Discussion forum for Pharma Quality events, Regulatory Actions
Warning letters, 483s, Recalls, Import Alerts, Audit observations
Warning letters, 483s, Recalls, Import Alerts, Audit observations
With contributions from: Venkiteswaran.T.K; Satish Reddy; Shashank Sharma; Srinivas Churya; Subrangshu Choudhary
The USFDA inspection at Indian API manufacturer Global Calcium Pvt Ltd unveiled critical deviations like fabrication of batch records, cleaning records, equipment log books, uncontrolled note books in QC and issuance and documentation of records in duplicate. The USFDA 483 issued to Global Calcium also cites lapses in stability programme, maintenance of plant and equipment, deviation investigations. The site was inspected by USFDA investigators Justin A. Boyd and Teresa I. Navas in July-Aug 2024.
Qvents post discusses the implications when critical data integrity issues are observed in regulatory inspections and remediation actions to be considered to regain the confidence of the regulatory agencies.
Systematic and Fundamental DI issues: The FDA investigators discovered during the inspection systematic and fundamental cGMP violations and Data Integrity issues. Plant Manager / Production Heads created detailed excel sheet plans for generating batch records, equipment logs, cleaning records and documentation for activities which did not occur. These excel sheets with dates for Production start and stop times, sampling dates and times, production weights etc were found attached to blank batch records. It was observed that Production employees created duplicate set of cleaning records and equipment logs for same date and time showing different batches were manufactured at the same time. Several instances were observed where QA has still not reviewed the batch records, but the batches were already released and shipped to US. Discrepancies were also observed between batch records and equipment usage and activities documented in the Plant Work Sheet Report which was used for communication. QA was found to be issuing equipment logs, cleaning logs etc in duplicate with same document number which were used to document activities which did not occur. In the QC analytical data was found to be recorded in uncontrolled note books which was further transcribed to controlled test reports.
Several instances were observed where stability samples could not be located as per the stability protocols; also samples were observed in stability chambers for which there were no protocols available.
Other cGMP violations: Other cGMP violations observed by the investigators included inadequate maintenance of plant and equipment with liquid dripping from overhead ceiling pipes near API unloading areas and inadequate impurity profile documentation for APIs. It was also observed that several equipment and instrument failures recorded in the Plant Work Sheet Report are not recorded in batch records and there were no maintenance records or investigations into the failures.
When fundamental GMP non-compliances, violations, and severe data integrity issues are discovered, regaining the confidence of regulatory agencies becomes extremely challenging, if not impossible. Sharing of information from drug inspections among regulatory bodies like USFDA, European Union, UK, WHO etc through Mutual Recognition Agreements (MRAs) and Rapid Alert System (RAN) when one reports serious non-compliances can lead to cascade of regulatory actions from multiple agencies. Serious lapses at API manufacturing sites, can have significant repercussions for finished dosage form manufacturers who rely on these APIs, potentially necessitating product recalls, source changes and more.
Immediate and Decisive Action From Top Management: Addressing major cGMP non-compliances requires serious, immediate action, with direct involvement from the highest levels of management. When serious data integrity issues implicate site or plant leadership, a complete overhaul of the site’s operational management is often necessary. Engaging reputed and expert third-party cGMP consultants is critical for a comprehensive assessment of the scope and extent of the cGMP deviations. Experienced personnel should be brought in to manage operations, working closely under the oversight of the independent GMP consultants.
Handling Widespread Data Integrity Issues: In cases where data integrity issues are widespread—such as fabrication of batch records, missing stability samples, and deficient protocols—all data supporting the distributed products is suspect. This will likely necessitate the recall of all impacted products. When such issues are observed at API manufacturers, finished dosage form (FDF) manufacturers who has used the APIs from the site must conduct a comprehensive assessment of the impact on their products and take necessary actions like filing Field Alert Reports (FAR), recall actions.
Reassessment of Product Dossiers and Supporting Data:Â Data integrity concerns cast doubt on the validity of data supporting approved product dossiers and certifications including process validations, method validations, and stability studies. A thorough reassessment of the reliability of these data is necessary. If issues are identified, revalidation of the processes and analytical methods should be conducted under the supervision of third-party GMP consultants. Fresh stability studies will need to be initiated to support product shelf life. Evaluating product samples from the market, including testing at third-party laboratories, may also be beneficial to confirm product stability and shelflife.
Comprehensive Facility Assessment:Â A thorough assessment of the manufacturing facility is essential, including the suitability and integrity of manufacturing equipment, ancillary equipment and systems, production support utilities (such as water, air, nitrogen, HVAC systems), clean rooms, control over computerized systems, and laboratory equipment. Identifying gaps and addressing them, including the replacement of non-compliant systems, is crucial.
Strengthening GMP Systems and Quality Management:Â The adequacy of cGMP systems and Quality Management Systems (QMS) must be evaluated, with remediation measures initiated to enhance procedures across all pharmaceutical quality operations. Consideration should be given to Computerisation, Digitalisation and Automation of different Quality System processes and GxP operations. Implementing measures such as electronic document management systems (eDMS), electronic batch records, Laboratory Information Management Systems (LIMS), and Learning Management Systems (LMS) etc. reduces or removes scope for manual interventions and manipulations.
Training and Quality Culture Enhancement: Programmes should be established to enhance the technical and cGMP skills and awareness of operating personnel. This includes hiring experts across various domains—Production, Quality Assurance, Quality Control, Engineering, Maintenance, R&D, IT systems. Training programs should focus on competency development and enhancing the quality culture. Regular ongoing training and awareness buildup programmes with a mix of classroom training on QMS procedures and SOPs, protocols, GMP topics, workshops discussing relevant issues such as FDA 483 observations, warning letters, recalls etc. should be established to build technical skills and competencies and GMP awareness of personnel.
Conclusion: Commitment to Comprehensive Remediation
Comprehensive remediation measures, with top management taking direct ownership, regular management reviews, and proactive and prompt corrective actions when deviations and quality incidents occur, are critical for regaining the confidence of regulatory agencies and customers.
Related Reads:
Leave a Comment
You must be logged in to post a comment.