In the previous post, I had begun to review the Warning Letter the FDA issued to Genetech, who was the supplier of cord blood-derived products to Liveyon, who in turn sold the contaminated vials of their product to physicians across the USA. While the most shocking observation the FDA made in the Warning Letter was that Genetech failed to screen patients for donor eligibility, I will cover a number of other failures on Genetech’s part in this post.
The next point in the Warning Letter highlights an important aspect of the failure to screen donors:
2. Failure to screen a donor of cells or tissues by reviewing the donor’s relevant medical records for risk factors for, and clinical evidence of, relevant communicable disease agents and diseases [21 CFR1271.75(a)]. For example, FDA has identified Zika virus (ZIKV) as a relevant communicable disease agent or disease…[requiring a]…review of relevant medical records …[to ensure]… that a potential donor is free from risk factors for, or clinical evidence of, ZIKV infection for the purpose of determining donor eligibility.
In the case of Zika virus, the FDA mandates that a potential donor answer questions about traveling to areas of the country in which Zika viral infections are prevalent. Genetech was supposed to review this type of information in a form provided by the facility supplying Genetech with the umbilical cord-derived material, but the FDA indicated that the form itself was faulty.
In case you thought that Genetech would be able to make up for its failures in handling the donor-derived eligibility paperwork by thoroughly testing the donor-derived material for the presence of various infectious agents, as specified by the FDA, you would be wrong:
3. Failure to test donor specimens 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, umbilical cord blood donor (b)(6) was tested for hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus-1 (HIV-I) nucleic acids with tests that were not FDA-licensed, approved, or cleared for donor screening. The test results for the HBV, HCV, and HIV-1 NAT or polymerase chain reaction (PCR) assay state: “This assay should not be used for blood donor screening, associated re-entry protocols, or for screening Human Cell, Tissues and Cellular Tissue-Based Products (HCT/P).” In addition, the cord blood donor’s specimen was not tested for total cytomegalovirus (CMV), human T-lymphotropic virus I/II (HTL V I/II), or West Nile virus (WNV).
I have to admit that I was really shocked that Genetech personnel would not test for all of the required infectious agents, but was even more shocked that it would test for some of the infectious agents with assays that weren’t approved for the screening of HCT/Ps, as indicated by the assay manufacturers’ own Instructions for Use. The infectious agents being assayed aren’t just going to give a recipient a mild case of the flu, but include seriously dangerous diseases like AIDS and several kinds of Hepatitis. It boggles the mind that a company could be so careless in its disregard for the safety of patients who might end up receiving their deficiently evaluated products.
And it gets worse. An important requirement of the testing of donor-derived material is stated in 1271.55(b)(1) concerning the information that is to accompany the HCT/P material (with edits):
(1) A statement that the communicable disease testing was performed by a laboratory:
(i) Certified to perform such testing on human specimens under the Clinical Laboratory Improvement Amendments of 1988…
If you aren’t familiar with CLIA, it is a regulatory system that requires on-going proficiency testing and extensive documentation of diagnostic assays that are used for making medical decisions, but in particular CLIA-compliant laboratories will use appropriately cleared or approved assays in screening materials like cord blood-derived HCT/Ps to determine if they contain infectious agents like HIV or Hepatitis. From the observations reported in Item 3 above, it would seem that Genetech was performing the screening assays in-house, since no self-respecting CLIA-certified third-party testing laboratory would use unacceptable assays for screening HCT/Ps. This means another sin of Genetech is that they did the testing internally, without being certified. Completely clueless, and especially disconcerting.
Based on the CDC’s report, it is believed that the vials of product were contaminated prior to physicians opening the vials and injecting patients. Thus, the bacterial contamination could have occurred at the site of umbilical cord tissue collection (e.g., in the hospital), or based on the next series of issues in the Warning Letter, Genetech could have been the source of the contamination:
7. Failure to establish and follow appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile [21 CFR 211.113(b)].
e. Your firm added non-sterile (b)(4) to approximately (b)(4) batches of your products between mid-2017 and June 2018. These (b)(4) are labeled “For research use only.”
8. Failure to have an adequate system for monitoring environmental conditions in an aseptic processing area [21 CFR 211.42(c)(10)(iv)]. For example, your firm has not established an adequate system for environmental and personnel monitoring in the aseptic processing area where the products are manufactured.
9. Failure to have an adequate system for cleaning and disinfecting the room and equipment to produce aseptic conditions [21 CFR 211.42(c)(10)(v)].
This set of failures on the part of Genetech associated with the in-house manufacturing process suggests a profound disregard for cGMP requirements. Genetech’s deficiencies are all the more shocking when you realize that the vials of product they are selling will be injected into humans, not only via intralesional injections, but by IV. Truly frightening.
I will shift my focus in the next post to Liveyon, the distributor of the contaminated vials of cord blood-derived product, and the role they have played in this tragedy.