FDA Warning Letter to Indian manufacturer due to an insufficient OOS procedure

In July 2018 the US FDA issued a Warning Letter to an Indian sterile manufacturer. The content of the letter primarily affects the inadequate procedures with OOS results. Besides, further deviations like in the visual inspection and the facility maintenance have been criticized.

The Warning Letter points back to the GMP deficiencies found during an inspection performed in July/August 2017. The response of the Indian company to the complaints was so insufficient for the FDA that a Warning Letter was issued.

Many of the GMP violations were found in the lab, e.g. during the testing of stability samples. In one case, the test point "Impurities" obtained an OOS result. Although there were no abnormalities in the chromatogram and the system suitability criteria were met, poor column efficiency was considered as the causal factor. The testing was repeated without taking into account the OOS result. In another case, contaminated sample vials were stated as the reason for the OOS result although the testing had been repeated with new vials and yielded OOS results too. Thereupon, retain samples have been investigated and because of the results within the specifications, the OOS results obtained haven't been taken into consideration. In a third situation, OOS results were yielded during the sample testing of an accelerated stability study. Here, the tests have been repeated until passing results were obtained and the OOS results have also been left aside.

The FDA criticises that in the three situations, there has been no investigation of the production as potential reason for the OOS results. Although the company has a noticeable history of several recalls (the FDA uses the term "worrisome history") the production quality has never been questioned - and that, in spite of many OOS results.

In another case during an inspection an employee has been observed entering the data in a document of a visual inspection performed one day before. The question how the document could be filled without corresponding data couldn't be answered by the Senior Manager called in.

The state of the manufacturing premises has also been criticized. Several traces of water damages have been found like for example warped ceiling panels, puddles, and water stains. The water damages have been attributed to the monsoon rains that fell a few days before the inspection. The FDA doubts that because of the rusting damages which suggest a longer-term problem. Besides, not sealed and thus leaking ceiling panels were discovered allowing ingress of air from unclean areas into "post-sterilisation" areas.

Many of these deficiencies are due to deficiencies in data integrity. Thus, it is not surprising that the FDA also dedicated a paragraph of the Warning Letter to the topic data integrity. To restore data integrity, the FDA requires an investigation which should help detecting the extent of this deficiency. Subsequently, the FDA requires a risk assessment of the consequences of the lacking data integrity on product quality. In addition, a management strategy is required to ensure the company's correct and complete handling of product-related data in the future.

For more information please also see the complete FDA Warning Letter to the Indian pharmaceutical manufacturer Claris Injectables Limited.