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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Olympia Womens Health 4/24/13

  

Department of Health and Human Services logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration
 
Seattle District
Pacific Region
22215 26th Ave SE, Suite 210
Bothell, WA 98021-4425
 
Telephone:      425-302-0340
FAX:    425-302-0402 

 

April 24, 2013
 
OVERNIGHT DELIVERY
SIGNATURE REQUIRED
 
In reply refer to Warning Letter SEA 13-18
 
James F Moruzzi, MD, PhD, Owner
Olympia Women’s Health
403 Black Hills Lane SW, Suite E
Olympia, Washington 98502
 
WARNING LETTER
 
Dear Dr. Moruzzi:
 
The Food and Drug Administration (FDA) conducted an inspection of your firm, Olympia Women’s Health located at 403 Black Hills Lane SW, Suite E, Olympia, Washington, from February 25 through March 1, 2013. During this inspection, the 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, Part 1271 (21 CFR 1271), and issued under the authority of Section 361 of the Public Health Service Act (42 USC 264).
 
The deviations documented on the Form FDA-483 (FDA-483), Inspectional Observations, 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 determine as ineligible a donor whose specimen tests reactive on a screening test for a communicable disease agent in accordance with 21 CFR 1271.85 [21 CFR 1271.80(d)(1)]. For example, the specimens from anonymous oocyte donor # (b)(6), collected on November 1 and November 17, 2011, tested positive for Chlamydia trachomatis. Donor #(b)(6) was determined eligible on November 7, 2011. Twenty-two oocytes were recovered from donor #(b)(6) on November 19, 2011.
 
  1. Failure to test a specimen from an anonymous or directed reproductive donor of cells and tissue, whether viable or non-viable, for evidence of infection due to relevant communicable disease agents [21 CFR 1271.85(a)]. For example:
 
a.       Testing for relevant communicable disease agents for all your anonymous and directed reproductive donors does not include human immunodeficiency virus, type 1 (HIV-1) and hepatitis C virus (HVC) by the nucleic acid test (NAT) method,
 
b.      The donor specimens collected from anonymous oocyte donor #(b)(6) on July 19, 2010, April 29, 2011, and November 1, 2011, were not tested for total antibody to Hepatitis B core antigen (anti-HBc) (IgG and IgM).   
 
c.       The donor specimen collected from anonymous oocyte donor #(b)(6) on September 8, 2010, was not tested for total antibody to Hepatitis B core antigen (anti-HBc) (IgG and IgM). 
 
d.      The donor specimen collected from anonymous oocyte donor #(b)(6) on February 18, 2012, was not tested for total antibody to Hepatitis B core antigen (anti-HBc) (IgG and IgM). 
 
  1. Failure to test using appropriate FDA-licensed, approved, or cleared donor screening tests, in accordance with the manufacturer’s instructions, to adequately and appropriately reduce the risk of transmission of relevant communicable disease agents or diseases [21 CFR 1271.80(c)]. Specifically, there is no documentation of which donor screening tests are used by your contract testing laboratory for donor testing for relevant communicable diseases, and that the test kits are FDA-licensed, approved, or cleared donor screening tests.
 
  1. 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 Parts 1271.80 and 1271.85 [21 CFR 1271.50(a)]. For example, there is no documentation of donor screening, donor testing, or a donor eligibility determination for three directed semen donors. Your “Cryopreservation Tank Inventory, 2/5/2013” form includes frozen semen from donors identified as “twin-brother’s sperm” (for recipient (b)(6)), “friend’s sperm” (for recipient (b)(6)), and “friend sperm” (for recipient (b)(6)). Semen collected from these donors was frozen on July 6, 2009, September 16, 2010, and March 3, 2010, respectively.
 
  1. 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)]. Under 21 CFR 1271.75(a), you must screen a donor of 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 1271.3(s) defines the term “relevant medical records” to include a current report of the physical examination of a living donor. For example, your records for anonymous oocyte donor #(b)(6) lack documentation of your review of a current report of the physical examination of the donor. For the donations on May 5, 2011, and November 19, 2011, the physical examination of the donor occurred more than six months before the date(s) of oocyte recovery.[1]
 
  1. Failure of a responsible person to determine and document the eligibility of a donor of reproductive cells or tissue [21 CFR 1271.50(a)]. For example, the records for anonymous oocyte donor #(b)(6), dated September 15, 2010, and anonymous oocyte donor #(b)(6), dated July 20, 2010, and May 5, 2011, did not contain documentation that the donors were determined “eligible” prior to donation. 
 
  1. Failure to affix a distinct identification code to the HCT/P container, e.g., alphanumeric, that relates the HCT/P to the donor and to all records pertaining to the HCT/P and, except in the case of autologous donations, directed reproductive donations, or donations made by first-degree or second-degree blood relatives, does not include an individual’s name, social security number, or medical record number [21 CFR 1271.55(a)(1)]. For example, the donor records for anonymous oocyte donor #(b)(6) are labeled with multiple identification codes to identify the donor (e.g. #(b)(6), #(b)(6), #(b)(6), #(b)(6), #(b)(6), #(b)(6)), although the records contain the same donor name and date of birth.
 
  1. 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)]. For example, your standard operating procedure “Human Cells, Tissues, and Cellular and Tissue Based Products (HCT/Ps) Procedure Manual for the Assisted Reproductive Technology Facilities” does not include HIV-1/HCV NAT as a required donor screening test to adequately and appropriately reduce the risk of transmission of relevant communicable diseases.

 

  1. Failure to prominently label an HCT/P with “NOT EVALUATED FOR INFECTIOUS SUBSTANCES,” unless you have performed all otherwise applicable screening and testing under 21 CFR Parts 1271.75, 1271.80, and 1271.85 [21 CFR 1271.90(b)(2)]. For example, semen stored for donor (b)(6) (#(b)(6)) and donor (b)(6) (#(b)(6)), and intended for use with a sexually intimate partner, is not labeled as required.

 

  1. Failure to quarantine an HCT/P until completion of the donor eligibility determination required by 21 CRF 1271.50 and failure to clearly identify as quarantined an HCT/P that is in quarantine pending completion of the donor eligibility determination.  The quarantined HCT/P must be easily distinguishable from HCT/Ps that are available for release and distribution [21 CFR 1271.60(a) and (b)]. For example, semen from three directed semen donors, identified as “twin-brother’s sperm” (for recipient (b)(6)), “friend’s sperm” (for recipient (b)(6)), and “friend sperm” (for recipient (b)(6)), was not identified as quarantined. A donor eligibility determination has not been completed for these donors. 
 
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.
 
We acknowledge receipt of your letter dated March 13, 2013, that provides a response to FDA’s inspectional observations (FDA-483). We have reviewed the corrective actions outlined in the response and we have determined that the response is not adequate to address our concerns. The response outlines changes to your donor testing and screening procedures, including implementation of revised forms. However, your response addresses only prospective changes to your practices and does not address the inadequacy of donor screening and relevant communicable disease testing for previous HCT/P donors. Further, you did not address the increased risk of communicable disease transmission for HCT/Ps remaining in storage at your firm. Use of these HCT/Ps is not in compliance with 21 CFR 1271.
 
We also have specific comments regarding your response, as follows:
 
In your response to FDA-483 Observation 1, you stated that anonymous oocyte donor #(b)(6) was “classified as acceptable, although she tested positive for Chlamydia 18 days before egg retrieval” and the recipient and her husband acknowledged the small risk of infection with Chlamydia and consented to proceed with the procedure. Also, you stated that your SOP allows consent to use known or suspected infectious material. Under 21 CFR 1271.80(d), you must determine to be ineligible a donor whose specimen test reactive on a screening test for a communicable disease agent in accordance with 21 CFR 1271.85. 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, and you document that you notified the physician using the HCT/P of the results of testing and screening [21 CFR 1271.65(b)]. 
 
You also indicated that you have excess frozen embryos in storage and that before transfer of these embryos a variance will be requested. You can request an exemption under 21 CFR 1271.155 (additional information can be found at: http://www.fda.gov/BiologicsBloodVaccines/TissueTissueProducts/RegulationofTissues/ExemptionsandAlternativeProcedures/default.htm).  However, please note that the 21 CFR 1271.155 regulation requires that you provide justification for use of HCT/Ps from this donor, 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. In this situation, this is the risk related to the oocyte donor not being tested for Chlamydia trachomatis and Neisseria gonorrhea per FDA regulations.
 
In your response to FDA-483 Observations 2 and 3, you stated, “I was surprised to learn that (b)(4) was not using FDA approved tests for each infectious disease panel.” Under 21 CFR 1271.150(c), before you enter into a contract, agreement, or other arrangement with another establishment to perform any step in manufacture for you, you must ensure that the establishment complies with applicable Current Good Tissue Practice requirements. It is your responsibility to ensure that your contract testing laboratories are in compliance with the requirements under 12 CFR 1271 when testing your HCT/P donors for relevant communicable diseases. We also note that your response does not address the failure to test your HCT/P donors for human immunodeficiency virus, type 1 (HIV-1) and hepatitis C virus (HVC) by the nucleic acid test (NAT) method and the total antibody to Hepatitis B core antigen (anti-HBc). HCT/Ps collected from these donors are not in compliance with 21 CFR 1271, as the required testing for relevant communicable disease agents is not complete, therefore the donor eligibility determination has not been completed.
 
In your response to FDA-483 Observation 4A, you stated, “Infectious disease testing of the sperm donor was recommended by me to each recipient, but we did not insist that the testing be performed or documented. Rather, the patients signed a waiver acknowledging that we had not performed infectious disease testing on these fresh sperm donors;” and “Frozen sperm from these donors is ineligible, because they did not have appropriate infectious disease testing or physical exam within seven days of collection.” Under 21 CFR 1271.50, you must determine whether a donor is eligible based on 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. This requirement applies to both anonymous and directed HCT/P donors and may not be waived by the recipient. Directed and anonymous donors who have not undergone all required testing and screening have an incomplete donor eligibility determination and must not be allowed to donate. In addition, donations from an anonymous reproductive donor who has been determined ineligible are not allowed under 21 CFR 1271.
 
In your response to FDA-483 Observation 4B, you stated, “We were not aware of the requirement to obtain a new physical exam within 30 days of each donation.” We would like to clarify the regulatory requirement for donor screening, as the statement you included in your response is incorrect. Under 21 CFR 1271.75(a), you must screen a donor of 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 1271.3(s) defines the term “relevant medical records” to include a current report of the physical examination of a living donor. Under 21 CFR 1271.75(e), an abbreviated donor screening procedure may be used on repeat donations from a living donor if the establishment has performed a complete donor screening procedure, including a physical examination, within the previous six months. 
 
In your response to FDA-483 Observation 5, you stated that the missing questions have been added to your Donor Medical History Interview Form and outdated verbiage has been removed. You also state that, “. . . the HIV antibody test performed by the (b)(4) is a (b)(4) test that detects HIV type O.” In the FDA guidance document titled “Guidance for Industry: Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)” (August 27, 2007) (available at:
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/ucm072929.htm),  FDA explains that establishments utilizing an FDA-licensed HIV-1/2 antibody donor screening test that is specifically as sensitive for detection of HIV group O antibodies may delete from their screening procedures the questions related to risk factors for HIV group O. We note that while this may apply to your future donors who are tested by the (b)(6) using the (b)(6) test, your previous donors were not tested for HIV group O and were not asked the questions related to risk factors for HIV group O. You did not address these prior donors in your response.
 
In your response to FDA-483 Observation 6, you stated, “Sperm freezing records will specifically address whether the specimen was tested for infectious substances before freezing.” You also provided a revised “Sperm Freezing” form that includes the statement “Evaluated for infectious substances” with an adjacent line to place a check mark if the semen donor has been tested for relevant communicable disease agents. However, we note that under 21 CFR 1271.90(b), if an HCT/P has been donated by a sexually intimate partner of the recipient for reproductive use, the HCT/P must be labeled with the statement, “NOT EVALUATED FOR INFECTIOUS SUBSTANCES,” unless you have performed all otherwise applicable screening and testing under 21 CFR Parts 1271.75, 1271.80, and 1271.85. The HCT/P must also be labeled with the statement, “WARNING: Advise recipient of communicable disease risks” when the donor eligibility determination under 21 CFR 1271.50(a) is not performed or is not completed, or the results of screening and/or testing indicate the presence of and/or risk factors for relevant communicable disease agents or diseases. 
 
In the FDA guidance document titled “Guidance for Industry: Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)” (August 27, 2007), FDA explains that the term “label,” as described in 21 CFR Parts 1271.60(d), 1271.65(b), and 1271.90(b) means either (1) a printed label affixed to the HCT/P container or (2) a printed label affixed as a tie-tag to the HCT/P container. However, if this is not possible because the container is too small or is frozen, the “Warning” statements may accompany the HCT/P. We do not believe your revised “Sperm Freezing” form meets the intent of the labeling requirements at 21 CFR 1271.90(b). In addition, you did not indicate whether you plan to review prior semen donor records to determine if the HCT/Ps have been labeled in accordance with the regulatory requirements.
 
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 Food and Drug Administration without further notice. 
 
Please notify this office in writing within fifteen (15) working days from the date you receive this letter of the specific steps you have taken to correct the noted violations, including an explanation of how you plan to prevent these violations, or similar violations, from occurring again.  If corrective action cannot be completed within 15 working days, state the reason for the delay and the timeframe within which the corrections will be completed.
 
Your response should be sent to LCDR Cynthia White, Compliance Officer, Food and Drug Administration, 22215 26th Avenue SE, Suite 210, Bothell, Washington 98021-4425. If you have any questions about the content of this letter, please contact LCDR White at 425-302-0422.
                                                                              
Sincerely,
/S/ 
Charles M. Breen
District Director


[1] Under 21 CFR 1271.75(e), an abbreviated donor screening procedure may be used on repeat donations from a living donor if the establishment has performed a complete donor screening procedure, including a physical examination, within the previous six months.