Inadequate Validation of Analytical Methods remains permanent Topic in Warning Letters to API Manufacturers

In the past fiscal year 2011 (October 2010 through September 2011) a total of 14 manufacturers of pharmaceutical ingredients received a Warning Letter after being inspected by the FDA. That is almost three times as many as in the previous fiscal year, where the US authority issued 5 Warning Letters.

Among the 14 companies receiving Warning Letters are 4 Chinese and 3 Indian API manufacturers as well as one from Canada, Spain and the UK. The remaining 4 companies are located in the US.

A more detailed analysis of the Warning Letters shows that the FDA almost always found deficiencies in the area of analytics. The authority most frequently objected to the use of not validated analytical methods, the lack of appropriate processes as well as instructions for investigations following OOS results. The handling of documentation and with analytical raw data was also criticised quite often.

The following listing shows a brief analysis of the 14 Warning Letters in the fiscal year 2011. The findings in the area analytics are marked bold.

Chinese API Manufacturers:

  • No PQ and Calibration of lab devices
  • Inadequate analytical procedures
  • No investigation of cause after complaints
  • Re-processing of API batches without supporting stability data
  • No analytical methods validation, no confirmation of stability indicating significance
  • No qualification and calibration of QC laboratory instruments
  • No testing of solvents before batch certification despite confirmation on the certificate
  • No SOP for preventing cross contamination

Indian API Manufacturers:

  • No SOP for Change Control, OOS investigations, management of deviations in production and in the lab
  • No process validation
  • Incomplete investigation after OOS results
  • Incomplete cleaning validation
  • Fundamental deficiencies in the work of the quality unit
  • No SOP for Change Control, OOS investigations, management of deviations in production and in the lab, complaint management, annual product review
  • No raw data from incoming test
  • Subsequent entry in the batch protocol
  • Impurities due to inappropriate building design
  • No SOP for preventing cross contaminations

API Manufacturers in Canada, UK and Spain:

  • Handling of raw data not GMP compliant
  • No stability studies to support the expiration date
  • Inadequate deviation management by the quality unit
  • No process validation
  • Inappropriate analytical methods
  • No stability testing
  • No qualification of the equipment for purified water
  • No investigation following OOS results
  • Inappropriate analytical methods
  • Missing analytical raw data

API Manufacturers in the USA:

  • Inadequate documentation and misinterpretation of analytical data
  • No analytical methods validation
  • No investigation following OOS results
  • No qualification of analytical instruments
  • Poorly trained personnel
  • No investigation following OOS results
  • No calibration of balances
  • Subsequent entry in the batch protocol
  • No cleaning protocols
  • No investigation following OOS results
  • No methods validation
  • Batch certification with invalid specifications
  • Release of an outdated Certificate of Analysis 
  • No investigation of cause after complaints
  • No qualification of contract labs, no supplier qualification
  • Inappropriate equipment resp. supporting tools, therefore contaminations

As can be seen in the listing, the deficiencies in the analytical lab area are independent from the location of the company. The FDA found these defects in Asian as well as in European and US companies.

GMP violations in analytics seem to be a permanent topic; the 5 Warning Letters from the fiscal year 2010 showed a similar trend.

CONCEPT HEIDELBERG has been collecting and analysing the FDA Warning Letters to manufacturers of medicinal products, blood and blood processing products as well as of APIs for the past 10 years. Centrepiece of the annual analysis are the excerpts from the original Warning Letters. These excerpts were shortened for reading reasons, but still convey the context in which the GMP deficiency was found. The Warning Letters Report for the fiscal year 2011 is now available. It is part of the complete analysis of the past 10 years which can be purchased as CD "FDA Navigator" for 399,- €. The CD also comprises all GMP relevant FDA Guidelines. Please see the ECA website to find out more and to order the CD.

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

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