Current FDA Warning Trends Point to Future Documentation and Lab Control Hot Buttons

FDA inspections continue to focus on CGMP violations related to basic GMP controls.  A survey of Warning Letters issued in 2013 on CMC (Chemistry / Manufacturing / Controls) violations reveals an emphasis on production, laboratory, and records systems.

Also, to date all CMC Warning Letters issued in 2013 for drug substance (API) and drug product manufacturers, whether domestic or foreign, involved manufacturing facilities outside of the US.  Leading violations included production and process controls (12%), laboratory controls (16%), records and reports (30%), and equipment (10%).

Less frequently observed were organization and personnel controls related to the quality control unit or training (6%), buildings and facilities controls especially those related to environmental controls (7%), and control of components especially raw materials testing and release (8%).  Rounding out 2013 Warning Letter observations for these manufacturers were non-GMP violations including marketing of non-approved drugs (2%) and deliberate obstruction of inspections (2%).   See Figure 1.

The leading categories observed ‐‐ production and process controls (12%), laboratory controls (16%), records and reports (30%), and equipment (10%) – generally involved failures to document, investigate, test, or otherwise control production and testing areas. Quality oversight, facilities controls, and failures to control raw materials were less often observed.  In May 2013 FDA published “Guidance for Industry – Contract Manufacturing

Arrangements for Drugs: Quality Agreements”. The Agency cited ICH Q7 (“Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients”), ICH Q9 (“Quality Risk Management”), and ICH Q10 (“Pharmaceutical Quality Systems”) to emphasize the sponsor’s role in assuring that their contractors adhere to CGMPs, and their ultimate responsibility in assuring the quality, purity, safety, identity, and effectiveness of drugs manufactured using CMOs.

FDA officials have stated in recent industry conferences that the Agency plans to perform more overseas inspections, pointing to strong quality agreements between sponsors and foreign contractors as a mainstay in ensuring product quality.

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