HPLC in FDA Warning Letters

GMP News No. 277

GMP News
10 January 2003

HPLCin FDA Warning Letters

We recently examined FDA Warning Letters and found that 48 of themcontained complaints referring to HPLC. These include quite generalfindings as well as very specific points, as the following list ofexamples for selected topics shows.

HPLC in Stability Testing:

  • Unidentified HPLC peaks found during stability testing were notidentified or evaluated
  • No attempt is made to identify or evaluate degradation productsduring routine stability testing. The HPLC recorder is turned off assoon as the analytical peak elutes
  • The stability indicating HPLC method used for related substancestesting of a product has not been fully validated in that the linearrange and Limit of Detection/Limit of Quantitation for all knownimpurities has not been determined

HPLC - Calibration/Qualification:

  • There is no documentation regarding calibration and preventivemaintenance for HPLCs used by QC Chemistry Laboratory
  • Procedure for HPLC Calibration Method 013 has no predeterminedacceptance criteria for the autosampler calibration. The autosamplercalibration does not demonstrate that the instrument is capable ofaccurately accessing linearity
  • The calibration procedure for HPLC systems is inadequate in that itdid not include integrator and detector's linearity, injector'sreproducibility, and accuracy of temperature settings for columnheater and detector

Computer Validation/Part-11 Compliance of HPLC:

  • The HPLC computer software, which is used for data acquisition,calculations, and change control, is not validated in that areas suchas system operations, system maintenance, change control, data back-upand archival, system security and disaster recovery have not beenevaluated
  • Lack of validation data to support the adequacy of the computersoftware used to run the HPLC systems
  • It was noted during the inspection that there is an option on theHPLC that allows analysts to delete results after they were processed

Other Findings:

  • Assay peaks with shoulders and unresolved peaks were observed onrelease and stability for…
  • Your firm did not perform the required standard injection bracketingrequired for the HPLC method for both assay and content uniformity
  • There is no assurance that the laboratory HPLC columns can produce valid, reliable and reproducible results
  • There is no data to demonstrate that the in-house HPLC method usedto release…is equivalent to compendial methods
  • The method for integrating HPLC peaks of the same product wasinconsistent

Considering that even the Warning Letters contain so many complaintsreferring to HPLC procedures, one can infer that the inspection reports(483s) themselves deal much more frequently with HPLC findings in FDAinspections.

Dr Günter Brendelberger



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