- Delivery Method:
- VIA UNITED PARCEL SERVICE
Recipient NameMs. Alice Ruby
Recipient TitleExecutive Director
- Reproductive Technologies, Inc.
2115 Milvia Street, 2nd Floor
Berkeley, CA 94704
- Issuing Office:
- Office of Biological Products Operations - Division 2
November 06, 2019
Warning Letter #OBPO 20-594292
Dear Ms. Ruby:
The United States Food and Drug Administration (FDA) conducted an inspection of your firm, Reproductive Technologies, Inc. (Reproductive Technologies), located at 2115 Milvia Street, 2nd Floor, Berkeley, California, from August 5, 2019 through August 16, 2019. 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. The items of concern include, but are not limited to, the following:
1. Failure to quarantine semen from anonymous donors until the retesting required under 1271.85(d) is complete [21 CFR 1271.60(a)]. For example:
a. Semen was collected from anonymous donor 5113 on 3/20/15, 4/9/15, and 4/29/15 and was distributed on 3/17/16, 6/21/16, and 3/10/16, respectively. However, the donor re-testing after six-month quarantine was not performed until 11/18/16.
b. Semen was collected from anonymous donor 5326 on 112/18, 1/5/18, and 1/9/18 and was distributed on 2/12/19, 2/1/19, and 12/17/18, respectively. However, the donor re-testing after six-month quarantine was not performed until 4/30/19.
c. Semen was collected from anonymous donor 5342 on 1/27/17 and 2/2/17 and was distributed on 11/16/17 and 11/10/17, respectively. However, the donor re-testing after six-month quarantine was not performed until 12/14/17.
2. Failure to test anonymous semen donors for West Nile Virus (WNV) using an FDA-licensed NAT donor screening test at the time of the first donation that is recovered within the June 1 through October 31 testing period and/or failure to retest anonymous semen donors for WNV at least six months after the date of donation of semen [21 CFR 1271.80 and 1271.85(d)]. For example:
a. Semen was collected from anonymous donor 5113 on 6/9/17, 8/8/17, and 8/17/17 and was distributed on 9/19/18, 10/22/18, and 5/15/18, respectively. Testing for WNV was not performed at the first donation of the testing period (6/9/17) or within seven days before or after that donation. Additionally, the donor was not re-tested for WNV at least six months after the date of the donations.
b. Semen was collected from anonymous donor 5531 on 6/6/18, 6/18/18, and 6/27/18 and was distributed on 6/6/19, 3/12/19, and 3/12/19, respectively. Testing for WNV was not performed at the first donation of the testing period (6/6/17) or within seven days before or after that donation. Additionally, the donor was not re-tested for WNV at least six months after the date of the donations.
c. Semen was collected from anonymous donor 5427 on 9/22/17, 9/25/17, and 9/27/17 and was distributed on 6/4/18, 5/17/18, and 6/4/18, respectively. The donor was not re-tested for WNV at least six months after the date of the donations.
3. Failure to determine as ineligible donors who are identified as having a risk factor for or clinical evidence of any of the relevant communicable disease agents or diseases for which screening is required [21 CFR 1271.75(d)(1)]. For example, since March 2016, your firm determined as eligible at least 7 anonymous semen donors who reported a history of having sex with another man in the preceding five years. During the inspection of your establishment, you informed the FDA investigator that this was a long-standing practice.
4. Failure to perform a complete donor screening procedure on a donor [21 CFR 1271.75]. A complete donor screening includes reviewing the donor's relevant medical records. Relevant medical records (21 CFR 1271.3(t)) include the donor medical history interview and a physical assessment of the donor. An abbreviated procedure, used to determine and document any changes in the donor's medical history since the previous donation, may be used for repeat donors if you have performed a complete donor screening within the previous six months.
For example, a full donor history questionnaire and review of relevant medical records is completed for all your anonymous semen donors at the time of acceptance into the program and an abbreviated screening procedure is performed for the donors at each repeat donation to assess changes in the donor's health history. However, your donors are provided a "Sperm Donor Six-Month Health Status Update" form, which is an abbreviated screening, every six months instead of a complete donor screening. This form does not include all the required donor screening questions to adequately evaluate a donor's risk for relevant communicable disease agents and diseases and is not considered a complete donor screening.
a. A complete donor screening procedure was performed for anonymous semen donor 5326 on 11/20/16, and the donor was determined eligible on 1/25/17. The donor continued to donate through 3/20/18; however, the donor was provided only abbreviated screening questionnaires on 6/6/17 and 11/14/17. Donor 5326 was determined eligible on 6/22/17 and 1/10/18 without a complete donor screening.
b. A complete donor screening procedure was performed for anonymous semen donor 5223 on 3/12/16, and the donor was determined eligible on 4/27/16. The donor continued to donate through 2/16/17; however, the donor was provided only an abbreviated screening questionnaire on 9/14/16. Donor 5223 was determined eligible on 10/12/16 without a complete donor screening.
c. A complete donor screening procedure was performed for anonymous semen donor 5284 on 8/2/16, and the donor was determined eligible on 9/6/16. The donor continued to donate through 2/21/17; however, the donor did not have a complete screening procedure six months after the prior complete screening.
5. Failure to screen a donor of reproductive cells or tissue by reviewing the donor's relevant medical records for risk factors for, or clinical evidence of, relevant communicable disease agents and diseases [21 CFR 1271.75(a)(l)]. Your donor screening forms, "Personal History Questionnaire," "TSBC HIV/STD Risk Assessment Questionnaire," and "Emerging Infectious Disease Risk Assessment Questionnaire" are used as relevant medical records to determine donor eligibility. However, the questionnaires 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 diseases are missing from your screening forms:
a. Persons who have had a medical diagnosis of Zika virus (ZIKV) in the past six months.
b. Persons who have had sex within the past six months with a person who has had a medical diagnosis of ZJKV in the past six months or resided in, or traveled to, an area with increased risk for ZIKV transmission in the past six months.
c. Persons who have tested positive or reactive for West Nile Virus (WNV) infection using an FDA licensed or investigational WNV NAT donor screening test in the preceding 120 days.
d. Persons who have had a medical diagnosis or suspicion of WNV infection in the preceding 120 days.
e. Persons who have had a smallpox vaccination in the preceding eight weeks or who acquired clinically recognizable vaccinia virus infection by contact with someone who received the smallpox vaccine.
J. Persons who have received a non-synthetic dura mater transplant.
k. Persons who are xenotransplantation product recipients or intimate contacts of a xenotransplantation product recipient.
6. 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 [21 CFR 1271.47(a)]. For example, your procedures do not include the following requirements:
a. Determining as ineligible male donors who provide a history of having sex with another man in the preceding five years.
b. Performing a complete donor screening procedure, which includes the donor medical history interview, a physical assessment, and reviewing the donor's relevant medical records, for repeat anonymous semen donors every six months.
c. Re-testing anonymous semen donors for WNV at least six months after the date of donation of semen.
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 statutory and regulatory requirements. You are responsible for reviewing your operations as a whole to assure you are in compliance with the law.
We acknowledge receipt of your letters dated September 11, 2019 and October 11, 2019, which provide responses and propose corrective actions to FDA's inspectional observations (FDA-483). We have reviewed this correspondence and have the following comments regarding your responses and proposed
corrective actions, as follows:
1. In your September 11, 2019 response to Observations 1 and 3, we acknowledge the changes you have made to your firm's practices and procedures to no longer determine as eligible male donors who provide a history of having sex with another man in the preceding five years. We also acknowledge that you have removed such donors from your active anonymous semen donor program. Your corrective actions with respect to this practice will be verified during the next inspection of your facility.
Additionally, FDA recommends notification of previous recipients and clinics who received semen from such donors who reported risk factors for relevant communicable disease agents and diseases.
2. In your September 11, 2019 response to Observation 2, we understand that the multiple donor screening forms used by your establishment were asking general health questions, however you are required to screen donors for specific conditions and behaviors that increase the donor's relevant communicable disease risk, in accordance with 21 CFR 1271.75. We acknowledge the changes you have made to your donor screening forms to include questions that capture these specific conditions and behaviors. In your response, you stated, "Once this new procedure is implemented, all of these questions will be collected before the first stored semen sample."
Please note that in accordance with 21 CFR 1271.75(e), you must perform a complete donor screening procedure every six months for repeat donors. This complete donor screening includes a donor history questionnaire that screens for all conditions and behaviors that increase the donor's relevant communicable disease risk, a physical examination, and a review of any new medical records, if applicable.
Your September 11, 2019 and October 11, 2019 responses noted that you will be performing a donor eligibility determination each time donor samples are released from quarantine by reviewing all screening and testing records and getting the signature of your Medical Director. The re-testing of anonymous semen donors for communicable disease agents following quarantine of HCT/Ps for at least six months is required for the purposes of releasing the HCT/Ps from quarantine. There is no regulatory requirement to perform a second donor eligibility determination after the re-testing of the donor. The documentation that a donor is "eligible" or "ineligible" can be done at any time prior to the distribution of the HCT/P(s) from that donor.
3. In your September 11, 2019 response to Observation 4, we acknowledge the changes you have made to your Summary of Records to include test results for Hepatitis B NAT and WNV NAT. The effectiveness of your corrective actions will be verified during the next inspection of your establishment.
In regard to the Summary of Records missing the results of Cytomegalovirus (CMV) testing, you stated, "If a blood test is reactive for CMV Total Antibody, reflex testing is performed to include CMV IgG antibody and CMV IgM antibody. All CMV testing is reviewed by our Medical Director to ensure that a donor is not infectious for CMV."
CMV is not a relevant communicable disease agent or disease. However, establishments are required to test donors of viable, leukocyte-rich cells or tissue for CMV. A donor who tests positive or reactive for CMV (total antibody) is not necessarily ineligible to donate HCT/Ps. You must establish and maintain a
procedure regarding donors whose specimens test positive or reactive for CMV total antibody, in accordance with 21 CFR 1271.85(b)(2). You should include procedures for communicating test results of donors who are positive or reactive for CMV total antibody such as how the CMV test results should be communicated to the physician responsible for accepting the HCT/P. For example, the procedure should require that this information appear in materials accompanying the HCT/P, so that physicians may rely on this information to make informed decisions about the use of an HCT/P in a particular
Please note that if you still have semen in storage from donors who were not screened for risk factors for relevant communicable diseases or disease agents in accordance with the regulations at 21 CFR Part 1271, FDA considers the donor eligibility determinations to be incomplete for these donors. This includes, for example, all donors who were screened using donor screening forms that were missing required screening questions. 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: http://www.fda.gov/BiologicsBloodVaccines/TissueTissueProducts/RegulationofTissues/ExemptionsandAlternativeProcedures/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.
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 and prevent their recurrence. Include any documentation necessary to show that correction has been achieved. If you do not believe your products are in violation of the FD&C Act, PHS Act, or applicable regulations, include your reasoning and any supporting information for our consideration. 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 the following address: Daniel W. Cline, Compliance Officer, U.S. Food and Drug Administration, 19701 Fairchild, Irvine, CA 92612 or emailed to Daniel.Cline@fda.hhs.gov. If you have any questions, please contact Mr. Cline at (949) 608-4433 or via e-mail.
Program Division Director
Office of Biological Products Operations - Division 2