• Zuhai United Laboratories Co. Ltd. (Guangdong, China) received a warning letter on June 27th, 2018 based on the outcome of an inspection ending September 15th, 2017. FDA suggests they employ consultant(s) to assist them in coming into GMP compliance in their manufacturing of APIs. Deficiencies include but are not limited to:
    • The firm failed to adequately investigate and manage OOS results. OOS results were invalidated without adequate investigation and assignment of root cause, and API was released on passing repeat test results. Results were invalidated based on ‘outlier’ test results that FDA said was not appropriate. FDA recommends they read the FDA guidance on OOS Test Results. FDA asks the firm to provide the following in response to the warning letter:
      • “Provide a retrospective review of all invalidated OOS results obtained for products on the U.S. market. Assess whether the scientific justification and evidence was conclusive. For investigations that established the laboratory root cause conclusively, determine the adequacy of the corrective action and preventive action (CAPA) plan and ensure the other laboratory methods vulnerable to the same root cause have been identified for remediation. For any OOS results that had an inconclusive or no root cause identified in the laboratory, include a thorough review of production, such as batch manufacturing records, adequacy of manufacturing steps, process capability, deviation history, and batch failure history. Provide a CAPA plan that identifies the potential manufacturing root causes for each such investigation. Include process improvements where appropriate.
      • Evaluate all instances in which a statistical outlier test was used to invalidate OOS results. Determine the potential effect on drug quality.
      • Assess your overall system for investigating OOS results. Provide a CAPA plan to improve the quality of OOS investigations. Your CAPA should ensure that your revised OOS investigations procedure includes improved quality unit oversight of laboratory investigations, identification of adverse laboratory control trends, and investigation of potential manufacturing causes when a laboratory cause cannot be conclusively identified.
      • Comprehensive independent assessment of your overall system for investigations of deviations, discrepancies, complaints, OOS results, and failures. Your CAPA should include, but not be limited to, improvements in investigation competencies, root cause analysis, written procedures, and quality unit oversight. Also include your process for evaluating CAPA effectiveness.”
    • The firm did not adequately investigate findings from their retrospective review of irregularities in chromatography data. This included the finding of data deletion, sample trial injections and missing audit trails. FDA asks the firm to provide:
      • “A copy of the deviation investigation, GOV-2017001, initiated in response to our inspectional findings;
      • Completed reports for all review stages in your retrospective review (protocol SD-Q0100011.000) including related annex documents; and
      • The additional information requested in the Data Integrity Remediation section of this letter.”
    • The firm failed to retain electronic data documenting decontamination cycles for the grade A area where sterile powders are manufactured. Electronic data were overwritten and only a ‘cursory’ written record was retained.
    • The electronic audit trail function for non-viable particle monitoring systems for grade A and B areas were disabled for specified durations, and data files were modified without recording what changes were made and who made them.
    • Investigators identified poor aseptic practices and asks the firm to provide:
      • “Your plan to assure appropriate aseptic practices and cleanroom behavior during production. Include specific steps to ensure routine supervisory oversight for all production batches. Also describe the frequency of quality assurance oversight during aseptic processing and other operations.
      • Comprehensive identification of all contamination hazards with respect to your aseptic processes, equipment, and facilities. Provide a risk assessment that covers all human interactions with the ISO 5 area, equipment placement and ergonomics, air quality in the ISO 5 area and surrounding room, facility layout, personnel flow, and material flow. Also include a detailed CAPA plan, with timelines, to address the findings of the contamination hazards risk assessment.”