Multiple Violations at Genetech Umbilical Cord Blood Facility

A 6/18-6/22/18 FDA inspection at a Genetech facility located in San Diego, CA, found multiple violations in the firm’s processing of human umbilical cord blood derived cellular products that are distributed to Liveyon LLC, Yorba Linda, CA. An 11/29/18 Warning Letter says the umbilical cord products are administered via intra-articular injection and in some cases intravenously or “applied directly to the affected soft tissue.” Information gathered during the inspection and from the Liveyon Web site indicates that the products are intended to treat a variety of orthopedic conditions, FDA says.

The letter says the umbilical cord blood products fail to meet regulation requirements for human cell, tissue, or cellular or tissue-based products (HCT/P) that they be intended for homologous use. Also, it says, the products are dependent on the metabolic activity of living cells for their primary function and are not for autologous use, allogenic use in a first-degree or second-degree blood relative, or reproductive use.

Because the products do not meet HCT/P requirements, the agency says, they are regulated as drugs and biological products and Genentech does not have an approved BLA or IND in effect and thus violate the Federal Food, Drug, and Cosmetic Act and the Public Health Services Act.

The inspection also documented significant deviations from current good manufacturing practice and current good tissue practice, the letter says. “The deviations in manufacturing practices observed as well as those noted in documents collected during the inspection indicate that the use of your products raises potential significant safety concerns,” FDA says. The letter says the agency has received “numerous reported safety concerns involving your products.” Specific violations reported on an FDA-483 were: 

•          failure of a responsible person to determine and document the eligibility of a cell or tissue donor based on the results of donor screening and donor testing;
•          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;
•          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;
•          failure to establish and maintain procedures for all steps performed in testing, screening, and determining donor eligibility, and complying with all other requirements of the regulations relating to donor eligibility;
•          failure to retain the accompanying records with the HCT/Ps at all times following a donor eligibility determination including a statement whether, based on the results of screening and testing, the donor has been determined to be eligible or ineligible, and a summary of records used to make the donor-eligibility determination;
• ·        failure to retain documentation of the results and interpretation of all donor screening for communicable diseases;
•          failure to establish and follow appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile;
•          failure to have an adequate system for monitoring environmental conditions in an aseptic processing area;
•          failure to have an adequate system for cleaning and disinfecting the room and equipment to produce aseptic conditions;
•          failure to establish and follow written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess;
•          failure to have separate or defined areas or such other control systems for operations as are necessary to prevent contamination or mix-ups during the course of manufacturing and processing operations;
•          failure to fully investigate any unexplained discrepancy, or the failure of a batch or any of its components to meet any of its specifications;
•          failure to establish and follow written procedures describing in sufficient detail the receipt, identification, storage, handling, sampling, testing, and approval or rejection of components and drug product containers and closures;
•          failure to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity;
•          failure to prepare batch production and control records that document each significant step in the manufacture, processing, packing, or holding of the umbilical cord blood products;
•         failure to establish and follow a written testing program designed to assess the stability characteristics of the manufactured umbilical cord blood products and to use results of the stability testing to determine the appropriate storage conditions and expiration dates;
•          failure to ensure that each lot of components, drug product containers, and closures are withheld from use until the lot has been sampled, tested, or examined, as appropriate, and released for use by the quality control unit;
•          failure to generate and maintain distribution records that contain the name and strength of the product and description of the dosage form, name, and address of the consignee, date and quantity shipped, and lot or control number of the drug product; and
•          failure to establish a quality control unit that has the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products, and the authority to review a production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated.

The agency acknowledges the firm’s responses in which Genetech said it acknowledged the violations and would work diligently to correct them. It says the documents the company submitted do not demonstrate that it has corrected the deficiencies noted on the FDA-483 and do not address the failure to have an approved IND in effect to study the products or an approved BLA to market the products. “We recommend that you review the deviations listed above, consider the potential serious risks to patients your manufacturing violations present, and consult with third-party experts to implement comprehensive corrective action,” the letter says.

Genetech was told to respond with steps it has taken or will take to correct the violations and prevent their recurrence, with documentation showing that corrections have been achieved and a timetable for completion.