The FDA addressed a Warning Letter to the Indian Manufacturer Cadila Healthcare Limited in India (two production sites for APIs and medicinal products) on 23 December 2015. The letter focuses on the inappropriate review of OOS results and the lack of data integrity. It specifically addresses the following issues:
OOS results in the laboratory haven't been properly examined. There have been deviations in the manufactured warfarin sodium tablets in association with potency and content uniformity specifications. Those deviations had already been observed in past inspections of the FDA. The CAPA measures taken so far were thus ineffective.
The manufacturing process for those tablets is not sufficiently controlled.
The company is asked to list all batches of the warfarin sodium tablets together with their OOS and Out-of-Trend (OOT!) results - not only those manufactured for the US-American market but all batches for all markets!
In its response to the FDA, the company should also make propositions on how to optimise process design in the manufacturing organisation in order to improve in the future content uniformity, assay, thickness or other relevant critical quality attributes. Concerning this, estimations with regard to the process capability should also flow in.
Furthermore - at Cadila - external complaints from diverse pharmacies or wholesalers haven't been completely followed up and no root cause analysis has ever been completed.
Integrity of data/ computerised system:
With regard to computerised systems, there are no sufficient controls in place before modifying or deleting data. In the QC laboratory, the inspection team found out that the laboratory manager had the ability to delete data from the Karl Fischer Tiamo software as the audit trail function wasn't activated. Moreover, 8 analysts had to share one single username and password combination. Consequently, it couldn't be demonstrated who had operated this instrument system.
The FDA also noticed that a data containing the moisture content results had been deleted. The deletion of the data hasn't been considered at all during the batch release decision - i.e. the deletion of this data has neither been identified nor reviewed.
Finally, the FDA criticised the records of "unofficial" lab notebooks for quality-related documents several times.
All in all, there are major concerns with regard to the authenticity and reliability of data generated in that company. The FDA has required a comprehensive CAPA plan within 15 workings days on receipt of the Warning Letter.
To find out more details please see the complete Cadila Healthcare Limited Warning Letter.
Source: FDA, USA