Data integrity Findings

During the inspection of the manufacturing site, in the frame of EDQM’s inspection progamme, 21 deficiencies against EU GMP were identified. One deficiency was classified as critical due to inadequate control of contamination and cross-contamination risk in shared facilities. The risk assessments and contamination control strategy for Workshop 2 and the dispensing area were insufficiently robust, specific, justified, and effectively implemented, notably for exposed product operations, gowning, area and equipment cleanliness, material entry, dispensing activities, and the use of shared equipment for potentially highly potent products. Furthermore, absence of contraindications between APIs manufactured in the shared facility was not evaluated consistently. These represent a potential risk to patient safety. Five deficiencies were classified as major and were related to the following areas: cleaning validation and cleaning procedures, preventive maintenance and equipment condition, data integrity, change control management, and batch release and compliance to CEP. In addition, 15 other deficiencies were found (i.e. records, quality system, personnel training, calibration, labelling management, equipment qualification). Action taken/proposed by the NCA: Requested Variation of the marketing authorisation(s) For medicinal products containing APIs manufactured by LIANYUNGANG GUIKE PHARMACEUTICAL CO. LTD. in Workshop 2, assessment of the MA to remove or substitute this manufacturer of active substances and intermediates should be considered. In addition, no new MAs should be granted for products relying on this API source while the statement of non-compliance remains in force. Recall of batches already released If there are alternative suppliers and there is no risk of shortage, recall of medicinal product should be evaluated by the involved NCAs following assessment conducted in conjunction with MAHs. Prohibition of supply Due to the nature of the non-compliance, prohibition of supply is recommended, unless there are no alternative suppliers and there is a risk of shortage. Suspension or voiding of CEP (action to be taken by EDQM) The EDQM had taken the decision to suspend all granted CEPs from LIANYUNGANG GUIKE PHARMACEUTICAL CO. LTD. CEP 2013-019 Atracurium besilate CEP 2021-236 Cisatracurium besilate CEP 2017-271 Entecavir monohydrate (intermediate)

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 is a contract testing laboratory that conducts testing of various application and nonapplication drug products for the US market. Your laboratory records lacked complete and original data demonstrating that you performed the required testing. You did not accurately complete laboratory records contemporaneously at the time you performed the laboratory activities. Our investigator observed (b)(4) microbial test samples that lacked complete documentation on raw data test sheets (e.g., the test sheets had blank spaces where entries should have been recorded). While your summary reports included final plate counts, your raw data test sheets for some of the samples covered in these reports lacked complete documentation of plate counts. In your response, you stated these samples were not from drug products intended for the U.S. market. However, your firm maintains one quality system and has one set of procedures for testing U.S. and non-U.S. drug products. Thus, the quality unit (QU) failure is applicable to all drug products you test. Additionally in your response, you identify the documentation deficiencies to be “consistent with an institutional procedural and cultural gap rather than individual misconduct or a coordinated effort to conceal or falsify results.” This indicates that these violative practices are used for all drugs you test, including those for the U.S. market. We acknowledge that your response indicated you will increase the QU presence during testing until procedural improvements, training effectiveness verification, and compliance monitoring demonstrate sustained adherence. Your response is inadequate because it does not include an assessment of your paper-based documentation system to identify and correct vulnerabilities in your current controls. Additionally, you did not provide evidence that you performed a retrospective review to identify any additional instances of incomplete or non-contemporaneous documentation. Microbial testing, an essential quality control step, is integral in preventing distribution of unsafe products. Integrity of data is fundamentally compromised when there is a failure to record or maintain complete and accurate records of test results or conditions associated with drug testing. Furthermore, the lack of reliable data compromises the QU’s ability to exercise its function of ensuring compliance with applicable standards. Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. See FDA’s guidance document Data Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/media/119267/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 comprehensive assessment of documentation systems used throughout your 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 (ALCOA) records throughout your operation. A comprehensive CAPA, 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 o signatures of personnel performing reading of microbial counts o provisions for verifications and routine quality assurance oversight.

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)). Your quality unit (QU) failed to establish and exercise its authority to adequately oversee the manufacture, packing, holding, review, and release of your (b)(4) over-the-counter (OTC) drug products, such as (b)(4) . Your firm’s inadequate quality oversight resulted in significant deficiencies in documentation practices, batch record review, investigations, and quality system controls to ensure compliance with CGMP requirements. For example, your QU failed to ensure: Investigation of any unexplained discrepancy or failure of a batch or any of its components to meet any specifications (21 CFR 211.192). Establishment of suitable quality oversight procedures (e.g., raw material handling, review of production records, and recalls) (21 CFR 211.22(a)). Batch production and control records that include documentation of the accomplishment of each significant step in the manufacture, processing, packing, or holding of the batch, for each batch of drug product (21 CFR 211.188(b)). Establishment of written procedures describing the handling of all written and oral complaints regarding a drug product (21 CFR 211.198(a)). In your response, you commit to procedural changes related to batch records, such as discontinuing the use of correction fluid (white-out) and improved temperature monitoring practices. However, your response is inadequate because it does not adequately acknowledge or address the QU’s failure to exercise its responsibility and authority to ensure the accuracy, integrity, review, and approval of CGMP records. Specifically, your response fails to address significant data integrity lapses documented at your facility which include backdating of quality release labels, entry of temperature data when the thermometer was inoperable, and lack of batch records to document manufacturing activities for drug products. Your firm’s quality systems are inadequate. For help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR parts 210 and 211, see FDA’s guidance documents: Quality Systems Approach to Pharmaceutical CGMP Regulations at https://www.fda.gov/media/71023/download Q9(R1) Quality Risk Management at https://www.fda.gov/media/167721/download ICH Q10 Pharmaceutical Quality System at https://www.fda.gov/media/71553/download 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 corrective action and preventive action (CAPA) plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, and contemporaneous records throughout your operation. A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should also include, but not be limited to: 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. A comprehensive assessment of your overall system for investigating deviations, discrepancies, complaints, out-of-specification (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.

Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements (21 CFR 211.67(a)). Your firm failed to adequately clean and maintain non-dedicated drug manufacturing equipment used to fill OTC drug products. For example, our investigator observed stagnant (b)(4) product residue inside the tubing on the filling line with residue accumulating in crevices and on surfaces that come into direct contact with the drug product. In your response, you state that you developed a comprehensive cleaning procedure and implemented a cleaning validation program. However, your response is inadequate because you fail to address the impact of your inadequate cleaning practices on drug products that remain in distribution. In addition, your response does not address how you will document cleaning in your batch record. It is your responsibility to ensure that you use only appropriately designed and maintained equipment in the manufacture of your drug products. In response to this letter, provide: A comprehensive, independent retrospective assessment of your cleaning effectiveness to evaluate the scope of cross-contamination hazards. Include the identity of residues, other manufacturing equipment that may have been improperly cleaned, and an assessment whether cross-contaminated products may have been released for distribution. The assessment should identify any inadequacies of cleaning procedures and practices and encompass each piece of manufacturing equipment used to manufacture more than one product. A CAPA plan, based on the retrospective assessment of your cleaning program, that includes appropriate remediations to your cleaning processes and practices and timelines for completion. Include the following as part of the assessment and CAPA plan: o a detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning. o a list of improvements with an explanation how each will enhance cleaning effectiveness. o improved ongoing verification of proper cleaning execution for all products and equipment. o any other needed remediations. Your CAPA plan to implement routine, vigilant operations management oversight of facilities and equipment. This plan should incorporate oversight from a qualified independent consultant and ensure, among other things, prompt detection of equipment/facilities performance issues, effective execution of repairs, adherence to appropriate preventive maintenance schedules, timely technological upgrades to the equipment/facility infrastructure, and improved systems for ongoing management review. Inadequate Microbiological Testing of Finished Drug Product Additionally, we observed deficient microbiological testing specifications and test methods for your finished non-sterile OTC (b)(4) drug products. We noted that you limited microbiological testing to aerobic plate counts only and used a method intended for non-pharmaceutical use. Test methods must be validated to show that they are suitable for their intended use and are equivalent to or better than applicable USP compendial methods. The reproducibility of your test methods is essential to determine if your drug products meet established specifications. Data Integrity Remediation Your quality system does not adequately ensure the integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. See FDA’s guidance document Data Integrity and Compliance With Drug CGMP: Questions and Answers (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/data-integrity-and-compliance-drug-cgmp-questions-and-answers) for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/media/119267/download. We strongly recommend that you retain a qualified consultant to assist in your remediation. In response to this letter, provide: A comprehensive investigation into the extent of the inaccuracies and inconsistencies in data, records, and reporting including results of the data review for drugs distributed in the United States. Include a detailed description of the scope and root causes of all data integrity deviations. A retrospective risk assessment of the potential effects of each observed deviation on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by each occurrence of a data integrity event. The assessment should also determine risks posed by current operational conditions, and any needed interim measures. A management strategy for your firm that includes the details of your global corrective action and preventive action plan to implement attributable, legible, complete, original, accurate, and contemporaneous records throughout your operation. The detailed corrective action plan should describe how you intend to ensure the reliability and completeness of all data, including microbiological and analytical data, manufacturing records, and all data submitted to FDA.

During the inspection, multiple critical and major deficiencies were identified across the facility, particularly in areas directly associated with the aseptic manufacture of medicinal products. The nature and extent of these deficiencies demonstrate systemic weaknesses in contamination control, aseptic behaviour, equipment integrity, data governance, and quality control practices, which collectively pose a significant risk to the sterility, safety and overall quality of the products manufactured in Block A. Critical failures were observed in facility design and pressure cascade maintenance, including inadequate differential pressures between classified and non classified areas, reversed pressure gradients, and layout constraints that resulted in sterile API being exposed in Grade B. These issues undermine the fundamental environmental controls required for aseptic processing. Serious concerns were also identified regarding personnel behaviour and aseptic practices, with operators failing to comply with gowning requirements, aseptic discipline, RABS handling procedures, and environmental protection measures. Such behaviours directly compromise sterility assurance and indicate insufficient training and oversight. The inspection further revealed equipment in poor condition, including rusted pass box, unclean balance and step ladder, and the use of open containers for rejected materials and IPC samples within Grade B. These deficiencies represent unacceptable contamination risks within critical manufacturing areas. Significant weaknesses were found in the organisation and control of materials and GMP documentation, including the presence of operational documents, microbiology records, Petri dishes, and other materials stored in uncontrolled areas such as the expansion zone. The discovery of a deteriorated and unidentified gas cylinder connected to a pipeline used for aseptic filling further heightened concerns regarding uncontrolled substances potentially coming into contact with the product. Critical data integrity failures were identified, including missing records, inconsistent entries, unclear terminology, and analytical activities reported but not performed. These issues undermine the reliability of GMP documentation and raise concerns regarding the accuracy of batch release decisions. In the Quality Control laboratories, essential tests for APIs were not performed by the manufacturer, retention samples were improperly stored, finished product samples lacked proper identification, and sterility testing was conducted using unsuitable equipment. These deficiencies critically affect the validity of analytical results and the assurance of product quality. Major gaps were also identified in the Contamination Control Strategy (CCS), which was implemented late and failed to address several contamination risks, including API exposure in Grade B, environmental monitoring vulnerabilities, personnel limits, HEPA filter replacement rationale, and disinfectant approval. Finally, batch documentation lacked evidence of required sampling and incomplete line clearance verification, compromising batch traceability and readiness for aseptic operations. Action taken/proposed by the NCA: Others The Portuguese market is not impacted, as no medicinal products have been placed on the market by the manufacturer concerned, and alternative manufacturers with medicinal products containing the same active substance and strength are authorised in Portugal. It was decided that, for the manufacturer concerned, a Non-Compliance Report (NCR) was issued until all critical and major deficiencies have been adequately addressed and their implementation confirmed through a follow-up inspection.

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