FDA Warning Letters in Fiscal Year 2021: Deficient Stability Tests Reason for most frequent Complaints

A look at the FDA's Warning Letters sent in the period October 2020 to September 2021 (fiscal year 2021) shows a particularly high proportion of complaints relating to Section 211.166 Stability Testing (Subpart I - Laboratory Controls) of the Code of Federal Regulations (CFR). In 12 of a total of 27 Warning Letters issued, deficiencies are described in relation to the requirements for stability testing of medicinal products laid down in 211.166.

Other deficiencies reported in the Warning Letters relate to the following 21 CFR sections:

  • 211.84 (Subpart E - Control of Components and Drug Product Containers and Closures) Testing and approval or rejection of
                  components, drug product containers, and closures
    (cited in 10 Warning Letters)
  • 211.22 (Subpart B Organization and Personnel) Responsibilities of quality control unit (cited in 9 Warning Letters)
  • 211.165 (Subpart I - Laboratory Controls) Testing and release for distribution (cited in 8 Warning Letters)
  • 211.67 (Subpart D - Equipment) Equipment cleaning and maintenance (cited in 7 Warning Letters)
  • 211.100 (Subpart F - Production and process Controls) Written procedures; deviations (cited in 7 Warning Letters)
  • 211.192 (Subpart J - Records and Reports) Production record review (cited in 7 Warning Letters)
  • 211.160 (Subpart I - Laboratory Controls) General requirements (cited in 5 Warning Letters)
  • 211.68 (Subpart D - Equipment) Automatic, mechanical, and electronic equipment (cited in 4 Warning Letters)
  • 211.188 (Subpart J - Records and Reports) Batch production and control records (cited in 2 Warning Letters)
  • 211.198 (Subpart J - Records and Reports) Complaint files (cited in 2 Warning Letters)

In reviewing the quality control areas of the inspected companies, FDA inspectors found essentially the following deviations from the regulations for GMP-compliant stability testing of active pharmaceutical ingredients and finished medicinal products:

  • Inappropriate stability studies due to
    - lack of stability testing of the active ingredient
    - missing microbiological tests
    - lack of quantitative content determinations
    - lack of testing for degradation products
    - unsuitable test methods (e.g. only visual tests, odour, pH-value)
  • Shelf-life data of the products are based on stability studies that are no longer up to date (different production site, different active ingredient suppliers)
  • Stability tests were not carried out in the usual market packaging
  • A compilation of all current stability studies could not be provided 
  • No long-term stability study with the active ingredient from a new supplier available for the production-scale validation batches
  • No detailed description of the stability testing programme

The lack of testing of the active ingredient for physicochemical as well as microbiological stability was the most frequently criticised. Among the 12 addressees of the Warning Letters are nine manufacturers of OTC products (OTC; over-the-counter; non-prescription medicines), two manufacturers of solid (tablets) and one manufacturer of semi-solid dosage forms (ointments).

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