USFDA issued a Warning letter to Intas, Matoda, Ahmedabad facility on 21 November 2023. This follows the 16 point USFDA 483 issued to Intas facility after inspection by USFDA investigators Rita Kabaso, Justin Boyd, Arsen Karapetyan in May 2023. The 483 raised serious cGMP violations related to Data Integrity and reliability, particulate matter in injection vials, inadequate failure investigations into particulates in injection vials, inadequate microbial contamination control procedures for sterile drug products. Intas Matoda facility was also placed under Import alert 66-40 (DWPE) by FDA in November 2023.
Qvents had published posts on the critical observations in Intas Matoda 483 earlier in July 2023.
Key issues highlighted in the Warning letter are
- Failure of Quality and Production units in ensuring data reliability –Observed manipulated visual inspection reports (of Injectables) from 2021, rejection rates were manipulated to keep within limits to avoid deviations. Warning letter cites lack of QA review and oversight which indicate QA is not exercising its responsibility.
- Failure of adequately investigate deviations into aseptic operations – Several visual inspection rejection rate failures, inadequate investigation and failure to identify particles or their sources, failure to define and characterise intrinsic and extrinsic particles; Several Non Viable Particulate (NVP) excursions in ISO 5 areas, multiple NVP excursions during manufacture of batches; but all NVP excursions in ISO Grade 5 areas are not investigated, if they do not persist for more than defined interval; Warning letter highlights that defining a time frame for NVP excursion to persist before triggering an investigation is not acceptable. . There is no procedural requirement to remove vials which were open during NVP excursion.
- Personnel qualifications for visual inspections are inadequate and do not assure inspector competency – Visual inspection challenge tests are inadequate, size of particles in the challenge test kit are not known and is not representative of the type of particles found during operations, no defect library maintained for training purpose.
- Process validation studies for tablets manufacturing are inadequate – do not assess inter batch and intra batch variability; no justification for size of inprocess samples collected during batches, processing time were left to operator discretion and variation of parameters observed between batches. Process validation study, and commercial manufacturing data do not provide assurance that consistency is maintained throughout batch operations.
- Procedures are inadequate to prevent microbiological contamination of drug products purported to be sterile – smoke studies are not conducted for critical areas under dynamic conditions (e.g.mobile LAF), equipment transport ports are not assessed with biological indicators.
Intas had responded to the USFDA 483 committing working with consultant and implement remediation plans; FDA acknowledged the responses to the observations in USFDA 483, but termed the responses inadequate highlighting several gaps, for e.g.
- No rationale of deploying the disqualified visual inspectors to secondary packing activity which is also GMP activity.
- Response fails to address managers’ failure to act on data integrity lapses and lack comprehensive review of management of operational practices, ineffective supervision and governance in production encompassing frontline supervisors to top operational managers.
FDA has asked for remediation plan which addresses providing adequate authority and resources to QA to effectively function; review of all batches and batch information; plans to prevent manipulation and enhance control on cGMP records; improved Production oversight including equipment & facilities and timely upgrades, qualified production supervisors, managers.
Firm is asked to provide:
- a comprehensive independent assessment of investigation procedures and capabilities & retrospective evaluation of all NVP excursions in aseptic areas, root causes and CAPAs.
- independent assessment of process validation programme; establish systems for vigilant ongoing monitoring of process performance and quality signals from both internal data and customers during the Product Lifecyle and integrate them to identify and improve areas of process variability.
- further evaluations to identify and assess the potential weak spots in the decontamination process and comprehensive independent assessment of all contamination hazards with respect to aseptic processes, facilities, human interactions, air quality, personnel and material flows.
FDA has also asked Intas to take measures for remediation of Data Integrity issues, assess extent of Data Integrity issues at the facility and current risk assessment of the potential effects of Data integrity issues on quality of drugs and patient safety. Firm is asked to take interim and long term measures to address Data Integrity issues and their impact, have audits by qualified consultant at least for two years to evaluate CAPA effectiveness and suggest hiring a Chief Integrity Officer. FDA is concerned about repeat observation of cGMP violations, ineffective Quality systems and want Intas executive management to assess global manufacturing operations and ensure compliance with FDA requirements.
Warning letter
USFDA 483
Read also the Qvents posts on the critical observations in the USFDA 483 to Intas:
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