Recent FDA Warning Letter: Issues with Monitoring of microbiological Environments

When confronted with critical violations of GMP requirements, the FDA issues a warning letter to the company involved. Said company then has 15 days time to provide the FDA with a corrective action plan.

Between December 14th, 2015 and January 15th, 2016, the FDA inspected US manufacturer Aplicare Inc. in Meriden. During that time, the inspectors came across several severe, partly recurring GMP violations. When the company could not offer a sufficient response to the list of deficiencies, the FDA issued a warning letter on December 15th, 2016, which focussed on four main points. The FDA refers the deficiencies in its warning letter to the corresponding paragraphs of 21 CFR Part 211.

This article describes recurring issues with the environmental monitoring.

1. "Your firm failed to have separate or defined areas or such other control systems necessary to prevent contamination or mix-ups - 21 CFR 211.42(c)"

The FDA criticises the inadequate extent to which the microbiological environment had been monitored; it doesn't provide insight on the expectations of the inspectors, however. It was also criticised that during environmental monitoring, spore-forming Bacillus species had been isolated on more than one occasion.

The manufacturer's response, to revise their monitoring program, was deemed insufficient for the following reasons:

  • There was no scientific rationale for establishing alert and action limits. The mentioned limits were based merely on historical averages and standard deviations without taking other factors into account.
  • Microbial limits for settle plates in a new cleanroom allowed an unnecessarily high level of air contamination.
  • There was no adequate program for identifying germs in the environment. So far, only a few microbes are identified and only when certain microbiological limits are reached.

Furthermore, the company is to establish a monitoring program to determine the bioburden before sterilisation. Adequate alarm and action limits are to be established in order to identify insufficient environmental conditions and commence corrective actions.

In response to the warning letter, the manufacturer is to provide a revised procedure for environmental monitoring, including the following items:

  • alert and action limits for every ISO-classified area,
  • regulations on investigating out-of-limit (OOL) microbiological results,
  • plans for routinely identifying microorganisms from the filling and sealing area.

Source: Warning letter to Aplicare Inc. from December 15th, 2016

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