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Warning letters, 483s, Recalls, Import Alerts, Audit observations
Warning letters, 483s, Recalls, Import Alerts, Audit observations
Piramal Pharma’s API unit at Navi
Mumbai was issued USFDA Form 483 with six observations after an audit in
February 2025. The site was inspected by USFDA investigator Guerlain Ulysse.
The USFDA 483 highlight deficiencies in investigations, follow-up of
discrepancies, adherence to procedures, and compliance with quality systems.
Audit Observations
Quality Systems: The Quality Unit was cited for its failure to ensure procedures were consistently followed. During the inspection, liquid was observed on the API area floors with no operator present. Additionally, multiple alarms in the equipment monitoring software remained unacknowledged and uninvestigated, reflecting a lapse in alarm monitoring.
Investigations: Deviation investigations were inconclusive and lacked proper follow-up. Despite recurring deviations during batch execution, no quality risk assessment was performed on manufacturing operations of subsequent batches. Manufacturing of batches continued while the investigations remained open. Deviation batches were not monitored for stability.
In another instance, a customer complaint involving foreign particles was inadequately addressed. The Firm tested reserve samples from a different batch instead of the actual batch in question. Reserve sample quantities from the complaint batch were found insufficient for thorough investigation.
Equipment Cleaning: Cleaning validation for shared equipment used in manufacturing APIs was inadequate; cleaning procedures are not validated for shared equipment used to manufacture crude APIs.
Production Records: Master Production and Control Records (MBRs) lacked complete and clear instructions. For example, the MBRs had grayed-out start and end time sections, review sections, and the operators were not able to record cycle start and end time.
Material Handling: Key starting materials requiring frozen or refrigerated storage were shipped and received at room temperature without any assurance of cold chain custody. Such lapses contravene essential material storage and transport condition requirements.
Core Takeaways
The observations in the Piramal 483 are not very complex and the GMP requirements underlying these lapses are very basic. Alarm handling procedure for equipment and systems, classifying alarms into critical and routine categories and review of the alarm logs is a core GMP expectation. Testing the reserve sample of the same batch related to a customer complaint is a basic requirement. Purpose of reserve sample is to help in investigations and if during investigations it is found the quantity of reserve samples is not sufficient for testing, try to get sample from the customer; also take proactive corrective action to review the reserve sample handling procedures and revise the quantity of control samples to prevent such exigencies in future. In cleaning validation, it is fundamental to cover the entire manufacturing equipment train to arrive at the maximum acceptable carry over (MACO) level and verify all the equipment for cleanliness levels. Observations like the MBR not having adequate instructions, provision for documenting cycle time reflect inadequate review of documents and GMP awareness among operators and reviewers. For materials requiring specific storage conditions appropriate transport conditions must be ensured. If they are transported at room temperature, the potential risk should be assessed and justified and accordingly, label storage conditions may be revised.
Key Learnings
Often many lapses that gets cited in 483s stem from inadequate Quality oversight of operations, ineffective review of documentation, lack of attention to detail. Strengthening monitoring of shopfloor operations (including laboratories, utilities and other critical areas) and review of documentation ensure compliance to procedures and Quality systems. Corrective action plans following such observations must address both immediate corrections and systemic improvement of the Quality system. This necessitates a comprehensive review of systems and processes, enhancement of procedures, and a sustained GMP and Quality System awareness-building program. Internal auditors and reviewers, at times get too used to the Firm’s processes and may miss obvious lapses. Engaging external GMP consultants or auditors can provide a fresh perspective and help uncover areas of concern that might escape internal reviews.Â
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