FDA's Evans Reviews Causes of Warnings and Recalls

October 27, 2005
Pharmaceutical Technology Editors

FDA's Evans Reviews Causes of Warnings and Recalls

In the Oct. 25 keynote address of the Institute of Validation Technology'sValidation Week conference in Philadelphia, PA, Kristen Evans presented the early statistical analyses of the US Food and Drug Administration's regulatory actions for Fiscal Year 2005. Evans leads the Guidance andPolicy Team in the Division of Manufacturing and Product Quality inFDA's Center for Drug Evaluation and Research (IVT is owned byAdvanstar Communications, which publishes Pharmaceutical Technology.)

While warning that some of the results are preliminary and may besubject to some refinement, Evans did highlight several trends:

Warning Letters and GMP Citations.The analysis of Warning Letters and GMP citations (see Table I),shortcomings in the performance of the quality control unit (21 CFR 211.22) and in testing and release for distribution (21 CFR211.165) jumped up in frequency to share first place among categoriesfor cited deficiencies. On the other hand, two previously leadingcauses of citations dropped out of the top ten altogether in 2005:lapses in production record review and failure investigations (21 CFR211.192), historically the second- or third-ranking citation, hasdropped to number 17 on the list. And poor personnel qualification (21CFR 211.25), has dropped to about number 20.

Recalls. The analysisof  354 product recalls in fiscal year 2005 (see Tables III and IV) showed thatCGMP deviations are increasingly the most common cause of productrecalls. Though CGMP deviations have historically been the primaryreason for recalls, accounting for 14.5% of the 3619 recalls from 1987through 2004, they caused 40.7% of the recalls in 2005. Thesecond-ranking cause of product recalls is failure of USP dissolutiontests, accounting for 12.9% of historical recalls and 15.5% of recallsin 2005. Evans noted the current discussion of the USP dissolution testitself, and referred to the Agency's scientific advisory board meetingon the topic this week.

Rank 2004Rank 2005SubpartTitle
13211.100Written Production Procedures
24211.67Equipment Cleaning and Maintenance
31211.22Responsibilities of Quality Control Unit
46211.113Control of Microbiological Contents
58211.160Laboratory General Requirements
61211.165Testing and Release for Distribution
74211.166Stability Testing
88211.188Production and Control Records
99211.84Testing and Approval or Rejection of Components, Drug ProductContainers, and Closures
1017211.192Production Record Review (Failure Investigations)
116211.42Design and Construction Features
1213211.198Complaint Files
1220211.25Personnel Qualifications

1211.22 (d)Responsibilities of Quality Control Unit
2211.110 (a)In-Process Sampling and Testing
3211.100 (b)Adherence to Production Procedures
4211.100 (a)Production Procedures (Validation)
5211.192Batch Review (Investigations)
6211.25 (a)Personnel Qualification
7211.160 (b)Laboratory Controls
8211.165 (a)Testing and Release
9211.188Batch Record Review
10211.68 (a)Equipment Maintenance

14440.7%CGMP Deviation
5515.5%Failed USP Dissolution Test Requirements
308.5%Microbial Contamination of Nonsterile Products
257.1%Lack of Efficacy
246.8%Labeling Error
185.1%Impurities and Degradation
174.8%Lack of Assurance of Sterility
164.5%Product Lacks Stability
133.7%Misbranded: Promotional Literature with Unapproved Claims

52314.5%CGMP Deviation
46712.9%Failed USP Dissolution Test Requirements
45412.5%Subpotent (Single-Ingredient Drug)
41411.4%Lack of Assurance of Bioequivalence
37910.5%Lack of Assurance of Sterility
3178.8%Penicillin Cross-Contamination
3118.6%Stability Data Do Not Support Expiration Date
3108.6%Labeling: Label Mix-Up
2416.7%Microbial Contamination of Nonsterile Products
2035.6%Marketed Without an Approved NDA or ANDA