Absolutely Natural

What FDA requested

Model-assisted summary. Consult the letter for complete requests and conditions.

• 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 Quality unit oversight of laboratory investigations o Identification of adverse laboratory control trends o Resolution of causes of laboratory variation o Initiation 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
• A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, OOS 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, quality unit 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 investigations trends, improves the CAPA program when needed, implements final quality unit decisions, and is fully supported by executive management.
• 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 evaluation of microbiological tests methods used to perform total counts and identification to evaluate suitability for intended use, followed by systemic CAPA, including but not limited to: o A comprehensive retrospective evaluation review of each test method to determine any inadequacies, including but not limited to those cited in this letter. o Where a method is found unsuitable for its intended use (e.g., inadequate capacity to enumerate), provide information on a new suitable method that will be employed o Improved systems to ensure selection and suitability of microbiological test methods in future before implementation. o Once this full evaluation is complete, provide all findings, data, and deviations encountered.
• Following review by an independent third-party, provide updated validation protocols and final reports that adequately address methods for each product, including specificity, limit of detection, robustness, ruggedness, and repeatability. This should include an evaluation of whether sample sizes are appropriate. Where you intend to use non-compendial methods, provide studies evaluating the equivalence or superiority of the method to the USP method.
• A commitment to establish release and stability specifications for the absence of BCC in drug products, and to implement risk-based sampling and testing procedures to monitor and control potential sources of BCC contamination. Updated analytical procedures, including confirmatory testing and speciation, that ensure regulatory compliance for all microbiological testing. This should also include an explanation of whether sample preparations are reserved to assist in conducting OOS investigations.