1Laboratory and QC controls
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 [21 CFR 211.160(b)]. For example, you have not established appropriate specifications and test procedures to assure that your products conform to appropriate standards of identity, strength, quality, and purity.
2Quality unit oversight
Failure to withhold from use each lot of components, drug product containers, and closures until the lot has been sampled, tested, or examined, as appropriate, and released for use by the quality control unit [21 CFR 211.84(a)]. For example, you failed to appropriately test or examine before release for use (b)(4) ( (b)(4) ) used in your products and the vials that contain the final product.
3Stability and storage
Failure to establish and follow a written testing program designed to assess the stability characteristics of drug products and to use the results of such stability testing to determine the appropriate storage conditions and expiration dates [21 CFR 211.166(a)]. For example, you have assigned two-year expiration dates to your exosome products without supporting data.
4Complaint and recall handling
Failure to follow written procedures describing the handling of all written and oral complaints regarding a drug product [21 CFR 211.198(a)] . For example, you have not investigated complaints received related to your products, including complaints involving reports of adverse events, in accordance with your written procedures, SOP Q-QC-005, Adverse Events Evaluating and Reporting, Rev. 00, Ver. 00 (Effective Date 01/27/2021) and SOP Q-QA-006, Complaint Investigation, Rev. 1.0 (Effective Date 09/25/2019).
5Aseptic processing and sterility assurance
Failure to establish and follow appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile, including procedures for validation of all aseptic and sterilization processes [21 CFR 211.113(b)]. For example: a. Your firm has failed to validate the aseptic processes used to manufacture Invitra UC-MSCTM, Invitra EXTM, and Invitra EV-OPTM. By the nature of their routes of administration, these products purport to be…
6Documentation and records
Failure to satisfy general biological products standards for sterility testing [21 CFR 610.12]. For example: a. Your firm began conducting in-house sterility testing in January 2021. Your firm was still conducting in-house sterility testing at the time of the inspection, but your sterility testing method(s) has not been validated to demonstrate that it can reliably and consistently detect the presence of viable contaminating microorganisms in your products. This also represents a failure to establish and document the accuracy, sensitivity, specificity, and reproducibility of test methods you employ, as required by 21 CFR 211.165(e). b. The number of samples for sterility testing specified in your “Batch Record for (b)(4) WJ MSC-Derived Exosomes,” used to manufacture Invitra EX™, is not appropriate in that it does not consider the size and volume of the final product lot. c. Your firm did not document performance or results of sterility testing of your products that was conducted in-house from January 2021 to March 2022.
7Aseptic processing and sterility assurance
Equipment used in the manufacture, processing, packing or holding of drug products is not of appropriate design to facilitate operations for its intended use [21 CFR 211.63]. For example, incubators used for sterility testing have not been qualified for that use. We also note that some of the written procedures collected during the inspection that your firm uses to manufacture Invitra UC-MSC™, Invitra EX™, and Invitra EV-OP™ were identified as “draft.” Your response to this…
8Material and supplier control
Failure of a responsible person to determine and document the eligibility of a cell or tissue donor based upon the results of donor screening and donor testing [21 CFR 1271.50(a)]. For example: a. Invitrx is the establishment responsible for making the donor eligibility determination, but since operations began, Invitrx has failed to determine and document the eligibility of hundreds of tissue donors. Tissue from these donors was used to manufacture your products, including Invitra UC-MSCTM. b. Invitrx has not reviewed relevant medical records it has received from its umbilical cord tissue suppliers to determine donor eligibility.
9Process validation
Failure to establish 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 [21 CFR 211.100(a)]. For example, the manufacturing processes for your products have not been validated.
10Documentation and records
Failure to prepare batch production and control records for each batch of drug product produced that include complete information relating to the production and control of each batch, including documentation that each significant step in the manufacture, processing, packing, or holding of the batch was accomplished [21 CFR 211.188(b)]. For example: a. You have not maintained batch production records for your in-process conditioned media or for your finished products, including Invitra UC-MSC and Invitra EV-OP, which are manufactured from human umbilical cord tissue. b. You have not documented the identity of each batch of component or in-process material used, for example the in-process conditioned media used to manufacture your products.
