FDA Inspections at API Manufacturers - current Warning Letter Trends

Taking a look at the Warning Letters the FDA issued after inspections of activesubstance manufacturers in the 2015 fiscal year, which ended on 30 September 2015, it is first of all striking that only non-American companies are among the addressees. Almost half of them are Indian companies. Overall the numbers look like this: India (3 WLs); China (2 WLs); Canada (1 WL); Thailand (1 WL); Czech Republic (1 WL).

The top issue in the Warning Letters is the non-GMP compliant handling of electronic data or missing data integrity. Each of the 8 warning letters contains the following comment in the same wording:

"Failure to prevent unauthorized access or changes to data and to provide adequate controls to prevent omission of data."

The lack of access control on electronic (raw) data is an issue the FDA investigators have been observing for a long time, especially during inspections in pharmaceutical companies. In this as well as in the last fiscal year there were significant deficiencies in several companies - medicinal product as well as API manufacturers - as the comments in the appropriate Warning Letters show. For more information also see the GMP news Another FDA Warning Letter with Focus on "Data Integrity" and FDA Warning Letter on Data Integrity.

Ultimately these deficiencies can be traced back to a failure of the quality assurance unit which also affects other areas. In the Warning Letters, the following examples can be found for this:

  • "Failure of your quality unit to ensure that materials are appropriately tested and the results are reported."
    "Failure of your quality unit to exercise its responsibility to ensure the APIs manufactured at your facility are in compliance with CGMP, and meet established specifications for quality and purity."
    Data were manipulated by laboratory staff (change of the file name), to fake results from identity tests in batches which in reality were not performed. Quality assurance was not able to uncover this manipulation.
    Despite an unknown peak in the examination for residual solvents the relevant batches were released. Upon receipt of a complaint regarding this peak an examination was conducted with the result that the contamination originated in the production process itself. Preventive control measures to avoid this contamination were not established.
  • "Failure to adequately investigate complaints and extend the investigations to other batches that may have been affected."
    As a result of a complaint (bad smell), a cause study was initiated which was completed prior to implementation of the preventive measures again. The CAPA measures subsequently carried out were obviously not associated with the reason for the complaint.
  • "Failure to have appropriate controls for issuance of batch records".
    The use of document templates for batch records is out of control. These can be printed out from the production staff's personal computers. Although there is an SOP for the control of batch records there are no appropriate training records.
  • "Failure to have appropriate documentation and record controls."
    Data for tracing raw materials are not available. Log entries are without date/visa and partly corrected with Tippex. There is an SOP prohibiting the use of correction fluid, however this was not trained.
  • "Failure to record activities at the time they are performed and destruction of original records."
    Original records of critical process data on uncontrolled memos were transferred subsequently in new report templates (after batch approvals) and then destroyed.

This selection of examples shows the lack of fundamental GMP principles which leads to a blatant misconduct of staff and ultimately to quality defects in the final product. The main responsibility usually has the quality unit, which task it actually would be to ensure a thorough training in production and quality control and to monitor compliance with the appropriate regulations. These examples of non-GMP-compliant behavior are not limited to active ingredient manufacturers; there are very similar findings in Warning Letters issued to medicinal product manufacturers. An analysis of these Warning Letters issued in the fiscal year 2015 will be part of one the coming newsletters.

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