1Aseptic processing and sterility assurance
Failure to establish laboratory controls that include scientifically sound and appropriate specifications, standards, and test procedures designed to assure that components, in-process material, and drug products conform to appropriate standards of identity, strength, quality, and purity [21 CFR 211.160(b)]. For example: a. Your approach to calculating the SAL for lots of finished unsterilized units of your products with TNTC pre-sterilization bioburden results is not…
2Aseptic processing and sterility assurance
Failure to follow established, approved written procedures and thoroughly investigate any unexplained discrepancy or the failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed [21 CFR 211.192]. Specifically: a. During the annual product review periods ranging from January 01, 2021 to February 28, 2022, approximately 28 batches/lots of your terminally sterilized products exceeded your firm’s action…
3Aseptic 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 establish that your sterilization process can achieve your established minimum sterility assurance level (SAL) of (b)(4) when TNTC bioburden levels are present in your finished unsterilized units. b. Your firm has failed to establish and follow appropriate written procedures to prevent microbiological contamination of finished units of your products prior to terminal sterilization. Bioburden control is critical for preventing a challenge to your validated sterilization process and to minimize bioburden-associated byproducts.
4Equipment and facility
Failure to maintain buildings used in the manufacture, processing, packing, or holding of drug products in a good state of repair [21 CFR 211.58]. For example, FDA’s inspection of mixing room (b)(4) revealed gaps in the ceiling that connect to the unclassified utility space, cracked and peeling surfaces on the floors and walls, flaking paint on the ceiling near air return vents, and a tarp collecting pooling water in the ceiling space approximately fifty feet from filling room (b)(4) . It is essential that your facility is in a good state of repair to protect drug products from potential routes of contamination.
5Quality unit oversight
Failure to test in-process materials for identity, strength, quality, and purity, as appropriate, and approve or reject by the quality control unit, during the production process [21 CFR 211.110(c)]. For example, your firm failed to reject lots of your bulk solutions (i.e., “mixing tanks”) and finished unsterilized units with in-process bioburden results of TNTC.
6Cleaning validation
Failure to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements [21 CFR 211.67(a)]. For example: a. Inspection of filling module (b)(4) on September 13, 2022, revealed an approximate two-inch hole on top of the HEPA box, broken edges and residue on the diffusion grate above the filling nozzles, tubing ports with missing tubing connections, and brown residue on filling equipment surfaces near the filling nozzle. This filling area is used to manufacture Amicus component solutions, Alyx component solutions, and Intersol. b. Inspection of mixing room (b)(4) on September 22, 2022, revealed apparent black growth on room-supply HEPA filters and black residue inside mixing tank (b)(4) 2 .
