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WARNING LETTER

April 30, 2024

Dear Dr. Asmar:

The United States Food and Drug Administration (FDA) conducted an inspection of your firm, Washington Fertility Center, located at 4316 Evergreen Lane, Annandale, VA, between October 11, 2023, and November 2, 2023. During the inspection, an FDA Investigator documented significant deviations from the regulations for human cells, tissues, and cellular and tissue-based products (HCT/Ps) set forth in Title 21, Code of Federal Regulations (CFR) Part 1271 (21 CFR 1271) and issued under the authority of Section 361 of the Public Health Service Act (42 U.S.C. 264).

The deviations documented on the Form FDA 483, List of Inspectional Observations (FDA 483), presented to and discussed with you at the conclusion of the inspection. These items of concern include, but are not limited to, the following:

1. Failure to test a specimen from an anonymous or directed reproductive donor of cells or tissue, whether viable or non-viable, for evidence of infection due to relevant communicable disease agents [21 CFR 1271.85(a)]. For example, the donor specimen collected from anonymous oocyte donor (b)(6), (b)(7)(C) on (b)(6), (b)(7)(C) End of
Translation , was not tested for human immunodeficiency virus, type 1 (HIV-1), hepatitis C virus (HCV), and hepatitis B virus (HBV) by the nucleic acid test (NAT) method. Oocytes were recovered from this donor on (b)(6), (b)(7)(C).

2.  Failure to screen a donor of reproductive cells or tissue by reviewing the donor’s relevant medical records for risk factors for, and clinical evidence of, relevant communicable disease agents and diseases [21 CFR 1271.75(a)]. FDA’s regulations at 21 CFR 1271.3(s) define the term “relevant medical records” to include a current donor medical history interview and a current report of the physical examination of a living donor. For example:

a) The records for directed oocyte donor (b)(6), (b)(7)(C) lack documentation of a current medical history interview and current report of the physical examination of the donor. Oocytes were recovered from this donor on (b)(6), (b)(7)(C).

b) Your donor medical history questionnaire, Donor Medical History Interview Questionnaire and Zika Virus Screening Questionnaire for Oocyte Donors, are used as relevant medical records to determine donor eligibility. However, the forms do not include screening for all conditions and/or behaviors that increase a donor’s relevant communicable disease risk. For example, questions for the following risk factors for relevant communicable disease agents and disease are incomplete:

i. Question 2 of the ZIKA Virus Screening Questionnaire for Oocyte Donors asks, “Have you resided in or traveled to an area (refer to Zika list, page two) with active Zika virus transmission, in the past 6 months?” This question should ask, “Have you resided in or traveled to an area with an increased risk for ZIKV transmission in the past 6 months?”

ii. The ZIKA Virus Screening Questionnaire for Oocyte Donors lists “Current Zika Affected Areas” as of March 27, 2019. However, this list has not been updated to include all the current ZIKA virus (ZIKV) risk areas around the world.

iii. Question 23 of the Donor Medical History Interview Questionnaire states, “Since 1980, have you ever lived in or traveled to Europe? (includes: Albania, Austria, Belgium, Bosnia-Herzegovina, Bulgaria, Croatia, Czech Republic, Denmark, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Liechtenstein, Luxembourg, Macedonia, Netherlands, Norway, Poland, Portugal, Romania, Slovak Republic, Slovenia, Spain, Sweden, Switzerland, and Yugoslavia).” Although the question asks if the donor has ever lived in or traveled to Europe, it is qualified by listing specific countries of travel. The U.K. (England, Scotland, Wales, the Isle of Man, the Channel Islands, Gibraltar, and the Falkland Islands) is not included in this list. If the donor answers “No” to question 23, the questionnaire instructs the donor to skip questions 23 (a-c) pertaining to CJD risk factors within the U.K. (travel and transfusion of blood or blood components).

3. Failure to determine whether a donor is eligible based upon the results of donor screening in accordance with 21 CFR 1271.75 and donor testing in accordance with 21 CFR 1271.80 and 21 CFR 1271.85 [21 CFR 1271.50(a)]. For example, the eligibility of anonymous oocyte donor (b)(6), (b)(7)(C) was determined and documented prior to the receipt of the results of donor testing for relevant communicable disease agents. A specimen for communicable disease testing was collected from anonymous oocyte donor (b)(6), (b)(7)(C) on (b)(6), (b)(7)(C). Donor (b)(6), (b)(7)(C) was determined eligible on December 7, 2021, but test results were not reported until December 9, 2021.

4. Failure of a responsible person to determine and document the eligibility of a cell or tissue donor [21 CFR 1271.50(a)]. For example:

a) The records for anonymous oocyte donor (b)(6), (b)(7)(C) (oocyte recovery date: (b)(6), (b)(7)(C)) did not contain any documentation of the donor eligibility determination, which must be based on the results of mandatory donor screening and testing.
b) The records for anonymous oocyte donor (b)(6), (b)(7)(C) (oocyte recovery date: (b)(6), (b)(7)(C)) did not contain any documentation of the donor eligibility determination, which must be based on the results of mandatory donor screening and testing.
c) The records for anonymous oocyte donor (b)(6), (b)(7)(C) did not contain documentation that the donor was determined “eligible.” The Summary of Records form for donor (b)(6), (b)(7)(C) included the name of the responsible person and the date, however the record did not document that the donor was determined eligible.

5. Failure to establish and maintain procedures for all steps performed in testing, screening, determining donor eligibility, and complying with all other requirements of Subpart C “Donor Eligibility” in 21 CFR Part 1271.45-1271.90. “Establish and maintain” means define, document, and implement; then follow, review, and as needed, revise on an ongoing basis [21 CFR 1271.47(a)]. For example:

a) Your procedures do not include the requirement to screen donors for risk factors for ZIKV.
b) Your procedures do not include HBV NAT as a required test for relevant communicable disease agent and diseases.
c) The current version of your Donor Medical History Interview Questionnaire, used to screen anonymous oocyte donors, was revised on November 17, 2021; however, the previous and obsolete questionnaire (revised on June 1, 2019), was the version included in the current procedure manual and was used to screen at least two donors.

6. Failure to establish and maintain a procedure governing the release of an HCT/P from a donor whose specimen tests reactive for cytomegalovirus (CMV) [21 CFR 1271.85(b)(2)].
For example, your procedures do not include how you will communicate test results of donors who are positive or reactive for CMV total antibody, including how the CMV test results should be communicated to the physician responsible for accepting the HCT/P.

The deviations identified above are not intended to be an all-inclusive list of deficiencies at your facility. It is your responsibility to ensure that your establishment is in compliance with all applicable requirements of the federal regulations. You are responsible for reviewing your firm’s operations as a whole to ensure that you are in compliance with all FDA regulatory requirements.

We acknowledge receipt of your letter dated November 10, 2023, which provides a response and corrective actions to FDA’s inspectional observations. We have reviewed the corrective actions outlined in the response and we have determined that they are inadequate to address our concerns. A previous inspection of your facility conducted between October 30, 2018, and November 14, 2018, resulted in the issuance of an Untitled Letter dated May 3, 2019. Despite your commitment to correct the previously noted violations, the current inspection (October 11, 2023 - November 2, 2023) documented some of the same or similar violations, indicating that your corrective actions were either not implemented or were not effective to prevent the recurrence of the previously identified violations. We have serious concerns about your ability to correct the violations noted above and prevent their recurrence.

Your July 13, 2019, response to the Untitled Letter included a corrective action plan that committed to both immediate and preventive corrections such as revisions to forms and procedures. For example:

1. In regard to screening donors for ZIKV, you stated, “Current Zika Virus screening form for Oocyte Donors is currently updated periodically and includes all areas at risk for ZIKA according to the CDC including area within the United States.” Yet the current inspection documented that you are continuing to screen donors with the ZIKA Virus Screening Questionnaire for Oocyte Donors that lists “Current Zika Affected Areas” as of March 27, 2019. Your form was not updated at the time of your response and has not been updated since. The latest update on areas with Zika virus risk from the Centers for Disease Control and Prevention is dated October 11, 2022.

2. Regarding the failure to perform a physical examination for donors, you stated, “The provider shall accurately complete the physical examination. All forms shall immediately be entered into the Donor’s (b)(4) Medical Record.” During the current inspection, at least two donors were missing documentation of a physical examination.

3. In regard to establishing and maintaining a procedure for the release of an HCT/P from a donor whose specimen tests reactive for CMV, you stated, “Our procedure now mandates that the release of HCT/Ps from all semen donors who test positive for CMV shall have this information appear in materials accompanying the HCT/P so that the physicians can make an informed decision about the use of an HCT/P.” However, the current inspection documented that this procedure was still missing.

4. In the May 3, 2019, Untitled Letter, we noted that our review of your Procedure Manual for the Washington Fertility Center (effective 12/03/13), found requirements that were not in accordance with 21 CFR 1271. For example, the “Donor Testing” section for anonymous donors stated that a positive test for Hepatitis B Surface Antigen (HBsAg), “may not make the donor ineligible.” In accordance with 21 CFR 1271.80(d)(1), a donor whose specimen tests reactive on a screening test for a communicable disease agent in accordance with 21 CFR 1271.85 must be determined to be ineligible. This applies to both anonymous and directed donors.

Additionally, the section discussing testing for directed donors states that positive results for the relevant communicable diseases listed “would require special labeling of HCT/P.” While special labeling is required for such donors under 21 CFR 1271.65(b)(2), we note that your procedure does not require that directed donors with positive test results for a relevant communicable disease agent be determined ineligible.

Our review of your HCT/Ps Procedure Manual v. 3.0, revised in February 2021 and in use during the current inspection, noted that these two requirements related to anonymous and directed donor testing had not been updated since the issuance of the Untitled Letter.

We recommend that you review your firm’s procedures and make the necessary changes to ensure they include all steps that you perform in testing, screening, determining donor eligibility, and complying with all other requirements of subpart C - Donor Eligibility.

Additionally, we have the following comments regarding your November 10, 2023, FDA 483 response and your firm’s corrective actions to the most recent inspection of your establishment.

1. We want to remind you of the labeling requirements for HCT/Ps from donors for whom a donor eligibility determination is not required under 21 CFR 1271.90(a) and (b). Please note that such HCT/Ps must be labeled in accordance with 21 CFR 1271.90(c).

2. Regarding the documentation of the donor eligibility determination, please note that in accordance with 21 CFR 1271.50(a), a responsible person must determine and document the eligibility of a cell or tissue donor. In accordance with 21 CFR 1271.55(d)(1)(iii), such documentation must include the name of the responsible person who makes the determination and the date of the determination. Under 21 CFR 1271.55(d)(2), all records must be accurate, indelible, and legible. If you designate more than one responsible person for such purposes, the donor eligibility determination documentation should reflect the person making the determination.

Please note that if you still have oocytes and/or semen in storage from donors whose screening and/or testing was not completed in accordance with 21 CFR Part 1271, FDA considers the donor eligibility determinations to be incomplete for these donors. For example, this includes donors who were not appropriately tested for relevant communicable disease agents and diseases (i.e., HIV-1/HCV/HBV NAT) and/or who were not appropriately screened for relevant communicable disease risk factors. Therefore, as required by 21 CFR 1271.60(a), you must keep these HCT/Ps in quarantine.

Should the need arise in the future to remove any of these HCT/Ps from quarantine, either for use in your own establishment or for transport to another establishment, you may request an exemption or alternative from a requirement in Subpart C, 21 CFR Part 1271, as specified in 21 CFR 1271.155. Additional information can be found at Exemptions and Alternatives | FDA. The email address for submissions is HCTPExemptions@fda.hhs.gov.

Please note that 21 CFR 1271.155 requires that you provide justification for use of HCT/Ps from these donors, as well as information on how you have mitigated the risk consistent with the goals of protecting the public health and/or preventing the introduction, transmission, or spread of communicable diseases. Before any of these HCT/Ps can be removed from quarantine, the request must be granted by FDA.

If you still have embryos in storage for which the donor eligibility requirements under 21 CFR 1271, Subpart C are not met, please note that FDA considers the donor eligibility determinations to be incomplete for these donors. Therefore, as required by 21 CFR 1271.60(a), you must keep these HCT/Ps in quarantine. Should the need arise in the future to remove any of these HCT/Ps from quarantine, either for use in your own establishment or for transport to another establishment, you may release these HCT/Ps from quarantine (21 CFR 1271.90(b)) provided they are labeled in accordance with the applicable regulations at 21 CFR 1271.90(c).

You should take prompt action to correct the violations addressed in this letter and prevent their recurrence. Failure to promptly correct these violations may result in regulatory action being initiated by the FDA without further notice.

We request that you respond in writing within fifteen (15) working days from your receipt of this letter, outlining the specific steps you have taken or plan to take to correct the noted violations, including an explanation of how you plan to prevent these violations, or similar violations, from occurring again. If you believe that your products are not in violation of the law, include your reasoning and any supporting information for our consideration. Additionally, include any documentation necessary to show that correction of any of the above-noted violations has been achieved. If you cannot complete all corrections within fifteen (15) working days, please explain the reason for your delay and the time frame within which the remaining corrections will be completed.

Your response should be sent to Alice Silva, Compliance Officer at the following email address: Alice.Silva@fda.hhs.gov. If you should have any questions, please contact Alice Silva, Compliance Officer via email.

Sincerely,
/S/

Michael W. Roosevelt
Program Division Director
Division 1 - Office of Biological Products Operations