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  1. Compliance Actions and Activities

WARNING LETTER

University Fertility Laboratory, Inc. MARCS-CMS 577584 — May 30, 2019

University Fertility Laboratory, Inc. - 577584 - 05/30/2019


Delivery Method:
VIA UNITED PARCEL SERVICE
Product:
Biologics

Recipient:
Recipient Name
Omid A. Khorram, M.D., Ph.D.
Recipient Title
Medical Director
University Fertility Laboratory, Inc.

23550 Hawthorne Blvd., Suite 210
Torrance, CA 90505
United States

Issuing Office:
Division of Biological Products Operations II

19701 Fairchild
Irvine, CA 92612-2506
United States


WARNING LETTER

 

 

VIA UNITED PARCEL SERVICE

SIGNATURE REQUIRED

 

May 30, 2019
                                                                                                [Warning Letter # OBPO 19-006]

Omid A. Khorram, M.D., Ph.D.

Medical Director

University Fertility Laboratory, Inc.

23550 Hawthorne Blvd., Suite 210

Torrance, CA 90505

 

Dear Dr. Khorram,

 

The United States Food and Drug Administration (FDA) conducted an inspection of your firm, University Fertility Laboratory, Inc., located at 23550 Hawthorne Blvd., Suite 210, Torrance, CA 90505

from December 7-13, 2018 and February 4, 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. Additional deviations were noted upon further review of the donor records and procedures collected during the inspection. These items of concern include, but are not limited to, the following:

 

1.  Failure to test a specimen from the donor of cells or tissue for evidence of infection due to relevant communicable disease agents [21 CFR 1271.85(a)]. The Guidance for Industry: “Use of Nucleic Acid  Tests to Reduce the Risk of Transmission of West Nile Virus (WNV) from Living Donors of Human Cells, Tissue, and Cellular and Tissue-base Products (HCT/P),” dated September 2016, Corrected May 2017, states that for establishments located within the United States (includes the 50 states and District of Columbia) the FDA recommends performing WNV testing of donors of  HCT/Ps recovered from June 1st through October 31st every year. This guidance supplements WNV donor screening recommendations in sections IV. E and IV. F., and supersedes the WNV section of the guidance entitled,“Guidance for Industry: Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps),” dated August 2007. The following oocyte donors were determined to be eligible without WNV Nucleic Acid Testing being performed. For example:

    1. Anonymous Oocyte donor (b)(6) had oocytes recovered on July 19, 2017 and September 11, 2018.
    2. Directed Oocyte donor (b)(6) had oocytes recovered on September 23, 2017.
    3. Anonymous Oocyte donor (b)(6) had oocytes recovered on August 18, 2018.
    4. Directed Oocyte donor (b)(6) had oocytes recovered on August 20, 2018.

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)]. Specifically, 

  1. FDA has identified the Zika virus (ZIKV), as a relevant communicable disease agent or disease under 21 CFR 1271.3(r)(2).  Therefore, review of relevant medical records, as defined in 21 CFR 1271.3(s), must indicate that a potential donor is free from risk factors for, or clinical evidence of, ZIKV infection for the purpose of determining donor eligibility. Your procedure, Risk [f]actors for Communicable Diseases or Disease Agents and your Donor Risk Assessment questionnaire (FDA SOP 01/01/2007), failed to assess a donor’s relevant communicable disease risk as it relates to ZIKV transmission. Examples include but are not limited to: Anonymous oocyte donors (b)(6) and (b)(6) and directed oocyte donors (b)(6) and (b)(6).
  2. Your Donor Risk Assessment questionnaire (FDA SOP 01/01/2007) is used as a relevant medical record to determine donor eligibility. However, this questionnaire does not include all conditions and/or behaviors to assess a donor’s relevant communicable disease risk. For example, the following questions are missing from your questionnaire:
  • Persons who have had a medical diagnosis or suspicion of West Nile Virus (WNV) infections (based on symptoms and/or laboratory results, or confirmed WNV viremia) you should defer for 120 days following diagnosis or onset of illness, whichever is later.
  • Persons who have tested positive or reactive for WNV infection using an FDA-licensed or investigational WNV NAT donor screening test in the preceding 120 days.
  • Persons who have been treated for or had syphilis within the preceding 12 months.
  • Persons who received any transfusion of blood or blood components in the U.K. or France between 1980 and the present.

3.  Failure to include both the name of the responsible person who made the donor-eligibility determination and the date of the determination as part of your donor eligibility records [21 CFR 1271.55(d)(1)(iii)]. A responsible person as defined in 21 CFR 1271.3(t), must determine and document the eligibility of a cell and tissue donor. On twelve occasions, a responsible person failed to document the donor eligibility determination date on the Summary of Records Form.

 

4.  Failure to determine whether a donor is eligible based upon the results of donor screening in accordance with 21 CFR1271.75 and donor testing in accordance with 21 CFR 1271.80 and 1271.85 [21 CFR 1271.50]. Directed/ Anonymous oocyte donors were determined to be eligible to donate prior to your firm receiving the results of all required testing for communicable disease. Examples include, but are not limited to the following:

    1. Communicable disease testing samples were collected for donor (b)(6) on March 2, 2018. Results for this communicable disease testing were reported on March 6, 2018. Your Summary of Records Form indicates “normal” communicable disease testing results were received on March 2, 2018.
    2. Communicable disease testing samples were collected for donor (b)(6) on November 16, 2017. Results for this communicable disease testing were reported on November 19, 2017. Your Summary of Records Form indicates “normal” communicable disease testing results were received on November 16, 2017.
    3. Communicable disease testing samples were collected for donor (b)(6) on November 15, 2017. Results for communicable disease testing were reported on November 17, 2017. Your Summary of Records Form indicates “normal” communicable disease testing results were received on November 15, 2017.

5.  Failure to establish and maintain procedures for all steps performed in testing, screening, and 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)].  Your firm failed to establish and/or update your standard operating procedure(s) and relevant medical records in order to evaluate donor eligibility. For example:

  1. Item 3 of your Interview for Donor Eligibility Determination (DED)procedure states, “(b)(4)”. However, this does not meet the requirements of 21 CFR 1271.75(e) that state if you have performed a complete donor screening procedure on a living donor within the previous 6 months, you may use an abbreviated donor screening procedure on repeat donations.
  2. Item 4 of your Interview for Donor Eligibility Determination procedure states if the donor eligibility interview is completed by telephone “(b)(4).” However, this is not adequate according to 21 CFR 1271.50(a) which indicates a responsible person, as defined in 21 CFR 1271.3(t), must conduct a visual physical assessment of the donor for clinical signs and symptoms and/or physical evidence of relevant communicable disease agents and diseases as outlined in 21 CFR 1271.3(s).
  3. Your Interview for Donor Eligibility Determination (DED) procedure and your Risk [f]actors for Communicable Diseases or Disease Agents” procedure does not include all steps performed in screening donors for all conditions and/or behaviors that increase a donor’s relevant communicable disease risk.

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 assure that you are in compliance with all of the FDA regulatory requirements.

 

Additional information regarding regulatory requirements for HCT/P’s can be located on the FDA website:

https://www.fda.gov/vaccines-blood-biologics/biologics-guidances/tissue-guidances

https://www.fda.gov/vaccines-blood-biologics/tissue-tissue-products

 

We acknowledge receipt of your response dated February 12, 2019 and received February 25, 2019, which provides a response to FDA’s inspectional observations. We have reviewed the corrective actions outlined in the response and we have determined that the response is inadequate to address our concerns.

 

In response to Observation 1, we acknowledge that your new Donor Eligibility Questionnaire/Exam Form that replaced your Donor Risk Assessment questionnaire (FDA SOP 01/01/2007) Form for screening donors of reproductive cells now includes screening questions for Zika Virus (ZIKV); however, this new questionnaire appears to be inadequate and/or incomplete for the following and does not address some of the questions as outlined in item 2b.

  • Question 14 of your updated Donor Eligibility Questionnaire/Exam form states, “Have you been diagnosed with West Nile Virus” should read as, “Have you had a medical diagnosis or suspicion of West Nile Virus (WNV) infections (based on symptoms and/or laboratory results, or confirmed WNV viremia) or have been deferred for 120 days following diagnosis or onset of illness, whichever is later.
  • Persons who have been diagnosed with vCJD (variant Creutzfeldt-Jakob Disease) or any other form of CJD.
  • Persons who have been diagnosed with dementia or any degenerative or demyelinating disease of the central nervous system or other neurological disease of unknown etiology.
  • Persons who are current or former U.S. military members, civilian military employees, or dependents of a military member or civilian employee who resided at U.S. military bases in Northern Europe (Germany, Belgium, and the Netherlands) for 6 months or more cumulatively from 1980 through 1990, or elsewhere in Europe (Greece, Turkey, Spain, Portugal, and Italy) for 6 months or more cumulatively from 1980 through 1996.
  • Questions 21 of your updated Donor Eligibility Questionnaire/Exam form states, “Between 1980 and 1996, did you spend time that adds up to more than 3 months in the UK?” However, it should read as, “Have you spent three months or more cumulatively in the United Kingdom from the beginning of 1980 through the end of 1996?”
  • Question 24 of your updated Donor Eligibility Questionnaire/Exam form states, “Have you had a blood or blood component transfusion in the UK or France between 19880 and the present?” We believe that there was a typographical error, however, it should read, “Have you had a blood or blood component transfusion in the UK or France between 1980 and the present?”
  • Question 38 of your updated Donor Eligibility Questionnaire/Exam states related to history or symptom of ZIKV infection does not meet the 6-month requirement for donor screening.
  • Question 39 of your updated Donor Eligibility Questionnaire/Exam states, “Have you had sexual contact in the past 4 weeks with a person who has been diagnosed with or had symptoms suggestive of ZIKV in 3 months prior to that instance of sexual contact?” However, it should read, “Have you had sex within the past 6 months with risk factors listed in Questions 40 and 41.

In response to Observation 2, you noted your plan to add both WNV and ZIKV testing to your donor testing panel. Please note that there is currently no FDA-licensed, approved, or cleared donor screening test for ZIKV.

 

It appears you still have oocytes in storage from donors whose screening and/or testing was not completed in accordance with the regulations at 21 CFR Part 1271. For example, donors who were not tested for WNV or other relevant communicable disease agents, donors who were screened using a donor history questionnaire that was missing required screening questions, and donors who were not screened for risk factors for ZIKV. 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 must 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/Regulati…).  Please note that the 21 CFR 1271.155 regulation 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.

 

And lastly, we would like to remind you that in the interest of confidentiality, a distinct identification code to the HCT/P container that relates the HCT/P to the donor and to all records pertaining to the HCT/P must not  include an individual’s name, social security number or medical record number except in the case of autologous donations, directed reproductive donations, or donations made by first­ degree or  second-degree blood relatives in accordance with 21 CFR 1271.55(a)(l).

 

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 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: Amy Graf, U.S. Food & Drug Administration, Office of Biological Product Operations – Division 2, 300 River Place Dr., Detroit, MI 48207, or emailed to Amy.Graf@fda.hhs.gov.  If you should have any questions, please contact Amy Graf, Compliance Officer at (313) 393-2034 or via e-mail.

 

Sincerely,

/S/

Karlton Watson

Program Division Director

Office of Biological Products Operations – Division 2