1Equipment and facility
Failure to establish written procedures describing in sufficient detail the cleaning methods, equipment, and materials to be used in cleaning the buildings and facilities [21 CFR 211.56(b)]. a. You have not validated the process for cleaning and disinfecting your (b)(4) . b. At the time of the inspection, your written procedure for cleaning and disinfection of (b)(4) was inadequate in that it did not include a description in sufficient detail of the cleaning schedules, methods, equipment, and materials to be used in cleaning the facility. Specifically, the written procedure lacked adequate instructions, including cleaning agents used, contact times for disinfectants, and use of a sporicidal agent.
2Material and supplier control
Failure to establish and follow written procedures describing in sufficient detail the receipt, identification, storage, handling, sampling, testing, approval or rejection of components and drug product containers and closures [21 CFR 211.80(a)]. Specifically, your firm lacks written procedures describing in sufficient detail the criteria for approval or rejection of incoming human umbilical cord tissue, amniotic membrane, other components, and drug product containers and closures.
3Aseptic processing and sterility assurance
Failure to routinely calibrate, inspect or check automatic, mechanical or electronic equipment or other types of equipment, including computers, or related systems that will perform a function satisfactorily, that are used in the manufacture, processing, packing and holding of a drug product, according to a written program designed to assure proper performance [21 CFR 211.68(a)]. Specifically, you have failed to routinely calibrate, inspect or check (e.g., certify) the LFH where your products are exposed to the environment during aseptic processing.
4Documentation 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)]. Specifically, your batch production records do not include documentation of the accomplishment of each significant step in the manufacture of…
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 the aseptic process [21 CFR 211.113(b)]. For example: a. You failed to validate the aseptic processes used to manufacture ActiveShot™, ActivePro™, and ActiveFlow™ (i.e., by performing media fill simulations) since product manufacturing began in (b)(4) . Your products purport to be…
6Process validation
Failure to establish written procedures for production and process controls 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: a. You have not validated the manufacturing processes for ActiveShot™, ActivePro™, and ActiveFlow™ with respect to identity, strength, quality, and purity. b. You have not established written procedures that describe the manufacture of ActivePro™, which was described to FDA investigators during the inspection as being manufactured from ActiveShot™ and ActiveFlow™ final bulk products. You also have not established written procedures that describe the manufacturing step involving controlled rate freezing of ActivePro™, ActiveShot™, and ActiveFlow™ in (b)(4) .
7Aseptic processing and sterility assurance
Failure to establish and follow written procedures for cleaning and maintenance of equipment used in the manufacture, processing, packing, or holding of a drug product [21 CFR 211.67(b)]. a. You have not validated your process for cleaning and disinfecting the LFH, the critical aseptic processing area where your products are manufactured. b. At the time of the inspection, your written procedure for the cleaning and disinfecting the LFH did not include a description in sufficient detail of the methods, equipment, and materials used in cleaning and maintenance operations. Specifically, the written procedure was found lacking adequate instructions, including information about cleaning agents that must be used, required contact times for disinfectants, and use of a sporicidal agent.
8Aseptic processing and sterility assurance
Failure to satisfy general biological products standards for sterility testing [21 CFR 610.12]. For example: a. You have not validated your in-house sterility test method used to demonstrate your method is capable of reliably and consistently detecting the presence of viable contaminating microorganisms in 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. Your written procedure for sterility testing does not include details regarding the composition of the culture media to be used, growth-promotion test requirements, and the number and volume of articles to be tested.
9Stability 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 appropriate storage conditions and expiration dates [21 CFR 211.166(a)]. Specifically, you assign a two-year expiration date to your products without supporting data.
