Warning Letters Report 2009 - Increasing number of Warning Letters

The increasing trend in the frequency of issued warning letters referring to CFR Part 211 continues: In Fiscal Year 2009, even more pharmaceutical companies, i. e. 26, received a warning letter than in the previous fiscal year. In contrast, the number of warning letters addressed to firms in the field of blood products and blood processing remained the same.

FY 2006 FY 2007 FY 2008 FY 2009
WLs on medicinal products (Part 211) 20 13 22 26
WLs on blood and blood products (Parts 600, 606 etc.) 10 6 5 5

Subjects and frequency are quite similar to those in the previous fiscal year. The most frequent deviations refer to the following paragraphs from the Code of Federal Regulations (CFR):

• Production record review (211.192)
• Responsibilities of quality control unit (211.22)
• Laboratory Controls, general requirements (211.160)
• Written procedures, deviations (211.100)

In the warning letters issued during fiscal year 09, deficiencies in the investigation and clarification of deviations  („unexplained discrepancies“) were criticised very often. The insufficient recognition of the quality unit's responsibilities and the lack of written procedures according to which these units are meant to operate were also mentioned very often in the warning letters. In the following we have listed the original wording of some typical examples:

“Failure to thoroughly investigate any unexplained discrepancy or the failure of any batch to meet any of its specifications, whether or not the batch has already been distributed, as required by 21 CFR § 211.192.”

“Failure to extend investigations to other batches of drug product that may have been associated with the specific failure or discrepancy. Failure to include conclusions and follow up in written records of the investigation as required by 21 CFR § 211.192.”

“Failure to follow written procedures applicable to the quality control unit and to establish adequate procedures in writing as required by 21 CFR § 211.22(d).”

“The quality control unit failed its responsibility to reject drug products that did not meet specifications impacting identity, strength, quality and purity of drug products. 21 CFR 211.22. It also failed to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated as per 21 CFR 211.22(a).”

As can be deduced from the listed quotations, the insufficiently assumed responsibility of the quality units is, of course, closely linked to the inadequate or omitted investigation into unexplained discrepancies, since the latter is one of the key tasks of the quality unit.

When comparing the quotations from the warning letters of the two previous fiscal years, one can see that the deficiencies spotted during FDA inspections have in the essence remained the same. For the time being, the trend towards a higher number of warning letters directed at manufacturers of medicinal products seems to go on. The warning letters are increasingly characterised by a greater detail density. Moreover, the described cases are easily comprehensible and thus make these documents a rich seam of case studies.

Concept Heidelberg has evaluated the warning letter quotations systematically and offers a comprehensive data compilation from meanwhile eight fiscal years (2002-2009). This evaluation can be purchased in the form of the CD "FDA Navigator" at the price of EUR 399. To find out more please go here.

Gerhard Becker
On behalf of the European Compliance Academy (ECA)

ECA Training Course Tip: How to Pass EU and FDA Inspections (GMP Compliance Auditor Course), Munich, Germany, 8-10 June 2010.

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