Testing of Medicinal Products is no Evidence against Cross-Contamination

During an FDA inspection at an Indian pharmaceutical manufacturer, residues were found in the non-dedicated manufacturing equipment for tablets. The manufacturer had attempted to rule out possible cross-contamination by testing retained samples.

The FDA inspectors had noticed residues inside multipurpose equipment even though it was labelled as 'cleaned'. The manufacturer confirmed the presence of several APIs with levels above the permitted limit. Residues of various APIs were also found in swabs of other equipment.
In the response to the FDA's deficiency report, the Indian manufacturer wrote that the testing of retained samples met the requirements and that no contamination with other APIs could be found in these tablets. A new cleaning process was also described, but this was not implemented for all systems/products.

Warning Letter follows inadequate response

This response is not sufficient for the FDA, which is why a Warning Letter has now been issued. According to the FDA, the cross-contamination is not uniform. The testing of control samples and placebo batches cannot scientifically prove that products are free of contamination from visibly contaminated facilities. Retained samples alone are not sufficient to determine the extent of cross-contamination and mitigate the associated risks.

In the Warning Letter, the FDA now requires an independent retrospective evaluation of cleaning effectiveness to assess the extent of cross-contamination risk. This includes the identity of residues and the assessment of other production facilities that may have been improperly cleaned. The aim is to check whether potentially cross-contaminated product batches have been released for distribution.

Furthermore, the FDA requires a CAPA plan based on this retrospective assessment that includes appropriate corrective actions for cleaning procedures and practices and a timeline for implementation for all products and facilities.

In addition to the holistic measures, specific CAPA activities are to be defined with the help of an independent consultant that contribute to the effective elimination of the cross-contamination risk. Among other things, this includes

• A list of all improvements to cleaning and maintenance procedures including frequency and locations to be cleaned in all relevant equipment 
• Identification of all sources of cross-contamination other than the facilities covered by the Warning Letter
• Verification of the suitability of analytical methods to detect possible cross-contamination
• Investigation of the unknown (unidentified) HPLC peaks detected in the testing of the retained samples

Other criticised GMP deficiencies

Another GMP deficiency according to the FDA is the handling of deviations or the manufacturer's deviation system. The FDA describes the case of missing pages in the batch record. Critical steps were entered 25 days after production. In another case, printouts of a balance were missing. Entries were made 22 days after the analysis. The manufacturer attributed this to employee carelessness without conducting an evidence-based root cause analysis or initiating a CAPA investigation. The inspection also revealed questionable practices in the disposal and destruction of GMP records by employees.

The Warning Letter to the Indian pharmaceutical manufacturer can be found on the FDA's website.