The number of Warning Letters issued to Drug Companies and API Manufacturers increases

Over a period of seven fiscal years, the number of Warning Letters issued by the FDA to drug manufacturers because of GMP deviations (21 CFR Part 211) has reached its climax. In total, 41 companies received such a Letter referring to the GMP deficiencies described in the corresponding paragraphs of Part 211. Compared to FY 2009, where 27 Warning Letters were issued, this strong increase is remarkable.

An interesting fact is that the number of non-US addressees is almost the same as in FY 2009. Last FY 2010, eight countries received a Warning Letter:

  • France (aseptic production)
  • Italy (aseptic production)
  • Italy (aseptic production)
  • Canada (tabletting)
  • Venezuela (aseptic production)
  • Singapore (semi-solid dosage forms)
  • India (2 companies: aseptic production and contract laboratories)

Compared to FY 2009, Warning Letters were issued to sites outside the USA in Great-Britain (aseptic production), India (aseptic production), Brazil (aseptic production) and Canada (two companies: aseptic production and tabletting). This compilation also clearly shows the high amount of sites manufacturing sterile dosage forms. Due to FDA's risk-oriented approach, the inspection of such sites is of high priority.

Regarding the most frequent deviations the fiscal year 2010 was no surprise. Since FY 2007 (four consecutive years) paragraph 211.192 Production Record Review has been at the top of the GMP deviation list. 211.192 requires:

  • Review of the drug product production and control records and determination of compliance with written procedures by the quality unit before the batch is released,
  • Thorough investigation and clarification of unexplained discrepancies or the failure of a batch or any of its components to meet any of its specifications,
  • Extension of the investigation to other batches that may have been associated with the specific failure or discrepancy.
  • Preparation of an investigation report with conclusions and follow-up actions included.

Although these requirements seem to be obvious, many companies do not comply with them. During FY 2010, 29 companies out of 41 breached these requirements (among them two out of the three European companies).

The following excerpts from original Warning Letters give examples of the main critics made by the FDA:

"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."

Over many years, the following paragraphs have always been among the most frequent deviations: 211.100 (written procedures; deviations); 211.22 (responsibilities of the quality control unit); 211.160 (laboratory controls - general requirements). Regarding the latter paragraph, please read our News from 2 February 2011.

Also API manufacturers can be found more and more among the Warning Letters addressees. In both FY 2009 and 2010, there were six API Warning Letters compared to three in FY 2008 and one in 2007. Most of the API suppliers are located in India and China, a fact that is reflected on the following placement:

In FY 2010 Warning Letters were issued to API manufacturers in the following countries:

  • France
  • Japan
  • China (two companies)
  • USA (two companies)

Compared to this API manufacturers in the following countries received a Warning Letter in FY 2009:

  • France
  • Italy
  • Germany
  • Japan
  • China (2 companies)

The Warning Letters issued by the FDA each fiscal year (a fiscal year begins in October of the previous calendar year and ends in September of the current year) to drug products manufacturers, firms working in the field of blood products and blood processing, and to API manufacturers are systematically collected and evaluated by Concept Heidelberg. The central part of each annual evaluation consists of data about the trends regarding the frequency of the most cited paragraphs of CRF Part 211 and of the excerpts taken from the respective original Warning Letters. These text extracts are shortened in order to improve their readability whilst the context concerning the GMP deviation can still be identified (e.g. OOS not explained in a HPLC Method).

This gapless evaluation of the issued Warning Letters has been performed since FY 2002.  

This 9-year complete collection of "case studies", numerous statistical evaluations, all the GMP relevant FDA Guidelines as well as inspection check lists based on the cGMP Guide in German and in English can be found in the "FDA Navigator" CD, which you can purchase for 399, - EUR. Find more here.

Dr Gerhard Becker
CONCEPT HEIDELBERG (a service provider entrusted by the ECA Foundation)

Go back


Stay informed with the GMP Newsletters from ECA

GMP Newsletter

The ECA offers various free of charge GMP newsletters for which you can subscribe to according to your needs.

To subscribe, please click here.