Findings citing 21 CFR 211.194

Your firm’s quality unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22). Your firm failed to establish an adequate QU with the responsibilities and authority to oversee the manufacture of drug products. For example, you failed to ensure: Adherence to a stability program that supports the drug products’ expiration dating (21 CFR 211.166(a)). Contemporaneous documentation of EM and personnel monitoring sampling data in laboratory records (21 CFR 211.194(a)). In response to this letter, provide: A comprehensive assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed CAPA plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous (ALCOA) records throughout your operation. A comprehensive assessment and remediation plan to ensure your QU is given the authority, independence, and resources to effectively function that includes, but is not limited to: o A determination of whether procedures used by your firm are robust and appropriate o Provisions for independent QU oversight throughout your operations to ensure satisfactory procedures and 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 o Also, describe how executive management will support robust quality assurance at your firm, including but not limited to timely provision of resources that enable proactive detection and resolution of emerging manufacturing/quality issues to assure a continuing state of control Ineffective Quality System Significant findings in this letter demonstrate that your firm does not operate an effective quality system in accord with CGMP. In addition to the lack of effective management oversight of your production and laboratory operations, we found your QU is not enabled to exercise proper authority and/or has insufficiently implemented its responsibilities. Executive management should immediately and comprehensively assess your company’s global manufacturing operations to ensure that your systems, processes, and products conform to FDA requirements. Your firm’s quality systems are inadequate. For guidance on establishing and maintaining CGMP-compliant quality systems, see FDA guidances: Q8(R2) Pharmaceutical Development at https://www.fda.gov/media/71535/download, Q9(R1) Quality Risk Management at https://www.fda.gov/media/167721/download and Q10 Pharmaceutical Quality System at https://www.fda.gov/media/71553/download. Drug Production Ceased and Suspended We acknowledge your commitment to suspend production of (b)(4) Drugs at this facility for the U.S. market and to cease production of all other (b)(4) solutions. If you plan to resume any manufacturing operations regulated under the FD&C Act, notify this office before resuming your drug manufacturing operations. If you resume CGMP activities, you are responsible for resolving all deficiencies and systemic flaws to ensure your firm is capable of ongoing CGMP compliance. In addition, based upon the nature of the violations we identified at your firm, you should engage a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements. The qualified consultant should also perform a comprehensive six-system audit 1 of your entire operation for CGMP compliance and evaluate the completion and efficacy of all CAPA, before you pursue resolution of your firm’s compliance status with FDA. Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance. In your notification to the Agency, provide a summary of your remediations to demonstrate that you have appropriately completed all CAPA. Repeats Violation at Facility In a previous warning letter (WL 320-19-01), FDA cited similar CGMP violations. You proposed specific remediations for these violations in your response. Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate. Additional Guidance on Aseptic Processing See FDA’s guidance document Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice to help you meet the CGMP requirements when manufacturing sterile drugs using aseptic processing at https://www.fda.gov/media/71026/download.

Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to ensure compliance with established specifications and standards (21 CFR 211.194(a)). Your firm conducts microbiological analyses of components and drug products for your customers. You perform (b)(4) pour plate methods for microbial enumeration of (b)(4) samples. During the inspection, our investigator observed that your microbiologist failed to record the (b)(4) results when they were assessed as too numerous to count (TNTC), recording only the pour plate counts. The investigator also noted that while the (b)(4) for the pour plate samples was cracked and desiccated, the pour plate counts were recorded as within acceptable limits. When (b)(4) plates are desiccated and cracked, the media can no longer reliably support uniform microbial growth. A result recorded from a compromised plate, even one that falls within specification, cannot be considered valid, as the physical condition of the media may have suppressed or obscured actual microbial recovery. Additionally, your data review procedure is deficient in that it does not require secondary verification when an initial plate count is recorded as 0 colony forming units (CFU), creating a systemic gap where microbial growth can go undetected. During the inspection, the investigator identified a colony on a plate recorded as 0 CFU by your analyst. Further, several samples with desiccated and cracked (b)(4) were recorded as 0 CFU and discarded without secondary analyst review. The practice of non-reporting of TNTC (b)(4) results, and the investigator's direct observation of a colony on a plate recorded as 0 CFU illustrates the unreliability of your data, and further demonstrates that lack of secondary verification is unacceptable. In your response, you state that analyst interviews and a retrospective review of laboratory data revealed inconsistent reporting practices dating back to February 2025. You acknowledge that some analysts were selectively recording test results, documenting only pour plate results when (b)(4) results were TNTC (out of specification), and only documenting (b)(4) results when they were within specification. You commit to revising your procedures, training analysts, and periodically auditing plate readings. Your response is inadequate. You do not address whether the selective omission TNTC (b)(4) results during this period affected the accuracy of certificates of analysis issued to customers, or whether any customers received incomplete or potentially inaccurate microbiological data. Although you updated your reporting procedure to require secondary review, you provided no evidence to verify the completeness and accuracy of the historical data reviewed. Reliability of data is compromised when there is a failure to maintain complete records of the conditions and data associated with all tests. Furthermore, the lack of complete data compromises the quality unit’s (QU) ability to exercise its function of ensuring compliance to applicable standards. 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 comprehensive assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed corrective action and preventive action (CAPA) plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous records throughout your operation.

Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to ensure compliance with established specifications and standards (21 CFR 211.194(a)). Your laboratory records did not include complete data to support the analyses performed. For example, your analytical notebooks documented approximately (b)(4) microbiology plates for finished drug products and approximately (b)(4) media plates for testing (b)(4) samples as…

Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to ensure compliance with established specifications and standards (21 CFR 211.194(a)). Your laboratory records lacked complete and original data to support the analyses performed. For example: A. During the inspection, we requested the testing worksheets from the (b)(4) studies you conducted on a compounding tank and its transfer line, which included endotoxin and…

Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to ensure compliance with established specifications and standards (21 CFR 211.194(a)). You failed to accurately document microbiology sampling and testing results for components used in your over-the-counter (OTC) drug products. Your laboratory records did not accurately reflect activities performed. For example, your microbiologist documented the collection of routine…

Your firm failed to establish an adequate quality unit and the responsibilities and procedures applicable to the quality control unit are not in writing and fully followed (21 CFR 211.22(a) and (d). The records and information you provided demonstrate that your quality unit (QU) did not effectively exercise its responsibilities to oversee the quality of your drug manufacturing operations. Specifically, your QU failed to: Ensure adequate control over laboratory data including…