Warning Letter due to GMP Deficiencies in Tableting

An Indian manufacturer of solid dosage forms recently received a Warning Letter from the US FDA after the authority had revealed serious deficiencies in the tablet production in February 2019. The reason for the majority of the deficiencies is the lack of data integrity - which in this case is demonstrated by the tablet production, but also in the laboratory.

Deficiencies in manufacturing data

The FDA found handwritten entries in numerous batch records, while the values generated by the tablet press were outside the specified range. Values for compression forces, filling levels and tablet weight are affected. For the latter, no data was available at all because the system for automatic measurement of tablet weights (Automatic Weight Control - AWC) had been switched off during production. The system for set-up of the tablet press also shows deficiencies. In addition, quality-relevant parameters were changed during the tableting process, and this was not documented. Many batches were released for the market by the quality unit despite the defective batch records.

The FDA points out that it is essential to keep the tableting process permanently under control by reacting quickly to variabilities and that sporadic loss of control is not acceptable.

CAPA Deficiencies

The above mentioned discrepancies between the values of the tablet press and the handwritten data for the compression forces were part of a deviation investigation of the manufacturing company. The Indian manufacturer stated that the manufacturing personnel assumed that it was OK to continue with the process if the tablets were OK, despite deviating values of the manufacturing equipment.

The FDA criticizes the investigations and expects, among other things, the following:

• A comparison of all system and handwritten values to determine the extent of the discrepancies
• An extension of the investigation to tablets of other strengths 
• A root cause analysis to find the reason for the non-compliant values
• An assessment of the risk posed by the batches with manufacturing discrepancies for the US market 
• An independent assessment to evaluate the overall system, how the company deals with deviations and OOS.

Lab OOS

According to the FDA, there were also complaints in the laboratory. For example, OOS results were found several times in the electronic data of the measuring systems for water content according to Karl Fischer and content determination, which had not been reported. In addition, the FDA criticized the handling of raw data in the laboratory. For example, chromatograms, scale printouts or usage logs of devices were missing. In its response, the Indian manufacturer stated that it had found ten more cases of unreported OOS results and 23 cases of repeated measurements with initial OOS findings without evaluating them (=testing into compliance).

Die FDA now expects, among others:

• An independent, retrospective evaluation of all OOS results not considered since June 2016 
• Extension of the investigation to raw materials, IPCs, etc. to check whether OOS results were also disregarded there. 
• A risk assessment for the batches that had been released for the US market despite OOS results.

Conclusion

The FDA rates the general handling of GMP relevant data as inadequate, i.e. the authority questions the integrity of this data. The FDA strongly advises to consult an independent consultant and expects a comprehensive investigation into the extent of the data integrity deficiencies and the resulting risk. In addition, the FDA expects a management strategy on how to implement a global CAPA system to address the systemic deficiencies. 

To get more information also see the FDA Warning Letter to Indoco Remedies Limited.