Intas, India issued USFDA Warning letter, following critical observations in an inspection at its Pharmez, Matoda, Ahmedabad facility in November 2022. The critical deficiencies include inadequate control of original cGMP documents and computer systems, severe data integrity deficiencies in laboratory and operations, quality function not exercising its responsibilities, failure of laboratory control mechanisms and ensuring validate test methods Read More

Intas facility was inspected by FDA investigators Jose E Melendez, Justin A Boyd, Pratik S Upadhyay resulting in a 36-page USFDA 483 with 11 observations. Warning letter was an expected outcome after the critical observations in the 483 and FDA had put Intas on an Import alert (66-40) in June 2023.

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Warning letter

USFDA 483

Qvents post on Observation 3 (Critical data integrity issues)

Major deficiencies and actions elaborated in the Warning letter are:

1. Inadequate oversight of original CGMP documents, deficient controls over computerized systems, insufficient laboratory investigations and aborted chromatographic sequences, severe data integrity deficiencies in production and laboratory departments, Quality Assurance function is not exercising its responsibilities. Specifically:

A. Failure to ensure integrity of analytical testing data:

• Torn and discarded original cGMP documents in QC scrap area, in a truck outside the premises; Analyst destroyed original analytical records; weighed multiple samples and did not report all test results; time stamp of balance print outs does not match with LIMS records

B. Failure to exercise controls over computerized systems

• Electronic batch records allowed to alter entries manually; an operator was observed changing a time entry, QA do not review audit trails of batch records
• Analysts manually reprocess chromatograms by adding unapproved integration events,
• Electronic data was not being saved in Instruments like KF, though it has the capability
• Corrective and preventive actions were not taken for numerous gaps identified in electronic manufacturing equipment in an Equipment Assessment report (2018). No similar assessment is performed on QC equipment

C. Failure to have oversight over laboratory investigations, implement CAPA to address high number of aborted chromatographic sequences

• Invalidation of multiple OOS results with probable root cause as contamination during sample preparation, with no explanation of why other samples analysed by same analyst in same sequence were not affected
• Hundreds of chromatographic sequences were aborted, but no trending and initiation of CAPA to address recurring issues

2. Laboratory records do not ensure complete data

• Analyst undercounting colony forming units (CFU) in the environmental monitoring (EM) data
• Missing laboratory raw data, paper print outs like pH could not be reconciled; unreported data could not be detected as instrument lacked audit trail

3. Failure to establish and follow laboratory control mechanisms

Failure to have appropriate procedures and control for chromatographic integration and review of data, using manual integration events

4. Failure to establish adequate procedures for production, process control and process validation

Process validation lacked evaluation of inter-batch and intra-batch variability of impurities. Firm failed to discuss or reference a failed fourth process validation batch in the validation summary report and validation was completed with a fifth batch.

5. Failure to perform validation or verification for the raw materials test methods

Intas response to the 483 observations to FDA are considered inadequate citing several gaps:

• It did not fully evaluate the scope of the deficiencies on control of cGMP original documents, computer systems and the impact to product quality, inadequate QC investigations
• It did not explain and address failure of operational management and QA in providing adequate oversight and exercising their responsibility to ensure integrity of all data.
• Failure to address how systems will be implemented to identify and address laboratory incidents and overall management strategy for improving all phases of laboratory investigations
• It did not provide investigation details into the discrepancies in EM data or missing raw data and did not commit a retrospective review of personnel and EM data and missing raw data, impact assessment and risk assessment
• It did not commit retrospective review of all chromatographic data; scope of third-party audit planned and did not address oversight of QC by QA department.
• It did not commit retrospective review other process validations, did not address reasons of omission of fourth batch in the validation summary report.

USFDA has asked Intas to provide:

• A comprehensive assessment and remediation plan,
• Ensure QA is given authority and resources to effectively function, top management support to QA and reliable operations,
• Retrospective and independent review of all invalidated OOS,
• Comprehensive and independent assessment and CAPA plan for computer system security and integrity including provisions for oversight from QA managers, executives, and internal auditors with appropriate IT expertise.
• Comprehensive investigation and retrospective evaluation into the extent of the inaccuracies in data records and reporting,
• Evaluation by competent third party, risk assessment of the potential effects of the observed failures on the quality of drugs and risk to patients, management strategy and global corrective action and preventive action plan.
• Independent assessment of all test methods and their suitability for the intended use