Philadelphia, PA (Oct.24)—Failures to review batch failures and unexplained discrepancies are the leading cause of Food and Drug Administration Form 483 observations and Warning Letter citations issued to pharmaceutical companies. Violations of the review requirement (21 CFR 211.192) accounted for 16.3% of 818 observations in the 2006 fiscal year, pushing the category into first place from number eight on last year's list (http://www.pharmtech.com/pharmtech/article/articleDetail.jsp?id=190230).

Kristen D. Evans, a senior regulatory operations officer in the Office of Compliance at FDA's Center for Drug Evaluation and Research, offered a summary of the past year's compliance statistics during his keynote address at the Institute of Validation Technology's Validation Week. (IVT is owned by Advanstar Communications, which publishes Pharmaceutical Technology.)

Warning letters and GMP citations
In Evans's analysis of Warning Letters and GMP citations (see Table I and Figure 1), the 21 CFR 211.192 failures were followed by last year's leading citation: shortcomings in the performance of the quality control unit (21 CFR 211.22[d]). Poor in-process sampling and testing (21 CFR 2110[a]) followed. Overall, these three categories accounted for 44% of the citations analyzed.

Failures to follow production procedures (21 CFR 211.100[a]), validate production procedures (21 CFR 211.100[b]), or establish proper laboratory controls(21 CFR 211.160[b]) followed on this year's list, each accounting for about 10% of citations. 

Rounding out the top ten were lapses in testing and release (21 CFR 211.165[a]), batch record review (21 CFR 211.188), personnel qualifications (21 CFR 211.25[a]), and equipment cleaning and maintenance (21 CFR 211.67[a]).

Recalls
Evans summarized the causes of 215 of the year's 361 product recalls (240 of prescription products and 121 of over-the-counter medications; see Table II and Figure 2). Subpotency was the most common reason (prompting 16% of recalls), followed by container defects, impurities and degradation products, and poor assurance of sterility (each of which caused about 12% of the recalls). Other causes included CGMP deviations, labeling errors, microbial contamination of nonsterile products, nonsterility, dissolution-test failure, and failure of stability data to support the stated expiration date.