Sagent Pharmaceuticals, Inc. — FDA Warning Letter Findings

Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)).

In response to Observation 6 of the Form FDA 483, you stated in part: the site will transition to compliance software for non-conformances and CAPAs; enhanced training for aseptic techniques and investigations will be developed; and SOP-QA-0157, Manufacturing Investigation Procedure, will be revised. However, you did not provide: a. CMT 2021-414 referenced in your response pertaining to your changes to investigations, CAPAs, and related training. b. A copy of SOP-QA-0157.

In response to Observation 4 of the Form FDA 483, you stated in part: the bag filling line would be decommissioned and a new corporate policy, PQL-QA-0025 will be implemented to ensure equipment is adequate for GMP processes. However, you did not provide a copy of PQL-QA-0025 or CMT 2021-444 referenced in your response for policy implementation and employee training.

Your firm failed to use equipment in the manufacture, processing, packing, or holding of drug products that is of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance (21 CFR 211.63).

You did not perform adequate product evaluation and take appropriate corrective action after microbial contamination was recovered within the ISO 5 aseptic processing area.

In response to Observation 3 of the Form FDA 483, you stated in part: limits for the ISO 5 zones will be changed to (b)(4) ; environmental monitoring limits will be standardized (b)(4) ; and the entire environmental monitoring program will be evaluated. Additionally, your response stated (b)(4) and (b)(4) . However, you did not provide: a. CMTs 2021-435 and 2021-436 referenced in your response pertaining to your environmental monitoring evaluation, revised procedures for ISO 5 zones, and changes to particle monitoring. b. Completed document change controls DCC-002749 and DCC-003733 referenced in your response pertaining to revised viable action limits.

Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or 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)).

Your firm failed to establish and 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)). 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…

The ISO-classified areas had visibly dirty equipment and difficult to clean surfaces. Specifically, chipped and missing paint, apparent rust, adhesive tape, and a build-up of residues were observed on and around (b)(4) equipment in an area where parisons are cut and conveyed to the point of aseptic filling.

Your firm does not maintain the sterility of inter seals and outer closures for IV bags during production. (b)(4) IV bags and caps with ports are exposed to worse than ISO 5 quality air prior to and during assembly/capping.

Your firm failed to ensure container closure systems provide protection against foreseeable external factors in storage and use that can cause deterioration or contamination of the drug product (21 CFR 211.94(b)).

In response to Observation 1 of the Form FDA 483, you stated in part: new smoke studies will be performed; environmental monitoring for particles will be revised; (b)(4) machinery and surrounding barriers will be assessed; integrity testing (leak check test) will be performed, equipment that remains in use will be relocated to ensure first pass air is not blocked; and employee training will be provided to include operator prevention of obstructing first pass air. However, you did not provide: a. CMTs 2021-424, 2021-426, 2021-427, 2021-428, 2021-429, 2021-430, and 2021-431 referenced in your response pertaining to (b)(4) smoke studies, changes to particle monitoring, equipment and barrier assessment, leak check testing, and operator training. b. Change controls 2021-109 and 2021-110 referenced in your response pertaining to decommissioning of filling lines, installation of (b)(4) particle monitoring equipment, and environmental monitoring revisions.

In response to Observation 2 of the Form FDA 483, you provided a written risk assessment for capping of (b)(4) IV bags and a study evaluating the sterility of caps. However, you did not provide any supporting documentation, such as air certification reports, to demonstrate that the caps and bags are not exposed to worse than ISO 5 quality air during loading, conveying, and capping.

Your smoke studies demonstrated that the air in an ISO 5 classified zone was turbulent and non-laminar near areas where IV bag filling and sealing are performed.

In response to Observation 5 of the Form FDA 483, you stated in part: the bag filling line would be decommissioned; an assessment would be performed for all product contact lubricants; and SOP-VAL-0103, Equipment/Utility and Software Validation/Qualification, would be revised to include (b)(4) . However, you did not provide a copy of the revised SOP-VAL-0103 or CMTs 2021-438 and 2021-439 referenced in your response for SOP revisions and employee training.

In response to Observation 7 of the Form FDA 483, you stated in part: SOP-VAL-0103, Equipment/Utility and Software Validation/Qualification, will be revised and employee training will be conducted. However, you did not provide a copy of SOP-VAL-0103 or CMT 2021-439 referenced in your response for SOP revisions and employee training.

Your facility is designed and operated in a way that first air is either not provided or blocked within ISO 5 areas where critical in-process operations are performed. For example: a. Lack of first pass air over unwrapped, open IV bags prior to filling. b. Blocked first pass air for exposed sterile closures (ports and syringe plungers) during introduction and conveyance on IV bag filling lines.

Your firm failed to ensure that substances required for equipment operations, such as lubricants and coolants, do not come in contact with components, drug product containers, closures, in-process materials, or drug products so as to alter the safety, identity, strength, quality or purity of the drug product beyond the official or other established requirements (211.65(b)).

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).

Your firm failed to establish an adequate air supply (b)(4) particulate air filters under positive pressure in the aseptic processing areas (21 CFR 211.42(c)(10)(iii)).

Sterilized equipment and utensils wrapped (b)(4) and (b)(4) were stored in your “transition area,” an unclassified area, without an established hold time to ensure that these items remain sterile. FDA investigators also noted CGMP violations at your facility, that caused your drug product(s) to be adulterated within the meaning of section 501(a)(2)(B) of the FDCA. The violations include, for example…

In response to Observation 8 of the Form FDA 483, you stated in part: revisions will be made to SOP-P-0435, Operation and Maintenance of the (b)(4) . However, you did not provide a copy of SOP-P-0435 or CMT 2021-411 referenced in your response. Additionally, you did not provide supporting documentation referenced in the attachment identified as (b)(4) including but not limited to third-party studies for the lethality of the (b)(4) . In addition to the issues discussed above…