use of factor concentrates?
DR. HOLNESS: The FDA has no specific regulations or guidance regarding the blood bank director's oversight of off-label use of factor concentrates. Your state or local laws may apply to the situation.
Question 3: Do regulations require segregation of volunteer donor collections/apheresis procedures from patient therapeutic or autologous collections/procedures in a donor collection area?
MS. CIARALDI: The applicable regulation for this is in the Code of Federal Regulations (CFR), 21 CFR 606.40, which is in the Facilities section of the Good Manufacturing Practices (GMP). 606.40(a) requires you to provide adequate space: (a)(5) is the storage of blood products awaiting distribution; (a)(6) is quarantine storage of products not suitable for use and (a)(7) is the orderly collection of blood components to prevent contamination. How, including where, you accomplish these objectives is really up to you. So, evaluate your process to determine if you are meeting those objectives.
MODERATOR: Okay, so nothing specifically to this – it's just an appropriate segregation of activities.
MS. CIARALDI: Well, the regulations don't include the word segregation. But, in the end, it is saying you must have adequate space so that these activities can occur without the possibility of contamination, and contamination is a broad term.
Question 4: According to the Federal Register Notice of 20 October 2009, cord bloods should be distributed as a licensed product or under an approved IND as of 20 October this year. While CT facilities and FDA have been actively working toward this goal/deadline a BLA (biologic license application) has not yet been approved, and we understand that FDA has not placed a clinical hold on existing INDs. Can you describe the processes cord blood banks and transplant centers should be following, and what notification process(es) will be used to notify them of changes? Going forward, how will FDA ensure that applicable facilities have a BLA or IND?
DR. LAZARUS: This is a very timely question. As of last week, unrelated allogeneic cord blood is manufactured and used under an IND or an approved biologic license when those approvals are obtained by the cord banks. In combination with all the efforts of the cord banks, and accrediting bodies such as AABB, we are now experiencing the culmination of quite a long process leading to all of our ability to ensure the safety and efficacy of all cord blood products being used to treat patients. I'm including cord blood products manufactured outside the US that are being used to treat patients in the US. So, I thank all of you who have been involved in that very long process for your patience and your input. As is noted in the comment in this question, FDA staff has been meeting individually with the cord banks to discuss the specifics of each bank's licensure application and their specific circumstances. Cord blood products that otherwise meet release criteria will still be permitted to be used under IND. And, the INDs are in place to assure this including the NMDP's (National Marrow Donor Program) umbrella IND. The agency does not intend to prevent access to products that are not yet fully in compliance with the IND requirements, provided that the IND sponsors or the IND holders are exercising their due diligence to complete the implementation process.
Regarding international cord banks (I did get a question about that earlier), a non-US cord bank is not required to submit an IND, though they may choose to do so. However, a cord blood product for clinical use in the US from a non-US bank that isn't a license holder can only be used under an IND, which may be a registry IND such as NMDP's or an IND held by the transplant center. Going forward, we'll continue to work with the cord banks and the transplant centers to complete the implementation process. Any changes to the existing requirements and recommendations that may occur would be communicated as usual through the agency's transparent guidance and rule-making processes and at public meetings such as this one. So, thank you for the opportunity to make a few comments about that.
MODERATOR: Thank you, Ellen.
Question 5: I understand that testing such as ABO/RH, antigen, and viral markers fall into the CLIA competency requirement (initial, 6 month and annually). What about other lab functions such as 1) pre-platelet count to determine donor eligibility to donate apheresis versus monthly QC (Quality Control) on products, 2) equipment/reagent QC, calibrations and PM, and 3) sample shipments (sending out for donor testing)?
MS. MEYERS: The regulations at 42 CFR 493.1451(a)(8) require the competency of all testing personnel to be evaluated. For part one of this question, platelet counts to determine donor eligibility are considered to be an assessment of donor health and thus are subject to all applicable CLIA requirements, including competency evaluation. On the other hand, platelet counts performed on blood products for QC purposes are not subject to CLIA regulations and thus the competency evaluation requirements do not apply.
For part two of this question, the regulations specifically require competency assessment evaluation to include, among other things, review of quality control records, and direct observation of performance of instrument maintenance and function checks. For part three of the question, packing samples for shipment is not subject to the formal competency evaluation requirements. However, the regulation at 42 CFR 493.1242 requires the laboratory to establish and follow written policies and procedures for specimen referral and the laboratory must also establish and follow written policies and procedures for quality assessment of its pre-analytic systems, which includes specimen referral.
MODERATOR: Thank you, Penny. I think someone is going to be very happy to have such a complete response to their question.
Question 6: Does the FDA have a recommendation at what age we should provide group O Rh positive blood to a pediatric male trauma patient?
DR. ILLOH: Do we mean here a provision of Rh positive blood to an Rh negative male trauma patient?
MODERATOR: To an Rh negative or I would say an unknown blood type.
DR. ILLOH: Okay, those are two questions but I think I can still answer the question. FDA does not provide regulations or recommendations on the age at which group O Rh positive blood should be issued to patients. I think this is a clinician's decision and we do not have any recommendations for that.
MODERATOR: So, if I had answered your question differently, what would you have said, Orieji?
DR. ILLOH: If you had asked me if you could give an Rh positive blood to an Rh negative male pediatric trauma patient, I would say yes, that is a decision a medical director can make, but either way, FDA does not have regulations or recommendations on whether you can give Rh positive blood to any patient.
MODERATOR: It sort of comes back to the same question that Dr. Holness answered for us. These are clinical decisions that FDA does not have regulations for and does not make recommendations for.
DR. ILLOH: Exactly.
MODERATOR: Thank you.
Question 7: Is it acceptable to perform supervisory review of proficiency test results before submission to the proficiency testing provider just as you would review results before reporting to a physician to ensure the results are reported correctly?
MS. MEYERS: 42 CFR 493.801(b) requires laboratories to examine or test proficiency testing samples in the same manner as it tests patients. Therefore, if the laboratory's procedure for patient specimens requires a supervisory review of test results before the test results are reported, then the proficiency testing results would be subject to the same review.
MODERATOR: Thank you, Penny.
Question 8: Is it necessary to perform parallel testing on new reagent lots of red cells and anti-sera used for ABO grouping and Rh typing before placing them in use?
MS. CIARALDI: We understood this to mean that part of the quality control procedures is to compare the old lot with the new lot that is now coming onto the shelf and that this is done during quality control procedures. That's how we interpreted this procedure. So, we hope we interpreted correctly. The applicable regulation for this is 21 CFR 606.65(c). It says representative samples of each lot of blood grouping reagent must be tested each day of use using methods described in your SOPs to determine their capability to perform as required. As you can see, there is no specific FDA regulation for parallel testing. Whatever procedures you decide to use, whether it is parallel testing or something else, should meet that final objective of determining if the reagents are able to perform as required. A lot of times we get questions about specific technical type procedures and is it covered in the CFR. As you'll notice, the CFR is not the same as an SOP. What it describes are final objectives that should be met and it gives you the flexibility to design procedures that will fit into your workflow. But in the end, keep asking yourself, during your validation, "does it meet the objectives in the CFR"?
MODERATOR: Thank you, Judy. And, I think you interpreted the question the same way that I did. So, hopefully, that will match up with the person who submitted the question.
Question 9: What are the requirements and responsibilities for a hospital transfusion service oversight of the perioperative blood salvage program that is administered totally by outside vendors?
DR. ILLOH: FDA does not have any requirements or recommendations on the responsibilities for a hospital transfusion service oversight of the perioperative blood salvage program. That is administered totally by outside vendors. Actually, we do not have any recommendations or requirements for perioperative services; however, we do recognize that there may be other accrediting bodies that have the latest standards to this issue. So, I think maybe look at AABB or CAP (College of American Pathologists).
MODERATOR: And there are a set of AABB standards for perioperative blood programs. Thank you, Orieji.
Question 10: (A favorite question) Please clarify the expiration date of FFP (Fresh Frozen Plasma), Plasma Frozen Within 24 Hours of Phlebotomy (PF24), and Aphersis FFP after thawing. The AABB BB/TS Standards and the Circular of Information (accepted by FDA) state 24 hours. The Technical Manual, 17th edition, lists 6 hours unless there is an FDA variance.
MS. FIELDS: I'll take that one. The expiration date for thawed FFP and Plasma Frozen within twenty-four hours is six hours, as described in 21 CFR 606.122(m)(3). However, FDA has granted a significant number of blood banks and transfusion services variances or alternative procedures to store their thawed FFP and PF24 for up to twenty-four hours. If you would like to store your thawed FFP or PF24 for up to twenty-four hours, please submit a variance to FDA.
MODERATOR: Thank you, Lore. The variance process has been in place for a number of years now. At this point in time, the Standards Program Unit and the Circular of Information task force just no longer mention the variance process. We do keep it in the technical manual so that everyone is aware of it. FDA is also updating that regulation and the update is in a proposed rule. We look forward to publication of a final rule that updates the regulation so that the variance is no longer necessary.
EDITORIAL NOTE: On 03 January 2012 FDA published a
Federal Register Notice (77 FR page 7) announcing the availability of
Final Rule: Revisions to Labeling Requirements for Blood and Blood Components, Including Source Plasma. The effective date of the rule is 02 July. 21 CFR 606.122(m)(3) – for Plasma – is updated from "When applicable, instructions to begin administration of the product within 6 hours after thawing" to "When applicable, instructions to begin administration of the product within a specified time after thawing".
Question 11: How do FDA guidance documents apply to the non-licensed blood product manufacturers and transfusion services?
MS. CIARALDI: FDA guidances explain regulations and GMP requirements. The GMPs apply to all blood establishments – licensed, unlicensed, registered, unregistered – this is described in the preamble in the Federal Register to the Current Good Manufacturing Practices (cGMP). Therefore, the guidance documents do apply to all blood establishments. However, some guidance documents do provide specific instructions that may either include or exclude a specific type of blood establishment. For example, the full length Guidance for Industry: "Implementation of Acceptable Full-Length Donor History Questionnaire and Accompanying Materials for Use in Screening Donors of Blood and Blood Components" includes instructions on how licensed blood establishments should report implementation of the DHQ and the accompanying materials. It goes on to include that unlicensed blood establishments may use the materials but do not need to report, so guidance documents do apply. Read carefully, because we may have additional instructions pointed to specific types of blood establishments.
MODERATOR: Thank you, Judy.
Question 12: In the following scenario does Pooled Cryoprecipitated AHF (Cryo) have an expiration of 4 or 6 hours? When preparing the pooled product prior to freezing, a vial of saline is entered by spiking with the spike on the transfer set (aseptic technique is used, but a sterile connecting device is not used). The transfer pack (plus saline) is then connected (using a sterile connecting device) to individual units of Cryo to create the pool. The pool is frozen within 1 hour.
MS. FIELDS: Prestorage Pooled Cryo AHF has a six hour expiration once it has been thawed for transfusion. I want to go on to mention though that we do not allow the process of spiking or opening the unit when you are manufacturing it. All steps in the manufacturing of prestorage Pooled Cryo should be either closed or what we consider functionally closed which is sterile connecting. If you are manufacturing it with an open system, you should probably contact your CSO to determine how to manufacture these products.
MODERATOR: Okay, thank you, Lore.
Question 13: Our hospital has subcontracted the labor of our transfusion service to an independent laboratory. The hospital owns the blood bank equipment, holds all agreements with blood suppliers, etc. The hospital is registered with the FDA and accredited by AABB. The independent laboratory hires and trains the staff for the transfusion service. The transfusion service does not collect any donors, including autologous donors, but does irradiate blood products. Does the independent laboratory need to be registered with the FDA?
DR. ILLOH: The hospital is registered with the FDA, and that is correct, they perform a manufacturing process. However, the independent lab, as it is written in this question, only hires and trains the staff for the hospital blood bank. Therefore the independent lab does not need to register.
MODERATOR: Thank you.
Question 14: Regarding the CLIA/CMS requirement that the Director who is named on the laboratory's CLIA Certificate must personally review all new and revised policies and procedures – is it permissible to define "substantially revised" so that the Director does not have to review clerical changes, updating of references, or minor changes, etc.? Does a definition already exist?
MS. MEYERS: And the answer to this is no. There is no CLIA regulation or policy that allows or contains a definition of "substantially revised".
MODERATOR: And the facilities should not create such a definition and use it as implied in this question.
MS. MEYERS: That is correct.
MODERATOR: Well, that sounds like a firm answer. Thank you, Penny. I must admit, we had several versions of this question. So, there are many facilities interested in the response.
Question 15: What would be an acceptable return policy for plasma products? Some plasma products are thawed (may be thawed at temperatures up to 37 C) and issued immediately and some are placed at 1-6 C prior to issue. Should separate temperature ranges be established or is it acceptable to have an all inclusive range?
MS. FIELDS: FDA does not have any policy guidance or regulation on acceptable return policies for plasma products. We suggest that you work with other groups – AABB, CAP, etc. – to determine how to handle this process at your facility.
MODERATOR: Okay, so there is no regulation, no guidance document about it, but possibly some best practices available. Thank you, Lore.
Question 16: What Guidance or criteria should blood centers use to determine when a medical director can make a decision versus contacting FDA for a decision?
MS. CIARALDI: This is a very important question. Whether a product that was manufactured and handled in a manner that was not consistent with GMPs – could that product be distributed? So, here we are not talking about a product that is made "without any question", rather something went wrong and now the question is "can we use that product"? As you know, the FDA office is not a twenty-four/seven operation. So, in emergency situations, when you cannot contact FDA before releasing the product, then the medical director must go ahead and evaluate any possible risks from using units that were not manufactured or handled according to GMPs, document that decision, and based on their medical judgment make a determination if the product can be released.
In this case, no report needs to be sent to FDA. In other words, we are not going to evaluate and approve the release of the product when the release has already been done. In other situations, during FDA's operating hours, if you do have a circumstance like this, where you want to use a product that is made or handled in a situation that is not consistent with GMPs, you should contact your CSO and determine if you do need to submit a variance or exception under 21 CFR 640.120. What that regulation does say, if you're worried about the emergency need, is in rare situations, if there is an emergency, the requester can call FDA and make a verbal request and FDA can give verbal approval. Of course, it is all followed up later on with a written request and a written approval. Even when we are not fully operational, there are possibilities for giving you a quick response. The bottom line is that after hours, if you do need to have this blood, and you are aware it was not made according to GMPs, the medical director can use medical judgment and determine if the product can be released and this should be fully documented. Again, you don't have to send it to us, because the deed is done, so to speak. So, we would not need to approve that. But, when we are open, please call us for consultation, and if it is one of those rare emergency situations, we can discuss verbal approvals. Thank you.
MODERATOR: Thanks, Judy.
Question 17: 2% Chlorhexidine Gluconate in 70% Isopropyl Alcohol is currently an approved agent to disinfect a donor's skin prior to blood collection. Is 3.15% Chlorhexidine Gluconate in 70% Isopropyl Alcohol also acceptable if shown to be effective by validation in the donor collection facility?
MS. FIELDS: Some arm scrub preparations are cleared to be used for blood collection, although we now understand that they may not be readily available. For those of you who wish to implement them, you can do your internal validation procedures and submit that in your annual report. However, if you are using one that is not cleared for use with blood collection, you will need to submit that to FDA. I would recommend calling your CSO and determine that the acceptable solution for arm scrub preparation can be used, and if you are a licensed firm, you would then submit your procedures as a prior approval supplement to your BLA or as directed by your CSO.
MODERATOR: Thank you, Lore.
Question 18: Recently, while making changes to existing product licensing information, our submissions have been rejected because they did not conform to FDA "guidances", even though the submitted procedures conform to current FDA "requirements". We have even been requested to conform to "draft guidances" that are still awaiting public comment. Can you explain this relationship between the guidance documents and regulations – in the context mentioned above – and especially how a draft guidance could be cause for not moving a BLA amendment forward?
MS. FIELDS: I know I usually keep my answers short and sweet, but this time I'm taking advantage. Final guidances are considered non-binding and I would like to read a paragraph that is in the guidance documents. It is usually somewhere on the first page. "FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the FDA's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited." And that is where we get into whether it is recommended or required. In our guidance documents, we do attempt to note anything that is directly related to a CFR citation, so that it is obvious what is a regulation and what is a recommendation. Sometimes, you will see us use the word "must", if it is a regulation, or "should", if it is a recommendation. For product licensure, we do ask that the firm submit an alternative approach if they are not going to follow our recommendations. And usually, at the beginning of the guidance document – in a big square box – there's a statement that says you can use an alternative approach if the approach satisfies the requirements of the applicable statutes and recommendations. If you want to discuss an alternative approach, contact the appropriate FDA staff.
As for draft guidances, these documents are published for comment and not for implementation. As most of you experienced or have seen in the past, our guidance documents frequently change when they come out in final version based on new scientific evidence or comments that we accept from industry. We encourage blood establishments to discuss any concerns with their application review process with their CSO and Dr. Holness, who is the branch chief of the Blood and Plasma Branch in the Division of Blood Application. And we may be able to more clearly describe our observation or better understand your process to come to an amicable solution.
MODERATOR: I do have a clarifying question. I believe I understand from what you just said and from what I already know, that the draft guidance recommendation should not have been a requirement in a BLA amendment.
MS. FIELDS: Correct.
MODERATOR: Thank you.
Question 19: How long can units of whole blood be left at room temperature before placement into transporters?
DR. HOLNESS: There are at least two regulations that refer to this issue. 21 CFR 640.24(b) states that if you intend to make platelets, the unit should be stored as close as possible to a range of 20-24 C during transport until the platelets have been separated, which should be within four hours or within the timeframe specified by your approved blood collection system. 21 CFR 640.4(h) states that if you are not making platelets, and I'm paraphrasing here, and the blood is transported, the units must be placed in temporary storage with sufficient refrigeration capacity to cool the blood continuously toward of temperature of 1-10 C. Blood from which a component is to be prepared must be held in an environment specifically for that component or as specified in the approved blood collection and processing system.
MODERATOR: So, it does not give a specific timeframe, but it just says that is should be placed in an environment to be cooled toward –
DR. HOLNESS: Continuously cooled toward 1-10 C.
MODERATOR: And thank you for providing the reference.
Question 20: When a Form 483 is issued to a blood center at the close of an inspection, why does the report not indicate the CFR regulation that we failed to follow?
MS. CIARALDI: Whoever submitted this – I really appreciate that you did, because I thought I knew the answer and as I researched this further, I realized there is more behind it. So, I was glad for the opportunity to learn something new and share it with you, and thank you right from the beginning. Just to let you know – backing up a long ways, the requirement to present Form 483 at the close of the inspection is in the Food, Drug, and Cosmetic Act (FD&C) – specifically, section 704(b). It says that we are required to present a written report at the close of the inspection listing any conditions or practices observed by the inspector which in his or her judgment could result in a product that may injure health. The applicable reference to delve in deeper to this is the Investigations Operations Manual (IOM). In the interest of transparency, this manual is available on the FDA Office of Regulatory Affairs (ORA) website:
http://www.fda.gov/ICECI/Inspections/IOM/default.htm. And what it says is that the determination of whether any condition is deemed violative – and violative means represents a violation of laws and regulations that are applicable to FDA purview – it is the determination of these conditions that is done by an agency decision made after consideration of all circumstances, facts, and evidence that is obtained during the inspection. It goes on to specifically say, "therefore don't quote the CFR sites on the 483". At the time the 483 is issued, it's not deemed a violation. It's deemed an observation. To go a little bit further, the IOM says that at the close of the inspection, we are to explain to the blood establishment being inspected, each listed condition and relate each condition to the applicable laws and regulations. We are also supposed to inform you that the listed conditions may, after further review by the agency, be considered to be violations of the FD&C Act and other statutes. Now, this review is done at several levels. It can be done by the inspector's supervisor, by the district office management, by the district office compliance officer, or by the CBER compliance officer. So, there is a lot of review that goes into the observations to determine if they are indeed violative. The bottom line is that, at the time of issuance, the 483 is a list of observations and not a list of violations. Therefore, there is not going to be a CFR site listed. Whether the observations are violations is determined after a complete review.
MS. CARR-GREER: Well, thank you, Judy. And I wonder who else in the audience knew that answer if you could raise your hand? I did not know the answer. I don't see any hands raised. Oh, did you see a hand? Well, a minority of people knew. Thank you.
Question 21: We have three hospitals in the health system. Soon there will be one medical record number per patient that will be used for all three facilities. Can a blood type performed at one facility count as a first or second type, when required, at another facility? For example, can an initial type at facility #1 be used to perform electronic crossmatches at facility #3? The three facilities have separate FDA registration numbers, AABB numbers and CAP numbers.
MS. CIARALDI: The CFR does not require two patient groups and types. So, we'll answer that first. But, having two patient groups and types is mentioned in a guidance document. Specifically, it is mentioned in the document titled: "Guidance for Industry: 'Computer Crossmatch' (Computerized Analysis of the Compatibility between the Donor's Cell Type and the Recipient's Serum or Plasma Type)". It was published as a final guidance in April 2011. What this guidance says is that you should determine a recipient's ABO and Rh antigens and you should either perform or maintain a record of a second test confirming the recipient's ABO and Rh. There is nothing in the guidance document that specifically prohibits the arrangement that is described in the question, but we feel that this would work best if the three facilities share information on the same computer system where the patient identity and the information about the patient, such as the group and type is the same format and is accessible by all three facilities. We feel that is the best way the objective of the guidance would be met.
MODERATOR: Thank you, Judy.
Question 22: With the ongoing transition from paper to electronic records, how are the FDA and CLIA transitioning inspectors from reviewing paper records to electronic? Blood banks have noted resistance from some inspectors at accepting and/or reviewing electronic records.
An example: a document is reviewed and the review signature is noted electronically, yet the inspector identified this as a discrepancy because there was no paper copy with review signatures
MS. CIARALDI: Penny and I are going to tag team on this one. From an inspector's point of view, the transition from paper to electronic is challenging. Having been doing inspections where everything is paper and then changing to looking at electronic records does require a new mindset – a new approach to reviewing information. But, we are in the process and since all of this started have been training our inspectors about electronic records and how to inspect them. And, it is an ongoing process because it is a different way of looking at the information.
From FDA's perspective, if you do have concerns about what your inspector is looking at and the comments that they are giving you about electronic records and any resistance or misunderstanding of where the information is, if these concerns cannot be resolved during the inspection with the inspector, then once the inspection is done, you are certainly free to contact the individual or the office that are mentioned in the top right-hand corner of the 482 and 483 – that is the main office of the area field investigator and they are listed for you so that you can call with any concerns or questions. But, from an inspector's standpoint, reviewing them does require some practice and everybody is learning as we go along.
MS. MEYERS: And from the CLIA point of view, CLIA does allow for both paper and electronic records and the required elements of laboratory records and test reports do not depend on their format. They must contain the same information whether paper or electronic. We also strive to ensure that all CLIA surveyors apply the regulations consistently and we will note the questioner's concern and will take it as a suggestion for a topic to emphasize in future surveyor training. We also request that laboratories assist their CLIA surveyors by orienting them to their electronic records system – some of which may not be familiar to them as there are many of them out there – and helping them find the records that they need to complete the survey.
MODERATOR: I was just thinking about the suggestion that with the variety of electronic systems available sometimes it may be a bit more than just the difference in paper and electronic, but the differences in electronic systems. I think Penny's suggestion – that some time spent orienting assessors to the electronic system being used – is helpful. Thank you.
Question 23: I think that Hemocue devices are considered waived testing. Yet CLIA inspectors sometimes insist that QC must be performed, along with external proficiency testing. Do Hemocue devices fall under waived testing?
MS. MEYERS: In order to determine that CLIA tests complexity of any test system, you can consult the FDA Center for Devices and Radiological Health (CDRH) CLIA database at:
FDA/CDRH/CLIA. When I looked this up yesterday, I myself was surprised to find that some Hemocue instruments are waived and there are others that are moderate complexity. So, for the waived instruments, CLIA requires that the manufacturer's instructions be followed and this is required at 42 CFR 493.15(e)(1). For those moderate complexity instruments, the CLIA requirements for moderate complexity test systems apply, of course. You should also be aware that some accreditation organizations and states may have requirements for waived testing that are more stringent than CLIA.
MODERATOR: Thank you, Penny. And now I don't feel at all bad about admitting I did not know this answer.
Question 24: I am very interested in the whole concept of "in-process" testing. Since the manufacturers are now requiring recovered plasma to be tested for Parvo B19 and HAV, many places are performing testing after 42 days (fresh products would not be available to recall if the test was positive). Donor notification does not occur with "in-process" testing. But the information, particularly Parvo positivity, could have medical importance for the donor or his/her contacts.
- What is the definition of "in-process" testing?
- Does "in-process" testing exclude donor notification and management?
DR. MIED: I would like to refer you to the July 2009 FDA Guidance Document for Industry:
Nucleic Acid Testing (NAT) to Reduce the Possible Risk of Parvovirus B19 Transmission by Plasma-Derived Products. In that guidance we recommend performing Parvo B19 NAT as an in-process test for source plasma and for recovered plasma that is used in the further manufacturing of plasma-derived products. So, the NAT testing is an in-process test. It is not performed on the finished products – the plasma-derived products. Human Parvo Virus B19 is a virus that is highly resistant to all commonly used inactivation methods, including heat and solvent detergent treatment. And, it is also difficult to remove by filtration because of its very small size. Parvo B19 can be transmitted by blood components and certain plasma derivatives and it may cause morbidity to susceptible recipients. The disease transmission by transfusion of blood components is very rare. However, extremely high levels of Parvo B19 – in some cases up to 1012 IU/mL – in plasma of acutely-infected but asymptomatic donors may present a greater risk in plasma derivatives due to the pooling of large numbers of plasma units in the manufacturing of these products.
The virus can be detected by NAT in plasma pools when there are high levels of Parvo B19 DNA in viremic donations. FDA's recommendation for mitigating the risk of Parvo B19 transmission by plasma derivatives is to limit the virus load in the manufacturing plasma pool by testing, as an in-process test, the plasma donations for high-titer Parvo B19 DNA using a minipool format. Testing in a minipool format to measure the viral load for Parvo B19 DNA in a manufacturing plasma pool is acceptable in order to exclude only the high-titer plasma donations, thereby avoiding too great a loss of plasma for further manufacturing and to not diminish the Parvo B19 antibody levels in plasma pools and in some of the resulting plasma-derived products. FDA recommends that when the high-titer individual unit from a positive pool is identified, you should not use that individual plasma unit if it has a high-titer of Parvo B19 DNA that might result in a plasma manufacturing pool exceeding a Parvo B19 DNA titer of 104 IU/mL.
Now, FDA recognizes that in the current business practice for Parvo B19 NAT in-process testing, several weeks can elapse between collection of the units of source plasma or recovered plasma and the identification of B19 NAT positive pools or units. FDA encourages manufacturers of plasma-derived products to employ practices that will reduce the time between product collection and in-process testing. This will allow for meaningful notification of blood and plasma collecting establishments of positive test results within the dating period of any blood components intended for use in transfusion. And FDA believes that timely notification of the donor of a positive unit could have medical benefit, especially in preventing secondary transmission of the Parvo B19 infection to the donor's contacts.
In summary, FDA encourages manufacturers to shorten the time between collection and testing. FDA encourages deconstruction of a positive pool of greater than 104 IU/mL to identify the individual high-titer unit or units. When that individual positive donation is identified, we recommend in the guidance that you not use that high-titer unit and we encourage timely notification of the collecting establishment so that positive donors may be notified so that transmission of the infection to the donor's close contacts may be prevented.
MODERATOR: Thank you, Paul. I just have a couple of questions for clarification – I was looking quickly over that guidance document before the session. The guidance is to the manufacturers of the finished product – the plasma-derived product, rather than blood establishments that collect the plasma. Is that correct?
DR. MIED: It is to the manufacturers of plasma-derived products.
MODERATOR: Concerning the recommendations for in-process testing – you mentioned the minipool is performed on the manufacturing pool of plasma.
DR. MIED: That is correct. Yes. Testing on the minipool.
MODERATOR: What I forgot to look for in the guidance document, so I wanted to ask you: is there a definition section in that guidance document where there is a definition of in-process? I didn't think there was.
DR. MIED: No, there is not. But, it is testing on the plasma units themselves in a minipool format that are in-process, in the manufacturing process, of finished products. So, it is not testing of the finished products themselves – the plasma derivatives, but it's testing of the plasma units.
MODERATOR: Thank you.
Question 25: I am not sure of CLIA requirements for point of care testing (POC), especially QC requirements related to point of care testing. Does CMS waive POC testing or do some POCs fall into other categories? References would be helpful.
MS. MEYERS: This is a really great question, because point of care testing has become so widespread in a variety of different healthcare settings. The fact that a test system is used in a POC setting does not exempt it, however, from CLIA requirements. The CLIA requirements are based on the complexity of the test, be it waived, moderate, or high complexity.
In fact, one of the fundamentals of CLIA is that patients are entitled to the same quality of laboratory testing regardless of where it is performed, whether it is in a traditional laboratory, a physician's office, at the patient's bedside, or in any other location. As stated earlier, you can find the test complexity of any test system on the
FDA/CDRH/CLIA website. If the test is waived, and many POC test systems are waived, but not all, there is a requirement for these waived test systems to follow the manufacturer's instructions for their use. If, however, the test is non-waived, then the CLIA requirements for non-waived testing, moderate or high, must be followed.
MODERATOR: Thank you, Penny.
Question 26: The 2012 Yellowbook and the electronic version has a great new addition of "risk". They actually tell us if a country has no risk, very low risk, low risk, moderate risk, or high risk. We hear a lot about the use of risk analysis in making decisions and would like to know how these new categories could be used to assist us in screening for malaria?
DR. MIED: In the Yellowbook, CDC frequently changes these malaria risk terminologies for different countries and different areas within a country. We need to keep in mind that the focus of the CDC Yellowbook is not on deferral and management of donors who visit these areas, but it is intended to be a sort of travel advisory on whether or not a traveler from the US should take malaria prophylaxis prior to the visit and also should they take precautions during their visit to that area. FDA considers that any degree of malaria risk – from the subjective designations of very low to high – for a particular area should cause that area to be considered a malaria endemic area, and should be sufficient to trigger deferral of a donor who has traveled to that area. Now, we intend to issue a guidance document and address this point and make it perfectly clear in future guidance.
MODERATOR: Thank you, Paul. The clarity will be appreciated.
Question 27: What is the expectation the FDA has as it relates to managing 200 mL and 300 mL volume losses in the previous 56 days for donors that switch between whole blood and apheresis donations?
For example - an apheresis donor has a rinseback loss but is still eligible to donate in 7 days, if that donor donates a whole blood donation how are you ensuring the donor is deferred for 112 days?
MS. FIELDS: I am going to answer that question in two parts. The first is that FDA's expectation is that red cell loss and plasma loss from the donors are tracked for the rolling twelve-month period and that the donors are deferred for the appropriate time period when appropriate.
As for the example here, I think I need to clarify something for this author. The 200 mL and 300 mL red cell loss criteria that are in the apheresis guidance documents – both "Collection of Platelets by Automated Methods" and the "Recommendations for Collecting Red Blood Cells by Automated Apheris Methods" applies only to incomplete procedures from those devices for those products. So, it doesn't account for normal routine red cell loss. In this example, this donor who had, I'm assuming, an initial loss of less than 200 mLs would only be deferred for fifty-six days instead of 112 days after their whole blood donation. The amount of red blood cell loss in a donor is a concern for the FDA, and we've been discussing it extensively both internally and externally. And just to make a short announcement, if I may, we will be having a hemoglobin workshop at NIH on November 8th and 9th that will have to do with donor hemoglobin eligibility issues.
MODERATOR: Thank you, Lore.
Question 28: Do we need to track (e.g., lot number and dates of use) blood administration sets?
DR. ILLOH: We do not have any requirements or recommendations on recording or tracking the lot numbers on blood administration sets.
MODERATOR: Some places might consider them a critical supply if they're being issued, or if it is within the hospital, but outside the blood bank, hopefully someone in the hospital is tracking them.
DR. ILLOH: Yes, we agree it is a good idea, but we do not have any regulations.
Question 29: Are there circumstances when a biologic crossmatch is recommended rather than an electronic crossmatch?
MS. CIARALDI: We were a little unsure about the term "biologic crossmatch". I guess there would be a lot of different explanations for it, but we interpret this to mean a serologic crossmatch and we answered the question from this perspective. We define a serologic crossmatch as a physical in vitro laboratory test. The applicable reference for this is the April 2011 computer crossmatch guidance document for industry: "Guidance for Industry: 'Computer Crossmatch' (Computerized Analysis of the Compatibility between the Donor's Cell Type and the Recipient's Serum or Plasma Type)". It recommends that a serological crossmatch be used in the following situations instead of the electronic crossmatch: (1) When ABO discrepancies are found in the potential recipient. (2) If the recipient has clinically significant antibodies. (3) If the donor has clinically significant antibodies, and (4) if the computer crossmatch process has not been fully or properly validated. In some cases, the computer system or the Blood Establishment Computer System (BECS) may actually require a serologic crossmatch in the event of clinically significant antibodies. That may be part of the programming. We have been asked if a serologic crossmatch is still needed for when serologic antibodies are present, particularly if the computer system has been properly programmed and validated and includes all the necessary information to identify compatibility between a patient and a donor matching up the antibodies and the phenotypes. We are looking more closely into this to see if that is feasible and we can have another look at that guidance document.
MODERATOR: Thank you, Judy, and for mentioning that FDA is looking again at the issue of allowing computer crossmatches when antibodies are present.
Question 30: The September 2003 guidance document "Notifying FDA of Fatalities Related to Blood Collection or Transfusion" provides instructions on notification of fatalities related to blood collection or transfusion, and 21 CFR 606.170(b) provides instructions for notifying FDA of complications that are confirmed to be fatal. Please clarify whether the requirement is to make a notification of death based on "related to" or "confirmed to be".
MS. CIARALDI: Thank you, Allene. The fatalities are handled not by OBRR, where I work, but by the Office of Compliance and Biologics Quality. I contacted my colleagues there and they provided me with the response to share with you. One thing I do want to point out is that the guidance document that's mentioned in the question also contains the term "confirmed to be". The reason is because it completely cites the regulation. So, it isn't that the guidance document only talks about "related to". It does include the phrase "confirmed to be", just like the regulation. What the office of compliance has told me to share with you is that the key phrase between both the guidance document and the regulation is "confirmed to be". He also wanted me to share with you the phrase "as soon as possible". So, two clean, clear phrases. Most reporters recognize the importance of reporting as soon as possible any fatalities and at that point, the investigation may not be complete enough to determine if a fatality is indeed confirmed to be due to the collection or the transfusion before submitting that initial report. The seven-day follow up report that is submitted usually includes information to determine if the fatality is in fact confirmed to be due to the collection or the transfusion. So, at the time of the initial report, you give us what you have, and there's a possibility it might be connected, but the seven-day follow up report is where the actual determination of confirmation or ruling out exists. The information is available on the web at:
MODERATOR: Thanks, Judy.
This brings us to the end of this year's session. I want to thank the audience, many of you, I hope, submitted the questions and I thank again our colleagues at FDA and at CMS for sitting on the panel and providing our responses. Thank you.