February 23, 2011
June A. Amoroso
Sunrise Medical Laboratories, Inc.
250 Miller Place
Hicksville, NY 11801
Dear Ms. Amoroso:
Your firm Sunrise Medical Laboratories, Inc. (or Establishment), located at 250 Miller Place, Hicksville, NY, performs testing of donors of reproductive human cells, tissues and cellular and tissue-based products (HCT/Ps) for relevant communicable disease agents and diseases. Your firm is therefore a manufacturer of human cells, tissues, and cellular and tissue-based products (21 CFR 1271.3(e)).
The Food and Drug Administration (FDA or agency) conducted an inspection of your Establishment between October 27 and November 19, 2010, and at the conclusion of the inspection, the FDA investigator issued to you a Form FDA-483, Inspectional Observations. Our review of the information and records examined and collected during the inspection revealed significant violations by Sunrise Medical Laboratories of Title 21, Code of Federal Regulations, Part 1271 (21 CFR 1271), issued under the authority of Section 361 of the Public Health Service Act (PHS Act) [42 United States Code (USC) 264]. The agency has determined that because your Establishment is in violation of 21 CFR Part 1271, you do not provide adequate protections against the risks of communicable disease transmission through the use of the HCT/Ps for which you perform testing for relevant communicable diseases. The agency has also determined that there are reasonable grounds to believe these violative HCT/Ps pose a danger to health, and, accordingly, this Order to Cease Manufacturing is effective immediately. This Order to Cease Manufacturing relates to conduct occurring on or after May 25, 2005, the effective date of the applicable regulations. FDA retains authority to pursue other actions and remedies.
Because of your failure to provide adequate protections against the risks of communicable disease transmission, pursuant to 21 CFR 1271.440(a)(3), Sunrise Medical Laboratories must immediately cease all manufacturing of HCT/Ps until compliance with the regulations in 21 CFR 1271 has been achieved and you have been provided written authorization from FDA to resume operations. Under 21 CFR 1271.3(e) manufacture means, but is not limited to, any or all steps in the recovery, processing, storage, labeling, packaging, or distribution of any HCT/P, and the screening or testing of the HCT/P donor.
Additionally, this is to advise you that FDA will notify, by copy of this Order, the client reproductive facilities for whom you performed donor testing since January 2008.
FDA’s inspection and record review noted significant noncompliance with the federal regulations including, but not limited to, the following:
A. DONOR TESTING
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 disease [21 CFR 1271.80(c)]. For example:
- The manufacturer’s instructions for the human immunodeficiency virus, types 1 and 2 (HIV-1/2) assay indicate that ---------------------------------(b)(4)----------------------------- ----------------------------------------------------------------------------------------------------------- -------------------------------------------. On May 17, 2010, ---------------(b)(4)---------------- absorbance readings was ------(b)(4)------, but this value was not excluded and the cutoff -----------(b)(4)-------------. As a result, an incorrect cutoff value was used to determine test results for HCT/P donors and two donors were erroneously reported as negative for anti-HIV1/2. The two specimens should have been ---------(b)(4)-------- in accordance with the manufacturer’s instructions.
- The manufacturer’s instructions for the hepatitis B core (HBc) assay state the absorbance value for the substrate blank must be greater than or equal to ---(b)(4)--- and less than or equal to ---(b)(4)--. The instructions further state that these criteria must be met in order for a plate (test run) to be considered valid. For 76 assays performed between January 2008 and October 2010, the blank absorbance value was greater than -(b)(4)-. The assays were not considered invalid and the results were reported to clients despite being obtained from an invalid test run.
- The manufacturers of the test kits used for HIV-1/2, HBc, hepatitis B surface antigen (HBsAg), and hepatitis C virus (HCV), require the use of a multichannel aspirator-washer capable of dispensing and aspirating 300µL to 800µL of wash solution per microplate well. In addition, the manufacturer’s instructions caution that strict adherence to the specified wash procedure is critical to ensure optimum assay performance. The instructions provide very specific steps to follow for washing the microplates. However, your firm’s procedure involves using a hand-held irrigation bottle to wash the wells, then inverting the microplates over a laboratory waste container to discard the wash solution. This method has been standard practice at Sunrise Medical Laboratories since January 2008, and was observed by the investigator during the inspection and documented in an affidavit signed by Mr. Paul Doherty, Laboratory Manager, on November 18, 2010.
- The incubation and washing steps for the HBc, HBsAg, HCV, and HIV-1/2 assays are not always performed for the required time specified in the manufacturer’s instructions. During the inspection, on October 28, 2010, the investigator observed that incubation times for specific steps in the assays were not documented or verified.
- The manufacturer’s instructions for the HBc assay require re-testing of donor specimens with an absorbance reading of less than -(b)(4)-. On 6/17/10, the absorbance reading for donor ----(b)(6)--- was -0.034. The donor specimen was not re-tested and the result of testing of this HCT/P donor was reported as negative.
Failure to maintain records concurrently with the performance of each step required in subpart D and subpart C of Part 1271. 21 CFR 1271.270(a) states that any requirement in Part 1271 that an action be documented involves the creation of a record, which is subject to the requirements of this section. In addition, this section requires that all records must be accurate, indelible, and legible and that the records must identify the person performing the work and the dates of the various entries, and must be as detailed as necessary to provide a complete history of the work performed and to relate the records to the particular HCT/P involved. For example:
- From January 2008 to October 2010, you did not document incubation temperatures and times; solution preparation and usage times; and stop solution addition times for HBc, HBsAg, HCV, syphilis, and HIV-1/2 assays.
- The identification of the individual performing HBc, HBsAg, HIV-1/2, and syphilis assays was not documented on 180 out of -(b)(4)- worksheets/plate reader printouts.
- Donor specimen numbers were not documented on 40 out of -(b)(4)- data sheets/plate reader printouts for HBc assays performed in 2008.
- The calculation of the average value of the negative controls was not documented for three HCV assays and four HBsAg assays performed in 2008 and 2009.
On December 15, 2010, FDA received your written response, dated December 10, 2010, to the FDA Form-483, List of Inspectional Observations, issued to Sunrise Medical Laboratories at the close of the inspection. We have reviewed the corrective actions outlined in the response and we have determined that they are inadequate. You agree that your donor testing practices were not in compliance with the applicable regulations in 21 CFR Part 1271 and promise to make corrective actions. However, your response only addresses prospective changes to procedures, personnel training, and recordkeeping. You did not address the inadequacy of relevant communicable disease testing for HCT/P donors performed since January 2008, nor did you discuss plans to review previous testing records to determine which donors had positive or invalid testing results that were reported as negative.
As noted, the above cites are examples of HCT/P donor testing not performed in compliance with the regulations in 21 CFR 1271. FDA requests that you perform a retrospective review of all testing performed on HCT/P donors by your Establishment since January 2008. This is in order to identify all testing that was not performed in accordance with manufacturer’s instructions. Specifically: improper washing of microplates; failure to monitor the time and temperature of each step performed in testing; failure to invalidate test runs which did not meet manufacturer’s acceptance criteria and misinterpretation of test results based on use of an incorrect cutoff value. In addition, once the retrospective review of testing has been completed, FDA requests that you inform your client reproductive facilities and FDA of each donor test result that was affected by non-compliance with the manufacturer’s instructions in order that the client can make an informed decision regarding the status of the donor and /or any affected HCT/Ps that may remain in their inventory.
This letter confirms the telephone conversation on February 23, 2011, in which notice was given that, pursuant to 21 CFR 1271.440(a)(3), upon receipt of this Order you must immediately cease all manufacturing operations. You may request a hearing under 21 CFR Part 16 within five (5) working days from receipt of this Order.
Instructions were given at the time of the telephone conversation to cease testing of HCT/P donors. Neither you, nor your Establishment, can resume operations without prior written authorization from FDA. Before FDA will issue such an authorization, you must ensure compliance with FDA’s regulations in 21 CFR Part 1271 – including, but not limited to, the Donor Eligibility and applicable current Good Tissue Practice requirements in 21 CFR 1271, Subpart C and Subpart D. Any shipment of HCT/Ps in violation of this order constitutes a violation of Section 368 of the PHS Act [42 USC 271], for which criminal penalties may be imposed.
Within five (5) working days from the receipt of this Order to Cease Manufacturing, you may request a hearing on the matter in accordance with 21 CFR Part 16 (copy attached), to Mary A. Malarkey, Director, Office of Compliance and Biologics Quality, Center for Biologics Evaluation and Research, 1401 Rockville Pike, HFM-600, Rockville, MD 20852 (telephone: 301-827-6190). A request for a hearing may not rest upon mere allegations or denials but must present specific facts showing that there is a genuine and substantial issue of fact that warrants a hearing. Pursuant to 21 CFR 16.26, a request for a hearing may be denied, in whole or in part, if the Commissioner or her delegate determines that no genuine and substantial issue of fact has been raised by the material submitted. A hearing will not be granted on issues of policy or law. Written notice of a determination of summary judgment will be provided, explaining the reasons for denial of the hearing. Should you need additional time in which to request a hearing, please notify us immediately, in writing, of your request for additional time.
Failure to request a hearing within the specified time period constitutes a waiver of the right to a hearing. You may also wish to inform yourself with respect to the agency’s guidelines regarding electronic media coverage of its administrative proceedings, which can be found at 21 CFR 10, Subpart C.
Karen Midthun, M.D.
Center for Biologics Evaluation and Research
Effective Date: ___________________________ Time: _______________________