1Deviation, CAPA, and investigation
Your firm failed to thoroughly investigate any unexplained discrepancy or 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). Outsourcing facilities must comply with CGMP requirements under section 501(a)(2)(B) of the FDCA. FDA’s regulations regarding CGMP requirements for the preparation of drug products have been established in 21 CFR parts 210 and 211. FDA intends to…
2Aseptic processing and sterility assurance
Regarding your failure to conduct hold time studies, we note that you have provided methods, such as media fill runs, to mitigate certain risks; however, these measures alone are insufficient. A hold time study remains necessary to evaluate container closures of the bulk holding material, testing of the bulk material being held prior to further processing, potential risk associated with sterility, contamination, product degradation, adsorption, or absorption. Furthermore…
3Aseptic processing and sterility assurance
Your firm failed to follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)).
4Deviation, CAPA, and investigation
Written records of investigations into unexplained discrepancies do not always include the conclusions and follow-up. More specifically, you failed to expand your investigations into other products using the same lots of affected material (i.e. bulk bags, syringes, or (b)(4) ). Although you state that a review was conducted, the deviation report does not include a list of the specific lots that were assessed. Relying solely on trending data is not sufficient to justify the…
5Aseptic processing and sterility assurance
Your firm failed to perform adequate smoke studies under dynamic conditions to demonstrate unidirectional airflow within the ISO (b)(4) area. Therefore, your products intended to be sterile are produced in an environment that may not provide adequate protection against the risk of contamination. The FDA investigator also noted CGMP violations at your facility that caused your drug products to be adulterated within the meaning of section 501(a)(2)(B) of the FDCA. The violations include, for example…
6Aseptic processing and sterility assurance
Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)).
7Aseptic processing and sterility assurance
Some of your facility’s drug products, such as Prednisolone/Moxifloxacin HCl/Bromfenac PF Sterile Ophthalmic Solution and Prednisolone/Moxifloxacin HCl PF Sterile Ophthalmic Solution, did not include the established name of the drug.
8Aseptic processing and sterility assurance
An operator rested their arms on the work surface of the hood during aseptic production. This practice may introduce contamination into the ISO (b)(4) work area.
9Process validation
Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).
10Aseptic processing and sterility assurance
Operators conducted aseptic manipulations in an area where the movement of “first air” in the ISO (b)(4) area was disrupted by operator manipulations, including the failure to limit unnecessary movement and make mindful, slow, deliberate movements within the ISO (b)(4) laminar flow hoods and within the ISO (b)(4) cleanroom suite.
11Validation and qualification
You did not provide training records and personnel qualification records for procedure S203005.3 Qualification of Personnel for Particulate and Defect Inspection Activities. Some of your corrective actions appear deficient…
12Aseptic processing and sterility assurance
You did not provide scientific justification for the selection of (b)(4) intensity to conduct visual inspection for all sterile products.
13Equipment and facility
Your facility did not submit adverse event reports to FDA in accordance with the content and format requirements established through guidance or regulation under section 310.305 of title 21, CFR (or any successor regulations).3 Specifically, your facility’s procedures for reporting adverse events are inadequate. For example, your documented procedures for reporting adverse events do not include the following information in the definition of what constitutes a “serious”…
