Deficiencies in Maintenance, OOS and Data Integrity lead to Warning Letter

Recommendation

17-19 September 2024

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A pharmaceutical manufacturer in India received a Warning Letter from the US-American FDA in December due to deficiencies in the areas of maintenance/cleanliness, OOS and data integrity. The inspection had already been carried out in July 2019 and the manufacturer was notified of the inspection deficiencies by a Form 483. As the FDA considered the response to this document to be insufficient, the Warning Letter was then issued.

During the inspection, the US-American inspectors noticed rust, dents and scratches on product contact surfaces. In response, the Indian manufacturer stated that it had not verified the cleanliness of these surfaces because they were dedicated equipment and that the Quality Unit verified equipment cleaning. In this case, the FDA would expect a plan that ensures routine maintenance in the facility, especially the maintenance of production equipment including repairs and replacements.

According to the FDA, the timely detection of equipment problems, the effective execution of repairs and the observance of preventive maintenance intervals must be ensured. In addition, the FDA expects a CAPA report, including a retrospective evaluation of the cleaning procedure, a list of weaknesses in the management of equipment cleaning and a programme to improve the cleaning system.

The FDA inspectors also found serious deficiencies in the handling of OOS results. The manufacturer purchases an API that is - among other things - tested for residual solvents. Here, OOS results were obtained and the test was repeated. The second test met the requirements, the result of the first test was ignored without justification and the API batches were released. An aggravating factor is that the tested solvent is a solvent which, due to its toxicity, should be avoided in the manufacture of pharmaceuticals. The manufacturer's response that all API batches were re-tested and the residual solvents were within specification is not sufficient for the FDA. Furthermore, according to the manufacturer, the OOS values initially obtained are not representative and have no influence on product quality. The FDA clearly disapproves of the lack of a scientific justification as to why OOS results could be neglected and how the quality unit intends to ensure that OOS results are handled in accordance with GMP in the future. In addition, the FDA now expects an independent, retrospective review of all OOS results (IPC, release and stability tests) for batches that impact the US market. The FDA also expects an overview of the relevant residual solvents, including a risk-based planning of how to limit the residual solvents in the ingredients and finished products.

As with almost all inspections, one topic included was data integrity. In this case, the laboratory equipment is affected, especially an HPLC system. The FDA had noticed that the laboratory employees use the Agilent Service Account Log-In to cancel or change chromatography runs, for example, without being able to assign this to the employee in the audit trail. The FDA is questioning the integrity of the company's data as a whole, so that the safety, efficacy and quality of the manufactured products must also be questioned.

In addition, since the Indian manufacturer receives APIs from a manufacturer that refused an inspection by the FDA and was therefore placed on "Import Alert", the Indian manufacturer itself was also placed on "Import Alert".

The complete Warning Letter addressed to the manufacturer GPT Pharmaceuticals Private Ltd. can be found on the FDA website.