FDA describes detailed CAPA Procedure in Warning Letter

An FDA Warning Letter is a formal communication from the US Food and Drug Administration (FDA) notifying a company or individual of regulatory violations. These typically describe observations made during an inspection and list violations found (referencing the specific sections of the FD&C Act, the Code of Federal Regulations (CFR), and other applicable laws as appropriate). In addition, specific measures are listed that the recipient must take to remedy the violations. It does not go into great detail, especially not with regard to instructions on the desired procedure.

In a Warning Letter issued to Sun Pharmaceutical Industries Limited (India) at the beginning of July, this is now different. It describes in great detail what the FDA considers to be appropriate CAPA measures in a specific case.

What happened?

The company was criticised for not adequately cleaning and maintaining the equipment used to manufacture drug products. According to the company's response, a defective valve was the cause of the observed liquid build-up. This was discovered in the course of investigating the cause following the inspector's observation. Affected batches were recalled, but this was not enough for the FDA, which now lists very specifically what to expect:

• A comprehensive, independent retrospective evaluation of the effectiveness of cleaning measures, including consideration of production equipment that may have been improperly cleaned.
• A corrective and preventive action plan (CAPA) based on the retrospective assessment of the cleaning programme, including appropriate corrective actions for cleaning procedures and practices and a timeline for completion.
• A detailed summary of weaknesses in the process for the life cycle management of equipment cleaning.
• Identification of improvement actions to the cleaning programme, cleaning effectiveness and improved ongoing verification of proper performance.
• Among other things, the CAPA plan should ensure that potential problems with equipment are recognised immediately so that, for example, repairs are carried out effectively. The plan should also ensure that appropriate action is taken across the organisation's network.
• The CAPA plan must comprehensively address any gaps identified by an external consultant when assessing the maintenance programme.

The review of the effectiveness of the CAPA measures must include at least the following:

• Evaluation of improvements to cleaning and maintenance procedures, including determining the specific frequency and locations to be cleaned at all relevant facilities
• Adequacy of maintenance and repair history analysis
• Assessment of all major production facilities for other sources of cross-contamination
• Adequacy of improvements to the method of analysis to identify residual carryover
• Adequacy of investigations of other unknown (unidentified) peaks
• Assessment of whether the scope of the investigation and the associated CAPA were sufficient
• However, the FDA was also not satisfied with the measures taken in the investigation of OOS results: "Your investigations of out-of-specification (OOS) results were inadequate because they lacked scientific rationale for root cause determinations."

Further details on the procedure, but also on the inglorious quality history of Sun Pharmaceutical Industries Limited can be found in the Warning Letter.