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  1. Warning Letters

WARNING LETTER

Cryos International USA LLC MARCS-CMS 639696 —

Delivery Method:
VIA UNITED PARCEL SERVICE
Reference #:
22-639696
Product:
Biologics
Recipient:
Recipient Name
Corey A. Burke
Recipient Title
Tissue Bank Director
Cryos International USA LLC

2200 N. Alafaya Trail, Suite 550
Orlando, FL 32826
United States

Issuing Office:
Division of Biological Products Operations I

United States

WARNING LETTER

October 24, 2022

Dear Mr. Burke:

The United States Food and Drug Administration (FDA) conducted an inspection of your firm, Cryos International USA, LLC, located at 2200 N. Alafaya Trail, Suite 550, Orlando, Florida between February 9, 2022, and March 8, 2022. 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 Part 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), were presented to and discussed with you at the conclusion of the inspection. The items of concern include, but are not limited to, the following:

1) Failure to test a specimen from an anonymous semen donor for evidence of infection due to relevant communicable disease agents [21 CFR 1271.80(a)]; and/or failure to retest anonymous semen donors at least six months after the date of donation of semen [21 CFR 1271.85(d)]; and/or failure to quarantine semen from anonymous donors until the retesting required under 21 CFR 1271.85(d) is complete [21 CFR 1271.60(a)]. For example:

a. The following repeat anonymous semen donors were not tested 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 were not retested for WNV at least six months after the date of donation of semen. In addition, semen was not quarantined as required until retesting was complete.

  i. Semen was collected from donor (b)(6) between (b)(6) and (b)(6). Testing for WNV was performed on 6/3/2021; however, semen vials from these donations were not kept in quarantine for at least six months after donation until retesting for WNV was complete. Even though retesting was not complete, semen vials from these donations were released from quarantine on 1/20/2022 for distribution within the U.S., and two semen vials (collection date (b)(6)) were distributed to (b)(4) on 2/10/2022.

  ii. Semen was collected from donor (b)(6) on (b)(6), (b)(6), and (b)(6). Testing for WNV was performed on 6/28/2021 and 8/13/2021; however, WNV testing was not performed at the first donation or within seven days before or after that donation. Additionally, semen vials from these donations were not kept in quarantine for at least six months after donation until retesting for WNV was complete. Even though retesting was not complete, semen vials from three donations were released from quarantine on 2/15/2022 for distribution within the U.S., and four semen vials (collection date (b)(6)) were distributed to (b)(4) on 2/28/2022.

  iii. Semen was collected from donor (b)(6) on (b)(6) and (b)(6). Testing for WNV was performed on 8/13/2021; however, WNV testing was not performed at the first donation or within seven days before or after that donation. Additionally, semen vials from these donations were not kept in quarantine for at least six months after donation until retesting for WNV was complete. Even though retesting was not complete, semen vials from both donations were released from quarantine on 12/17/2021 for distribution within the U.S., and one semen vial (collection date (b)(6)) was distributed to (b)(4) on 2/14/2022.

  iv. Semen was collected from donor (b)(6) between (b)(6) and (b)(6). Testing for WNV was performed on 6/29/2021; however, WNV testing was not performed at the first donation or within seven days before or after that donation. Additionally, semen vials from these donations were not kept in quarantine for at least six months after donation until retesting for WNV was complete. Even though retesting was not complete, semen vials from these donations were released from quarantine on 1/5/2022 and 1/14/2022 for distribution within the U.S., and one semen vial (collection date (b)(6)) was distributed to (b)(4) on 1/27/2022.

  v. Semen was collected from anonymous donor (b)(6) between (b)(6) and (b)(6). Testing for WNV was performed on 6/12/2020; however, semen vials from these donations were not kept in quarantine for at least six months after donation until retesting for WNV was complete. Even though retesting was not complete, semen vials from these donations were released from quarantine on 4/13/2021 and 6/8/2021 for distribution within the U.S., and five semen vials (collection dates (b)(6) and (b)(6)) were distributed to (b)(4) on 5/20/2021 and 7/21/2021.

  vi. Semen was collected from anonymous donor (b)(6) between (b)(6) and (b)(6). Testing for WNV was performed on 6/15/2020; however, semen vials from these donations were not kept in quarantine for at least six months after donation until retesting for WNV was complete. Even though retesting was not complete, semen vials from these donations were released from quarantine on 6/8/2021 for distribution within the U.S., and one semen vial (collection date (b)(6)) was distributed to (b)(4) on 7/1/2021.

b. The following repeat anonymous semen donors were not retested for Chlamydia trachomatis, Neisseria gonorrhea, Treponema pallidum, and cytomegalovirus (CMV) at least six months after the date of donation of semen. In addition, semen was not quarantined as required until retesting was complete.

  i. Semen was collected from anonymous donor (b)(6) on (b)(6) and (b)(6); however, semen vials from these donations were not kept in quarantine for at least six months after donation until retesting for Chlamydia trachomatis, Neisseria gonorrhea, Treponema pallidum, and CMV was complete. Semen vials from these donations were released from quarantine on 1/14/2022 for distribution within the U.S., and one semen vial (collection date (b)(6)) was distributed to (b)(4) on 1/27/2022.

  ii. Semen was collected from anonymous donor (b)(6) between (b)(6) and (b)(6); however, semen vials from these donations were not kept in quarantine for at least six months after donation until retesting for Chlamydia trachomatis, Neisseria gonorrhea, Treponema pallidum, and CMV was complete. Semen vials from these donations were released from quarantine on 4/13/2021 for distribution within the U.S., and two semen vials (collection date (b)(6)) were distributed to (b)(4) on 5/13/2021.

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)(1)]. Your firm’s donor history questionnaires are used as relevant medical records to determine donor eligibility. However, the multiple versions of the form do not include screening for all conditions and/or behaviors that increase a donor’s relevant communicable disease risk. For example:

a. Your donor history questionnaire FORM 08.05.01.01.21 Questionnaire Sperm Donor (b)(6), (ver 1, 01.10.2021) is missing questions to assess a donor’s relevant communicable disease risk for the following:

  i. Men who have had sex with another man in the preceding 12 months.

  ii. Persons who have engaged in sex in exchange for money or drugs in the preceding 12 months;

  iii. Persons who have injected drugs for non-medical reason in the preceding 12 months, including intravenous, intramuscular, or subcutaneous injections;

  iv. Persons who have been exposed in the preceding 12 months to known or suspected HIV, HBV, and/or HCV-infected blood through percutaneous inoculation (e.g., needle stick) or through contact with an open wound, non-intact skin, or mucous membrane;

  v. Persons who have lived with (resided in the same dwelling) another person who has hepatitis B or clinically active (symptomatic) hepatitis C infection in the preceding 12 months;

  vi. Persons who acquired a clinically recognizable vaccinia virus infection by contact with someone who received the smallpox vaccine;

  vii. The question that asks about spending 6 months or more at U.S. military bases in Northern Europe from 1980 through 1990, or elsewhere in Europe from 1980 through 1996 does not ask if the time was cumulative.

  viii. Persons who have had a medical diagnosis of ZIKV in the past 6 months.

  ix. Persons who have resided in, or traveled to, an area with an increased risk for ZIKV transmission within the past 6 months.

b. Your firm’s FORM 08.01.02.01.05 Change in Risk Behaviours (Ver 2.2, 15.10.2021) is missing questions to assess a donor’s risk for Zika virus (ZIKV) infection, as follows:

  i. Persons who have had sexual contact with a person within the past 6 months that has traveled to or resided in another country with an increased risk for ZIKV transmission within the past 6 months; and

  ii. Persons who have had sexual contact with a person within the past 6 months that has had a medical diagnosis of ZIKV within the past 6 months.

3) Failure to perform a complete donor screening procedure on a donor by reviewing the donor’s relevant medical records as set forth in 21 CFR 1271.75(a). Relevant medical records (21 CFR 1271.3(t)) include the donor medical history interview and a physical assessment of the donor. An abbreviated donor screening procedure may be used for repeat donors if you have performed a complete donor screening procedure on a living donor within the previous six months. An abbreviated donor screening procedure must determine and document any changes in the donor’s medical history since the previous donation that would make the donor ineligible. For example:

a. Semen was collected from repeat anonymous donor (b)(6) on (b)(6) and (b)(6). Complete donor screening procedures were performed on 6/5/2020 and 1/28/2021. However, semen vials from these donations were released from quarantine on 7/26/2021 for distribution within the U.S. without a complete donor screening procedure within the previous six months. Two semen vials (collection date (b)(6)) were distributed to (b)(4) on 9/3/2021.

b. Semen was collected from repeat anonymous donor (b)(6) on (b)(6) and (b)(6). Complete donor screening procedures were performed on 11/19/2020 and 6/15/2021. However, semen vials from these donations were released from quarantine on 1/20/2022 for distribution within the U.S. without a complete donor screening procedure within the previous six months. One semen vial (collection date (b)(6)) was distributed to (b)(4) on 1/24/2022.

c. Semen was collected from repeat anonymous donor (b)(6) on (b)(6). Complete donor screening procedures were performed on 3/10/2020 and 9/22/2020. However, semen vials from this donation were released from quarantine on 4/28/2021 for distribution within the U.S. without a complete donor screening procedure within the previous six months. One semen vial (collection date (b)(6)) was distributed to (b)(4) on 8/31/2021.

4) 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 firm’s procedure Human Cellular and Tissue-Based Products (HCT/Ps) Reproductive Tissue Bank Manual, updated 6/6/2019, is deficient in that:

a. The Syphilis infection section states that “persons who have had or have been treated for syphilis or gonorrhea during the preceding 12 months” would be ineligible. However, the procedure does not include Chlamydia trachomatis.

b. The CJD or vCJD infection section states that persons who “received any transfusion of blood or blood components in the U.K. between 1980 and the present” would be ineligible, but this section does not include France.

c. The CJD or vCJD infection section does not ask about a cumulative timeframe for the question related to current or former U.S. military members, civilian military employees, or dependents of a military member or civilian employee.

d. The West Nile Virus section states, “effective October 1st, 2016 all donors will be screened for West Nile Virus seasonally. All donors will be tested for West Nile Virus at their first donation between the months of June through October each year. Egg donors will be screened within 30 days of their scheduled donation procedure. Sperm donors will be screened when they provide their first donation during the included months and at each batch close during those months.” However, the procedure does not require West Nile Virus testing at least six months after the date of donation for the retesting of anonymous semen donors.

e. The Zika Virus section states, “All donors are screened for travel to affected areas within the previous six months, have had a diagnosis of Zika in the previous six months, or in the case of oocyte donors, had sex with a and who has traveled to an affected area or been diagnosed with Zika in the previous six months.” The question does not screen for donors, to include semen donors, who have had sex with a person who has traveled to an affected area or been diagnosed with Zika in the previous six months.

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 applicable FDA regulatory requirements.

We acknowledge receipt of your letter dated March 22, 2022, in response to the FDA 483. We have reviewed the corrective actions outlined in the response, and we have determined that they are inadequate to address our concerns.

In response to observation 1, you object on the basis that FDA’s guidance documents contain “non-binding” recommendations. Indeed, it is FDA’s regulation at 21 CFR 1271.3(r) that provides a definition of “relevant communicable disease agent or disease” (RCDAD) and lists specific disease agents identified as RCDADs. FDA regulations also provide a mechanism for designating additional RCDADs in the future, based on the risk of transmission, severity of effects, and development of appropriate screening measures and/or the availability of an appropriate FDA-licensed, approved or cleared screening test for donor specimens. At the time these regulations were promulgated, the agency stated that it would issue guidance that notifies HCT/P establishments when the agency believes additional relevant communicable disease agents or diseases meet the definition in 21 CFR 1271.3(r)(2).

In September 2016, FDA identified WNV as a RCDAD, based on the risk of transmission, severity of effects, and availability of appropriate screening measures. In accordance with 21 CFR 1271.75, you must screen HCT/P donors for risk factors for, and clinical evidence of, RCDADs. In accordance with 21 CFR 1271.80 and 1271.85, you must test HCT/P donors for evidence of infection due to relevant communicable disease agents to adequately and appropriately reduce the risk of transmission of relevant communicable diseases.

An FDA-licensed donor screening NAT assay for WNV is available and testing is required in accordance with 21 CFR 1271.85(a). Additionally, in the case of a repeat anonymous semen donor from whom a specimen has already been collected and tested, and for whom retesting is required under 21 CFR 1271.85(d), you are not required to collect a donor specimen at the time of each donation (21 CFR 1271.80(b)(2)). However, you should collect a specimen for WNV NAT at the time of (or within 7 days before or after) the first donation that is recovered within the June 1st through October 31st testing period, even if an earlier specimen was already collected and tested. You must also quarantine semen from anonymous donors until the retesting required under 21 CFR 1271.85(d) is compete, as required under 21 CFR 1271.60(a).

We have the following additional comments regarding your response to the FDA 483:

  • Regarding Observation 1, your response states, “…samples collected before the WNV NAT testing seven day window still in inventory will be destroyed and investigations for samples that were shipped out to clients will receive letters stating that these were in fact, not eligible.” Please note that for donors who were not tested in accordance with regulatory requirements, the donor eligibility determination is considered incomplete. Donors whose screening and/or testing were not performed in compliance with 21 CFR 1271 cannot be determined “eligible” or “ineligible.”
  • Your response to Observation 2B references “FDA’s proposed protocol” for retesting anonymous semen donors at least six months after the date of donation. The six-month retesting for anonymous semen donors is a regulatory requirement under 21 CFR 1271.85(d), and the semen must be quarantined in accordance with 21 CFR 1271.60(a) until retesting is complete. The Agency does not object to more frequent testing of anonymous semen donors for the purposes of treating an active infection sooner. This observation relates to the failure to quarantine semen from anonymous donors for at least six months until the retesting under 21 CFR 1271.85(d) is complete.

For example, you stated, “(b)(6) testing for these communicable diseases listed above was performed on 6/29/21, 9/14/21, 10/19/21, 11/23/21, 12/13/21, and 1/27/22 before the release of the samples and all results were negative or non-reactive.” The donations in question were collected on (b)(6) and (b)(6). The six-month quarantine period for these donations would end no later than 12/17/2021, 12/22/2021, and 12/29/2021, respectively. These donations were released from quarantine on 1/14/2022 for distribution within the U.S. Testing of the donor for Chlamydia trachomatis, Neisseria gonorrhea, Treponema pallidum, and CMV was performed on the dates noted above, which were either before the end of the six-month quarantine or after the release of the units from quarantine.

We acknowledge your intent to implement retesting for Chlamydia trachomatis, Neisseria gonorrhea, Treponema pallidum, and CMV at least 6 months after donation, along with retraining.

  • Your response to Observation 4 states that the 21 CFR 1271 regulations do not define the meaning of “six months” and that Cryos defines six months as “two weeks prior to the first day of the sixth month up to the last day of the six month to complete donor screening.” Our concern is not how you define “six months” since as you note, there are varying numbers of days in each month and donors may not be able to return on a specific day due to scheduling conflicts. However, if a donor is unable to return for a complete screening after the six-month period has ended, semen should not be recovered from the donor until the complete screening can be performed.

Please note that if you still have oocytes or semen in storage from donors whose screening and/or testing was not completed in accordance with 21 CFR 1271, FDA considers the donor eligibility determinations to be incomplete for these donors. For example, donors who were not tested for WNV, donors who were screened using a donor history questionnaire that was missing required screening questions, and donors who were not appropriately screened for ZIKV 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 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).

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. Include any documentation necessary to show that correction has been achieved. If you cannot complete all corrective actions within fifteen (15) working days, please explain the reason for your delay and the timeframe within which the remaining corrections will be completed.

Given the seriousness of these violations, we also request your attendance at a Regulatory Meeting, within 30 calendar days of receipt of this letter, to discuss the status of the specific steps you have taken since the inspection to correct the noted violations. We will host the meeting virtually on Zoom. This meeting will also allow you to ask any questions you may have and to provide FDA additional information regarding implementation of corrective actions. Please contact Colleen Aspinwall, Compliance Officer, at (561) 416-1065, ext. 1105 or by email at Colleen.Aspinwall@fda.hhs.gov for confirmation of the meeting date and time. A call-in phone number for the Zoom meeting will be provided at that time.

Your response should be sent to Colleen Aspinwall, Compliance Officer at the following email address: Colleen.Aspinwall@fda.hhs.gov. If you should have any questions, please contact Ms. Aspinwall at (561) 416-1065 ext. 1105 or via e-mail.

Sincerely,
/S/
Michael W. Roosevelt
Program Division Director
Office of Biological Products Operations - Division 1

cc:

Ms. Helle Myrthue, Interim CEO
Cryos International
Vesterbro Torv 3
8000 Aarhus, Denmark
Tel: (+45) 86 76 06 99

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