Findings citing 21 CFR 211.192

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 operates as a contract manufacturer of sterile injectables for (b)(4) . You failed to adequately investigate a sterility test failure as well as recurring mold recoveries in the ISO 5 (Grade A) filling area. Sterility Failure You did not adequately investigate a failed sterility test result for your aseptically filled (b)(4) mg/ (b)(4) ml. Your firm identified Ustilago spermophora , a fungi, in (b)(4) medium. Your investigation’s root cause finding of “undetermined” was inadequate. Although your firm rejected this batch, your investigation did not thoroughly examine all possible root causes including but not limited to potential routes of fungi migration through your classified areas (e.g., personnel/material flow hazards, HVAC hazards, inadequate disinfection). Additionally, your investigation lacked adequate corrective action and preventive action (CAPA) responses. In your response, we acknowledge your intentions to strengthen investigation requirements, perform a retrospective review of investigations, and review the facility’s contamination control strategy. However, your response does not specifically address the sterility failure investigation. Environmental Monitoring (EM) Action Level Excursions Your firm’s investigations into multiple instances of fungi contamination on and below the (b)(4) of aseptic processing lines have been inadequate. For example: On March 20, 2024, Chaetomium globosum was recovered below the (b)(4) of the (b)(4) vial machine in suite (b)(4) after filling a batch of (b)(4) mg/ (b)(4) ml. Your investigation was inadequate as it did not adequately evaluate potential root causes, including whether the mold was introduced during filling operations. You released the product without sufficient investigation. On May 16, 2025, fungi was recovered in two locations within the (b)(4) filling line in suite (b)(4) . The passive air sample recovered Didymella glomerata during the filling of (b)(4) injection. You attributed the mold recovery to a power failure that occurred during filling. Notably, surface monitoring below the (b)(4) also recovered Mycosphaerella africana after the power was restored. The investigation lacked sufficient CAPA. On June 4, 2025, Chaetomium cruentum/globosum was recovered from the (b)(4) of the (b)(4) vial machine in suite (b)(4) after filling a batch of (b)(4) mg/ (b)(4) ml. Your firm rejected the batch but failed to adequately investigate likely root causes. You stated within the investigation, “historically there has never been a mold hit isolated on the grade A space on the (b)(4) filling Line,” however the same mold, Chaetomium globosum , had been recovered, on March 20, 2024, on the same line. The investigation lacked CAPA. Overall, trends of fungal recoveries within your suites (b)(4) , and supporting cleanrooms, have significantly increased since 2023. Your firm has closed investigations without implementing robust CAPA. Your firm also has not adequately evaluated the ongoing trend of adverse findings of fungi within your aseptic production area, directly within product, and on product contact surfaces over time. In your response you commit to revise your procedures to perform routine trend analysis and strengthen your investigations. Your response is inadequate because you indicate that product impact conclusions in investigations were appropriate based on a lack of sterility failures, adverse environmental monitoring trends, and complaints, but fail to sufficiently address contamination sources. Your firm has not demonstrated that you have remediated your investigational capabilities to ensure scientifically rigorous investigations to effectively identify root causes so that appropriate CAPA can be implemented. To ensure proper root cause analysis and appropriate CAPA implementation, investigations must be thorough, well-documented, scientifically sound, and timely. Procedural updates and training alone do not address the systemic failures that allowed deficient investigations to persist undetected by quality unit (QU) oversight. In response to this letter, provide: A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, out-of-specification results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, QU oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted. An independent assessment and remediation plan for your CAPA program. Provide a report that evaluates whether the program includes effective root cause analysis, ensures CAPA effectiveness, analyzes investigation trends, improves the CAPA program wherever needed, ensures final QU decision authority, and is fully supported by executive management. A comprehensive, independent risk assessment of all contamination hazards with respect to your aseptic processes, equipment, and facilities, including but not limited to, the following: o All human interactions within the ISO 5 area (e.g., risk reduction or elimination of manual interventions wherever possible) o Equipment suitability (e.g.…

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 quality unit (QU) failed to thoroughly investigate multiple microbial count results that exceeded (b)(4) colony forming units/milliliters from your (b)(4) system. You use (b)(4) from this system as a component to manufacture your drug products. Instead, you continued to use (b)(4) from this system with out-of-limit (OOL) test results to manufacture drug products that were ultimately released, distributing potentially contaminated drug products to market. Your response is inadequate. You provided your (b)(4) System Monitoring Program procedure and CAPA-2026-005 which references enhanced (b)(4) monitoring and investigation procedures. However, neither document addresses specific microbiological alert or action limits, sampling frequencies, or acceptance criteria for (b)(4) used in drug product manufacturing. Furthermore, your response does not demonstrate that your firm has implemented adequate investigation procedures or completed retrospective reviews of the OOL events. Inadequate investigations can lead to unidentified root causes, ineffective CAPAs, and recurring problems that compromise your ability to manufacture safe and effective drug products. In response to this letter, provide: A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, OOL results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, QU oversight, and written procedures. Address how your firm will ensure that all phases of investigations are appropriately conducted. A detailed risk assessment addressing the potential effects of the observed (b)(4) system failures on the quality of all drug product lots currently in U.S. distribution or within expiry. Specify actions that you will take in response to the risk assessment, such as customer notifications and product recalls.

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). You failed to adequately investigate multiple microbiological out-of-limit (OOL) and chemical out-of-specification (OOS) results from testing the water you used to manufacture over-the-counter (OTC) (b)(4) drug products, including (b)(4) and (b)(4) . For…

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 manufactures active pharmaceutical ingredients and sterile injectable drug products. The sterile injectable products include aseptically filled (b)(4) . Your firm failed to conduct adequate investigations. For example, you inadequately…

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 open adequate investigations into out-of-specification (OOS) results. For example, (b)(4) batch (b)(4) failed initial testing due to unknown impurities. Your firm opened an out-of-specification investigation that included performing…

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 did not adequately investigate out-of-specification (OOS) and out-of-limit (OOL) results. Your investigations of sterility failures and significant environmental monitoring excursions lacked adequate scientific rationale to support root causes…