CHARTS: FDA WARNING LETTERS REPORT 2010
Over a period of seven fiscal years (FY) the number of Warning Letters the US FDA issued to medicinal product manufacturers due to GMP violations (21 CFR Part 211) has temporarily reached a peak. Overall 41 companies received a Warning Letter referring to a corresponding paragraph in Part 211. Compared to the 27 Warning Letters issued in the fiscal year 2009 this increase is remarkable.
Recommendation
Berlin, Germany4/5 December 2024
Root Cause Analysis
It is quite interesting that the share of foreign - non-US - companies receiving a Warning Letter is almost the same as in the last fiscal year. In the fiscal year 2010 this list comprised eight companies from the following countries:
- France (Aseptic Production)
- Italy (Aseptic Production)
- Belgium (Tablet Production)
- Canada (Tablet Production)
- Venezuela (Aseptic Production)
- Singapore (Semi-solid Dosage Forms)
- India (2 Companies: Aseptic Production and Contract Laboratory)
Compared to this: In the fiscal year 2009 non-US companies from the UK (Aseptic Production), India (Aseptic Production) and Canada (Two companies: Aseptic Production and Tablet Production) received Warning Letters. This compilation clearly shows the high percentage of operations manufacturing sterile dosage forms. Due to the FDA's risk-based approach the inspection of these operations has a high priority.
With regard to the most frequent cited deficiency the fiscal year 2010 does not provide any surprises though. Since the fiscal year 2007 - and this means throughout the last four years, the paragraph 211.192 Production Record Review is on the top. This paragraph requires
- The review of the manufacturing and process documentation of the medicinal product and its compliance with the written instructions by the quality unit before batch release,
- The thorough investigation and clarification of deviations from the predefined specifications of a batch or its components,
- The extension of the investigation to other batches associated with the deviation,
- The drafting of an investigation report with measures and scheduled tracking.
As obvious as these requirements may sound, they are apparently not as obvious for many companies. In the fiscal year 2010 after all 29 of 41 companies violated these requirements (among them two of the three European companies).
The following excerpts from original Warning Letters clearly illustrate what the FDA investigators found during their inspections:
"Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed [21C.F.R. § 211.192]. For example, no corrective or preventive action was documented regarding […], a drug product that your firm stated was light-sensitive. Your firm incorrectly packaged this product in non-light resistant packaging."
"Your firm failed to thoroughly investigate the failure of a batch to meet its specifications whether or not the batch has already been distributed [21 C.F.R. § 211.192]. For example, OOS results were obtained during validation of the manufacturing process for [...] Tablets without initiating a subsequent investigation."
Further paragraphs cited throughout the last couple of years are: 211.00 (Written procedures; deviations); 211.22 (Responsibilities of the quality control unit); 211.160 (Laboratory controls - general requirements).
API manufacturers can also be found among Warning Letter addressees more often again - compared to six in the fiscal year 2008 and one in 2007 there were six in the fiscal year 2009 and in 2010 respectively. Many suppliers providing APIs are located in Far East; for that reason there are always Chinese and Indian operations amongWarning Letter addressees. However, even at European API manufacturers the FDA finds GMP deficits as shown in the following list:
Warning Letters issued to API manufacturers in the fiscal year 2010:
- France
- Japan
- China (2 Companies)
- USA (2 Companies)
Warning Letters issued to API manufacturers in the fiscal year 2009:
- France
- Italy
- Germany
- Japan
- China (2 Companies)
Recommendation
22/23 January 2025
HPLC Data Integrity - Live Online Training
Every fiscal year (October of the previous year to September of the current year) the FDA issues Warning Letters to medicinal product manufacturers, manufacturers of blood products and blood processing operations as well as to manufacturers of active pharmaceutical ingredients (APIs). Concept Heidelberg systematically collects and analyses these letters. As a central piece these analyses provide a trend regarding the frequency of the cited paragraph CFR 211 as well as excerpts from the respective Warning Letter originals. These excerpts are reduced for reasons of readability, but still reflect the context in which the GMP violation was found (e.g. not clarified OOS in a HPLC method).
Author:
Dr Gerhard Becker
CONCEPT HEIDELBERG
