USFDA 483 to Sun Pharma points to lack of Quality Unit oversight

The USFDA 483 issued to Sun Pharma, Dadra unit in India (FEI 3004561553) published by USFDA demonstrates the depths audits go to identify non compliances and highlights the evolving expectations of auditors. The site was inspected by USFDA investigator Pratik S Upadhyay in December 2023 with six observations in a detailed 17 page USFDA 483 issued. The USFDA 483 identified inadequate Quality Unit oversight in several areas: Control of GMP (Good Manufacturing Practice) documents, Complaint investigations, Filing of field alert reports, Annual verification of reserve (control) samples. Other observations pertain to Inadequate OOS investigation and Facility maintenance.

Sun Pharma Dadra USFDA 483 (December 2023) / Pratik S Upadhyay

• 1. Quality System  – Inadequate OOS investigation, impact analysis and evaluation of integrity of analysis, efforts to identify unknown peaks, no scientific hypothesis studies to justify probable root causes identified.

An OOS for dissolution was invalidated with root cause likelihood of dissolution basket falling off from shaft without scientifically demonstrating it through hypothesis testing. Preliminary investigation did not identify any laboratory error. The root cause was of dissolution basket falling off was concluded based on interview of QC analysts, who admitted the dissolution checklist was filled without verifying actuals. Even after identifying the data falsification by analysts, there was no evaluation of integrity of all analysis performed by the analysts. OOS and FAR was closed after repeat analysis by second analyst

An OOS for unknown peak in related substance analysis was invalidated with root cause assigned as sample solution preparation error with respect to improper rinsing of volumetric flask or sample handling. However the unknown peak was present at BLQ (Below Quantifiable Level) in other stability samples analysed in same sample set suggesting that the unknown peak is not due to contamination from dirty glassware. Also there was no effort to identify the peak / source of the peak by looking into analysis and sample preparation of other products in the same area as OOS batch.  

• 2. Facility and Equipment System – Equipment and utensils are not cleaned and maintained at appropriate intervals to prevent contamination

Stagnant liquid was observed inside Air purification unit (APU) which on testing was found to have TNTC (too numerous to count) colonies of microorganisms, yeast and mould and also peaks due to APIs and impurities. As per the Firm stagnant liquid was probably due to leakage of water after last preventive maintenance. Holes and rough surfaces were observed in an equipment with potential for powdery material to get accumulated. There were no swab samples collected and evaluated for chemical and microbial parameters from these areas during change over cleaning. This has potential for contamination of drug products manufactured where this equipment is used.

Lack of Quality Unit oversight

• 3. Lack of Quality unit oversight in issuing, handling, retrieval, reconciliation of GMP documents like QC forms, Production Forms, Forms used in Warehouse. Documents can be printed from the EDMS by all employees including documents not related to their department. Original GMP documents like balance print out are allowed to be destroyed. The record for documents placed in disposal bins showed reconciliation gaps between pages placed in the bin and actual number of pages in the document. These were not investigated. There were no usage log books for microbiology incubators.
• 4. Quality unit failed to investigate Product Quality Complaints (PQCs). No procedures or guidance to 3^rd party call centre receiving PQCs to ask meaningful follow up questions. In high number of PQC complaints received every month between 2019 and 2023 for tablet count variability, there were no meaningful efforts to establish root cause and CAPAs. Historical trend evaluation were covering only limited period.
• 5. Field Alert report (FAR) was not submitted within three working days. Several repeat count variability complaints for tablets were substantiated upon investigation, but no FAR was filed. In the CAPAs initiated for several count variability complaints, this issue was not addressed and the CAPA effectiveness check was pertaining to other issues like broken tablets, crumpled tablets and was irrelevant. Complaints pertaining to lack of efficacy are not investigated and are closed as non-substantiated since batch number is not known, no adequate CAPAs are taken, no Quality oversite over third party service provider to ensure adequate attempts were made to receive the complaint batch information. Even in complaints where product details and batch number were available, no controlled sample evaluation or testing was performed; investigation reports simply relied upon stability data, analytical trend, Annual product review (APR). Investigations were closed simply rewriting investigation summary, root cause, CAPA even as repetitive PQCs were being reported and no FAR was filed.
• 6. Annual verification of reserve samples is deficient. Each lot of control samples are not verified at least once a year, there was no provision in logbook for recording discrepancies observed during verification. Selecting limited number of batches for annual verification is ineffective to identify issues when there are several repeat product quality complaints and is not justified.  The control sample verification is not effective with the QA personnel has not reported any discrepancy for several years; whereas PQC investigation manager has observed count variability in controlled samples