Cross Contamination: One of FDA's Current Issues

In a current Warning Letter from November 2018, the FDA criticised insufficient cleaning validation and verification at a pharmaceutical manufacturer. They referred to 21 CFR 211.67 (a). What was the reason for this?

On several occasions, visible residues of intermediate products were found although the facility was deemed clean. This happened although the manufacturing and quality assurance personnel had performed visual inspections. The yellow intermediate product remained visible though ... Failed swab tests - also with regard to difficulties in recovering the detergent - had led to a change of detergent. However, the old detergent was still used to clean on site. Moreover, there was no justification for the locations and the number of swab samples. Besides, insufficient documentation of the cleaning procedures during cleaning validation/ verification and the validation plans were not consistently followed. Validation and verification reports were not finalized for periods as long as 6 years. New products haven't been evaluated in depth on whether they fitted in with the existing cleaning validation / verification concept. Initial swab samples with unknown analytical peaks were partly invalidated without adequate investigation. The location in question was re-cleaned and then re-sampled. Swab samples were sometimes lost or not accounted for in the documentation.

What are FDA's expected countermeasures?

  • A scientific demonstration in the course of a validation programme that APIs and detergents are removed through the cleaning programme.
  • A justification for the number, location, timing and frequency of swabs.
  • A justification for the selection of products and equipment parts in the course of the cleaning validation and verification activities
  • An assessment of all equipment in which product residues were discovered.
  • A retrospective investigation of all swab failures with root cause analysis
  • A CAPA plan for future investigation of cleaned equipment
  • A description of the cleaning training programme including measures for success monitoring

As often lately, the FDA has recommended a GMP consultant due to the extent of GMP deficiencies. In that case, the FDA even "strongly" recommended it.

Conclusion: For the FDA, cleaning validation and verification based on scientific facts play a decisive role in preventing cross contamination.
For more detailed information please see the complete FDA Warning Letter for Mylan Pharmaceuticals.

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