Discussion forum for Pharma Quality events, Regulatory Actions
Warning letters, 483s, Recalls, Import Alerts, Audit observations
Warning letters, 483s, Recalls, Import Alerts, Audit observations
Sun Pharma Dadra unit was inspected by USFDA in December 2023 by FDA investigator Pratik S Upadhyay. The inspection resulted in issuance of USFDA 483 with six observations. The issues highlighted in the USFDA 483 included inadequate OOS investigation, impact evaluation on other batches, Cleaning and Maintenance issues, lack of Quality unit oversight over document control, complaints handling.
The FDA’s 483 observations underscore the importance of robust quality systems, thorough investigations, and effective CAPAs in the pharmaceutical industry. Learning from these observations, help Quality personnel to proactively strengthen quality management practices and avoid similar compliance issues.
The observation on inadequate OOS investigation highlights multiple deficiencies in the investigation process. In an OOS incident in dissolution test during stability studies root cause is attributed to basket falling off from the shaft. In another incident batch during stability studies was OOS due to unknown peaks and this was attributed to glass ware contamination.
In the dissolution OOS no laboratory error was noted during preliminary investigation and no discrepancies were noted on the dissolution analysis checklists. But later during interview, the analysts admitted that checklists were simply filled up without verifying parameters (falsifying documents). The QC technician cleaning the equipment also did not report the unusual observation of fallen basket. Â The hypothesis studies to evaluate dropping of the dissolution basket from the shaft was inconclusive. Despite analysts admitting Data integrity issues, the investigation did not evaluate impact of such practices in all other activities performed by the analysts.
For the OOS result a of batch due to unknown peaks, the root cause was attributed to glassware contamination though same peak was observed in other batches (but within the limits for unspecified impurities). This indicate that the peaks may not be due to contaminants and could be degradant peak of the product which was not investigated. The investigations also did not attempt to identify contaminants (if it was due to improper rinsing of glassware) considering all other analysis and sample preparation activities that was performed in the lab during the analysis of the OOS batch.
Robust Documentation: Always include supporting evidence such as photographs, videos, and detailed instrument printouts in OOS investigation documentation.
Comprehensive Impact Assessment: When data integrity issues are identified, conduct a thorough evaluation of the potential impact on all other activities performed by the personnel involved, not just the incident observed.
Expanded Investigations When root cause is inconclusive: Recognize that OOS root causes like dissolution basket falling off or glassware contamination are examples of inconclusive laboratory error. They are hypothesis with no hardcore supporting evidence. Treat such incidents as triggers for extended investigations that encompass manufacturing processes and other potential contributing factors.
Systematic Investigation: When investigating OOS results due to unknown peaks, follow a systematic approach – Review trends in other batch analysis, stability trend, forced degradation studies, review inherent impurities, contribution from excipient matrix over shelflife Attempt to establish identity of peak, considering other activities in the area. Document all investigations thoroughly.
Checklist Training: Provide comprehensive training to laboratory personnel on the purpose and proper use of analysis checklists. Emphasize that checklists are tools to prevent errors and omissions, not simply routine paperwork.
Focus on Root Cause: Prioritize a scientific and systematic approach to identify the true root cause of OOS results. Avoid creative shortcuts or premature conclusions aimed at quickly closing investigations to release batches. The goal is to implement effective corrective and preventive actions (CAPAs) to prevent recurrence.
Comprehensive Impact Assessment: Initiate a thorough evaluation of the extent to which inconclusive OOS investigations or data integrity issues may have affected other batches or products. This assessment should encompass all distributed products within their expiry period.
Re-evaluate all invalidated OOS: Rvaluate all cases of invalidated OOS, identify whether the root cause is conclusive or inconclusive laboratory error. Where it is conclusive laboratory error, evaluate possibility of similar error occurring in other analysis, tests and implement CAPAs. In case of inconclusive laboratory error, expand investigations to include manufacturing processes and other potential root causes. Thoroughly document all investigations and conclusions with scientific rationale.
Data Integrity Deep Dive: For Data Integrity (DI) issues, evaluate possibility of similar issues involving other analysis /activities performed by persons involved and establish extent of DI issues. Take up impact evaluation of all analysis / all batches analysed by persons where DI issues are identified. Document the evaluation and conclusions with scientific rationale. Â
Recall Consideration: If the investigation reveals a risk of OOS or substandard batches being in the market, take prompt action, including product recall if necessary
Equipment and utensils are not cleaned and maintained at appropriate intervals to prevent contamination
The FDA’s second observation focused on inadequate cleaning and maintenance practices for equipment and utensils, posing a risk of contamination. Inspector observed an air purifier with stagnant liquid, likely resulting from a water leak after preventive maintenance two months prior. Analysis of this liquid revealed an alarmingly high level of microbial contamination (TNTC) and various chemical impurities. This stagnant, contaminated liquid posed a significant risk of contaminating the air passing through the section of the air purifier at high velocity.
Additionally, a non-dedicated piece of equipment was found with rough surfaces and holes that could accumulate powdery material, further contributing to potential product contamination.No swab samples had been collected or tested from these vulnerable areas of the equipment, leaving the extent of contamination unassessed.
Comprehensive Equipment Knowledge: Develop a deep understanding of all equipment and systems used in the manufacturing process. This includes identifying potential contamination risks, such as residue buildup, water stagnation, and material accumulation in crevices or rough surfaces. Establish a cross-functional team (CFT) comprising representatives from Production, Engineering, Quality Control (QC), and Quality Assurance (QA) to develop and maintain comprehensive cleaning and maintenance procedures.
Risk-Based Cleaning and Maintenance: Perform risk assessment for each equipment, system to identify Where contamination build up, water stagnation etc can happen. Align equipment cleaning, verification maintenance programme and frequency with risk assessment.
When significant deviations in equipment cleanliness, residue buildup, or maintenance practices are observed it calls for comprehensive corrective and preventive actions (CAPAs).
Thorough Impact Assessment: Conduct a meticulous evaluation to determine which products and batches may have been impacted by the observed deficiencies. Consider factors such as the nature of the contamination, the equipment’s role in production, complaint trends, and any existing control measures. Document the evaluation and conclusions, providing a strong scientific rationale.
Control Sample Analysis: Analyze retained control samples from potentially affected batches for specific contaminant residues. While the absence of contaminants in control samples does not definitively rule out contamination as cross-contamination will not be uniform, this data can support the overall contamination risk assessment.
Comprehensive Risk Evaluation: Undertake a comprehensive risk evaluation of all equipment, focusing on vulnerabilities that could lead to contamination. This evaluation should be conducted by the cross-functional team (CFT) and involve a thorough physical inspection of equipment. Identify areas prone to stagnant liquid or water accumulation, sealant fragment contamination, residue buildup in holes or rough surfaces, and other potential issues. Develop and implement appropriate remediation measures based on the assessment’s findings.
SOP and Checklist Review: Review and update cleaning and maintenance standard operating procedures (SOPs) and checklists for all equipment. Ensure that these documents comprehensively address all areas of product residue buildup and contamination, including the areas identified during the risk evaluation. Enhance SOPs and checklists with detailed instructions, verification steps, and clear criteria for acceptability.
Various lapses are cited to point out lack of Quality oversight.
Document Control Deficiencies: Department personnel had unrestricted access to print controlled documents used to record original cGMP data, including those from other departments, directly from the electronic document management system (EDMS). There was no log to monitor the issuance and retrieval of these documents. Observation of balance print outs in scrap yard revealed that it was allowed to dispose of balance print outs in case of printing or weighing errors. . Review of the log for disposal of documents in disposal bin showed the documents disposed were not getting reconciled with number of pages in the controlled document. In Microbiology lab, there was no logbook for incubators to record its usage, calibrations, breakdowns.
Inadequate Complaint Handling: There were several Product Quality Complaints (PQC) with repeat complaints for tablet count variability, Â substantiated on investigations and categorised Minor. The Complaint investigations were closed with similar reports, root cause and CAPAs simply rewriting these sections. The PQC historical trend evaluations covered only limited period, and was ineffective to identify repetitive complaints, their root cause and to take adequate actions like filing FAR (field alerts) and recall. Firm failed to file timely FARs. The corrective and preventive actions (CAPAs) initiated for PQCs pertaining to count variability were not relevant to the issue and instead were addressing various other issues like powder generation, broken tablets, crumpled tablets etc. The CAPA effectiveness verification also failed to address the count variability issue. Several PQCs for lack of efficacy and adverse drug event (ADE) were non-substantiated for the sole reason that batch number was not available. There was no adequate oversight, directions or procedures for the third (3rd) party service provider / call centre receiving complaints for following up on the complaints to get information of batch numbers, samples, pictures. There were no thorough investigations of PQCs for lack of efficacy, no evaluation of control samples, physical verification of samples and investigations simply relied upon stability trend reports. There was no Health Hazard Evaluation (HHE) and FARs were not filed. Again, PQCs were concluded by rewriting same investigation reports, root cause and CAPAs, without any meaningful investigation.
Ineffective Control Sample Verification: The annual verification of control samples programmes was ineffective. Despite high number of repetitive PQCs for count variability, broken tablets, lack of efficacy etc.the annual verification of control samples evaluated only select batches and not all the batches. Throughout the product life cycle these limited number of selected batches were only verified. The control sample verification log had no provision to record discrepancies or observations during verification and just noted OK. The QA officer and Manager who were engaged in control sample verification for several years did not report any discrepancies over the years; while the PQC Investigation Manager observed count variabilities while investigating complaints.
Streamline Document Control: Make document control procedures meaningful and effective to prevent potential for creation of duplicate data and documents. Adding additional layers of documentation (like logs for disposal bins) may not help in effective document control and may actually be counter productive. More documentation, paper prints mean mote problems. Instead focus on limited paper prints, use more electronic records. And review the electronic records, document and justify if activities are repeated or extended (like weighing, extending operations).
Proactive Complaint Management: When faced with recurring complaints that suggest potential batch-wide issues, promptly file Field Alert Reports (FARs) to notify regulatory authorities. If investigations confirm the batch issues, initiate timely actions, including product recalls if necessary, to protect patient safety.
Comprehensive Complaint Investigations: Make complaint investigations meaningful. Limiting the period for historical evaluation (for e.g. reviewing complaints during last six months) could result to missing to note key trend changes, reappearance of past incidents and ineffective CAPAs. Historical trend evaluation should help identify repetition of issues and evaluate effectiveness of corrective actions taken. Make complaint investigations thorough with available information – review past events, quality events during production and testing, control samples evaluation to identify any issues that could throw light on the complaint. Make efforts to collect complete information on complaint by engaging with third party service providers or complainants directly when complaints are repeating; document the efforts made to collect information. There shall be binding agreement with third party service providers detailing service levels, periodic performance review of the service provider and corrections based on review. Quality and Safety of the product and compliance is ultimately the responsibility of the Firm and the Quality Unit should have adequate oversight and control over the same.
Control sample verification programme: Define the control sample verification programme and number of lots to be evaluated with due consideration of trend of complaints, quality events on the product. Based on the trend increase (or decrease) the number of batches to be verified, address the same in the SOPs.
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