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 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 investigate aberrant media conditions (e.g., cracked or desiccated (b)(4) plates) used for testing raw material and drug product samples in your microbiological laboratory. In your response, you state that you opened an investigation to determine the scope of affected samples and adequacy of results and transferred microbial samples into an alternative incubator as an interim measure. Based on analyst interviews and a limited records review, you concluded that the results are valid. We acknowledge your plan to retest affected samples as a means of confirming your initial test results. Your response is inadequate. Without photographic evidence of plate conditions at the time of reading, there is no basis to retroactively confirm any result. Your conclusions rely solely on analyst interviews and data records that you acknowledged are unreliable. Furthermore, you did not commit to discontinuing the use of damaged plates for microbiological testing. Data integrity depends on complete and accurate documentation of test results and conditions. Failure to maintain such records undermines the reliability of your data. The use of deficient media similarly compromises the validity of microbiological test results and raises questions about the suitability and robustness of your methods. In response to this letter, provide: A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, out-of-specification results, out-of-limit 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. A comprehensive CAPA plan, overseen by a qualified consultant, for handling microbiological sampling media to ensure robust and reliable data. Establish a system that ensures uninterrupted custody and full reconciliation of all microbiological samples, including but not limited to: o Unique labeling of each sample o Signatures of all staff who handle the sample o Complete tracking of sample integrity and custody o Date and time of each activity (e.g., sample collection, delivery, incubation, removal from incubator) o Digital time-stamped photos of all plates at the time of reading. Ensure full implementation of photographic evidence to support all results obtained. o Signatures of personnel performing reading of microbial counts o Provisions for verifications and routine quality assurance oversight.

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 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 conduct an adequate and timely out-of- specification (OOS) investigation for your (b)(4) drug product. Your contract testing laboratory reported an OOS result for (b)(4) on August 28, 2024, but you did not initiate the Phase II investigation until December 4, 2024. Despite the ongoing investigation, your quality unit (QU) released the batch on (b)(4) , and subsequently shipped the batch for the U.S. market on (b)(4) , after your firm retested the sample and obtained passing results. A root cause was not determined for the OOS result, and the investigation was closed on July 11, 2025. In your response, you state that you opened a corrective action and preventive action (CAPA) plan that includes updating your procedure for releasing drug products, and you conducted a risk assessment to determine the final disposition of this lot, which is still within expiry and any subsequent market action. Your response is inadequate because it fails to provide a justification for not completing your OOS investigation for nearly 11 months. Additionally, while you state that the OOS drug product was shipped because of a breakdown in your drug product-release procedure, you did not determine the root cause for the actual OOS result, nor did you conduct a comprehensive assessment of your quality system to ensure that all OOS investigations have been adequately investigated. Inadequate investigations can lead to unidentified root causes, ineffective CAPAs, and recurring problems that compromise your ability to manufacture safe and effective drug products. For more information about handling failing, OOS, out-of-trend, or other unexpected results and documentation of your investigations, see FDA’s guidance document Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production at https://www.fda.gov/media/71001/download. In response to this letter, provide: A retrospective, independent review of all invalidated OOS (including in-process and release/stability testing) results for U.S. products currently in the U.S. market and within expiry as of the date of this letter, and a report summarizing the findings of the analysis, including the following for each OOS: o Determine whether the scientific justification and evidence relating to the invalidated OOS result conclusively or inconclusively demonstrates causative laboratory error. o For investigations that conclusively establish laboratory root cause, provide rationale and ensure that all other laboratory methods vulnerable to the same or similar root cause are identified for remediation. o For all OOS results found by the retrospective review to have an inconclusive or no root cause identified in the laboratory, include a thorough review of production (e.g., batch manufacturing records, adequacy of the manufacturing steps, suitability of equipment/facilities, variability of raw materials, process capability, deviation history, complaint history, batch failure history). Provide a summary of potential manufacturing root causes for each investigation, and any manufacturing operation improvements. A comprehensive review and remediation plan for your OOS result investigation systems. The CAPA should include but not be limited to addressing the following: o QU oversight of laboratory investigations o Identification of adverse laboratory control trends o Initiation of thorough investigations of potential manufacturing causes whenever a laboratory cause cannot be conclusively identified o Resolution of causes of laboratory variationsInitiation of thorough investigations of potential manufacturing causes whenever a laboratory cause cannot be conclusively identified o Adequately scoping of each investigation and its CAPA o Revised OOS investigation procedures with these and other remediations.

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 adequately investigate viscosity failures obtained during stability testing of distributed OTC drug products. Specifically, stability testing records documented (b)(4) out-of-specification (OOS) results without adequate root cause determination, CAPA, or documented justification for the established (b)(4) specifications. In your response, you attribute the root cause to inadequate documentation of the (b)(4) specification changes and commit to evaluating the adequacy of supporting data, conducting a retrospective review of past OTC stability failures, updating your procedure, and training staff. Your response is inadequate because you did not include a risk assessment for previously distributed products with viscosity OOS results, a CAPA plan with clear timelines, documented justification for your established (b)(4) specifications, and an updated procedure supported by staff training records. It is essential to conduct thorough well documented, and scientifically sound investigations to identify root causes of OOS results, evaluate all potentially affected batches, and implement timely and effective CAPA plans. For more information about handling failing, out-of-specification, out-of-trend, or other unexpected results and documentation of your investigations, see FDA’s guidance document Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production at https://www.fda.gov/media/158416/download. In response to this letter, provide: A comprehensive independent assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system. A retrospective, independent review of all invalidated OOS (including in-process and release/stability testing) results for products currently in the U.S. market and within expiry as of the date of this letter and a report summarizing the findings of the analysis, including the following for each OOS: o Determine whether the scientific justification and evidence relating to the invalidated OOS result conclusively or inconclusively demonstrates causative laboratory error. o For investigations that conclusively establish laboratory root cause, provide rationale and ensure that all other laboratory methods vulnerable to the same or similar root cause are identified for remediation. o For all OOS results found by the retrospective review to have an inconclusive or no root cause identified in the laboratory, include a thorough review of production (e.g., batch manufacturing records, adequacy of the manufacturing steps, suitability of equipment/facilities, variability of raw materials, process capability, deviation history, complaint history, batch failure history). Provide a summary of potential manufacturing root causes for each investigation and any manufacturing operation improvements. A comprehensive assessment and remediation plan to ensure your quality unit (QU) is given the authority and resources to effectively function. The assessment should also include, but not be limited to, the following: o A determination of whether procedures used by your firm are robust and appropriate. o Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices. o A complete and final review of each batch and its related information before the QU disposition decision. o Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products.

Failure to 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, as required by 21 CFR 211.192. For example, between August 2023 and June 2025, (b)(4) lots of your finished product failed sterility testing. While you discarded these lots, you did not conduct investigations to determine the root cause(s) and whether other lots were impacted.