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WARNING LETTER

April 2, 2020

Warning Letter #OBPO 20-605068

Dear Dr. Lee:

The United States Food and Drug Administration (FDA) conducted an inspection of your firm, American Fertility Medical Center, Genetic Infertility & Andrology Lab, located at 2 Hughes, Suite 175, Irvine CA, between January 14 and January 22, 2020. 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, were presented to and discussed with you at the conclusion of the inspection. FDA has found additional significant violations upon further review of the documents collected during 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 records for anonymous oocyte donors #(b)(6) and #(b)(6), directed oocyte donor (b)(6), and directed semen donor (b)(6) (#(b)(6)) were missing results of testing for relevant communicable diseases, including HIV-1/2, hepatitis B, hepatitis C, syphilis, gonorrhea, and chlamydia.

2. Failure to determine as ineligible a donor whose specimen tests reactive on a screening test for a communicable disease agent in accordance Sec. 1271.85 [21 CFR 1271.80(d)(l)]. For example:

a. The record of the physical examination for directed semen donor (b)(6) (#(b)(6)), dated May 13, 2019, documents that the donor had a history of being treated for syphilis three times, including having completed the last treatment on April 29, 2019. A specimen collected from donor (b)(6) on May 13, 2019 tested reactive for T pallidum. Donor (b)(6) was not determined ineligible, as required.

b. Specimens collected from directed semen donors, (b)(6) (#(b)(6)), (b)(6) (#(b)(6)), and (b)(6) (#(b)(6)), on March 2, 2019, September 6, 2019, and May 18, 2018, respectively, tested reactive on a screening test for the antibody to hepatitis B core antigen (anti-HBc). None of these donors were determined ineligible, as required.

3. 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. Our review of your donor records found that seven donors were missing documentation of a screening for risk factors for, and clinical evidence of, relevant communicable disease agents and diseases. For example:

a. Two donor records were missing documentation of a medical history interview.

b. Five donor records were missing documentation of a physical examination.

4. Failure of a responsible person to determine and document the eligibility of a donor of reproductive cells or tissue based on the results of donor screening and testing [21 CFR 1271.50(a)]. For example, a review of your donor records found that the donor eligibility determination was not performed in accordance with the regulations. The donor records did not include forms documenting that the donors were determined "eligible" or "ineligible" based on the results of donor screening and testing, the signature of the responsible person who made the determination, and the date of the eligibility determination.

5. Failure to establish and maintain a standard operating 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 the CMV test results will be communicated to the physician responsible for accepting the HCT/P so that they may rely on the information to make informed decisions about the use of an HCT/P in a particular recipient's situation. At least seven of your directed semen donors tested positive for CMV.

6. Failure to establish and maintain procedures for all steps performed in testing, screening, and determining 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 (in writing or electronically), and implement; then follow, review, and as needed, revise on an ongoing basis [21 CFR 1271.47(a)]. For example, you did not have procedures for all steps that you perform in donor testing, screening, and determining donor eligibility of semen and oocyte donors.

To date, we have not received a response to the observations on the FDA-483 provided to you at the close of the inspection; therefore, we are unable to evaluate what, if any, corrective actions you have implemented, or plan to implement and whether they are adequate to address our concerns.

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 the applicable requirements of the federal regulations. You are responsible for reviewing your firm 's operations as a whole to assure that you are in compliance with all the FDA regulatory requirements.

Finally, we have the following additional comments regarding your firm's operations:

1. Our review of your form, Screening Questionnaire (Final Edit: 12/26/2018, Form 2010), noted questions that do not adequately screen donors for risks of communicable disease agents or diseases, as follows:

a. Question #8 states, "Had sex in the preceding 12 months with any person described in Question 1-4 above ... " However, the question is supposed to address the risk factors associated with the four questions directly above question #8 (ie: questions 4-7). Instead, the question directs donors to address questions #1-3, which are not regulatory requirements under 21 CFR 1271.

b. Question #40 states, "Have you had sex within the past 6 months with a male who is known to have ... " The question should ask, "Have you had sex within the past 6 months with a person who is known to have ... "

2. As required under 21 CFR 1271.80(d)(l), you must determine to be ineligible, a donor whose specimen tests reactive on a screening test for a communicable disease agent, in accordance with 1271.85. Also, as required under 1271.75(d)(1), you must determine to be ineligible a donor who is identified as having a risk factor for, or clinical evidence of, any of the relevant communicable disease agents or disease for which screening is required under 1271.75(a)(1), (b), or (c). Use of HCT/Ps from an ineligible donor is not prohibited in the case of a directed reproductive donor, provided the HCT/P from the donor is properly labeled with the appropriate warning labels, as described in 1271.65(b)(2) and you document that you notified the physician using the HCT/P of the results of testing and screening, as required under 1271.65(b)(3).

3. A review of your donor records noted that the records are not accurate, indelible, and legible, as required under 21 CFR 1271.55(d)(2). For example:

a. The Anonymous/Known Egg Donor Screening form appears to be a summary of records required under 21 CFR 1271.55(a)(3), although it does not contain all the required information. As such, this form must not contain the donor's name or other personal information that might identify the donor, as stated in 1271.55(c). The Anonymous/Known Egg Donor Screening form for anonymous donor #(b)(6) contains the donor's full name.

b. The Screening Questionnaire form for directed semen donor (b)(6) (#(b)(6)) is missing the identifying information (i.e.: the donor's name or number) to relate the HCT/P to the donor and to all records pertaining to the HCT/P.

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, donors who were screened using a donor history questionnaire that was missing required screening questions, and donors who are missing a required donor history questionnaire, physical examination, and/or testing for relevant communicable disease agents and diseases. 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 oocytes or semen 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: http://www.fda.gov/BiologicsBloodVaccines/TissueTissueProducts/Regulationoffissues/ExemptionsandAltemativeProcedures/default.htm). 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 part 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 addresses 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 cannot complete all corrections within fifteen (15) working days, please explain the reason for your delay and time frame within which the remaining corrections will be completed.

Your response should be sent to the following address: Marc Jackson, U.S. Food & Drug Administration, Office of Biological Product Operations - Division 2, DFC - BLDG 20 - W 6th Ave & Kipling St., Denver, CO 80225, or emailed to Marc.Jackson@fda.hhs.gov. If you should have any questions, please contact Marc Jackson, Compliance Officer at (303) 236-3083 or via e-mail.

Sincerely,
/S/

Karlton Watson
Program Division Director
Office Biological Products Operations - Division 2