HPLC in FDA Warning Letters

GMP News No. 277

GMP News
10 January 2003

HPLC in FDA Warning Letters

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

HPLC in Stability Testing:

  • Unidentified HPLC peaks found during stability testing were not identified or evaluated
  • No attempt is made to identify or evaluate degradation products during routine stability testing. The HPLC recorder is turned off as soon as the analytical peak elutes
  • The stability indicating HPLC method used for related substances testing of a product has not been fully validated in that the linear range and Limit of Detection/Limit of Quantitation for all known impurities has not been determined

HPLC - Calibration/Qualification:

  • There is no documentation regarding calibration and preventive maintenance for HPLCs used by QC Chemistry Laboratory
  • Procedure for HPLC Calibration Method 013 has no predetermined acceptance criteria for the autosampler calibration. The autosampler calibration does not demonstrate that the instrument is capable of accurately accessing linearity
  • The calibration procedure for HPLC systems is inadequate in that it did not include integrator and detector's linearity, injector's reproducibility, and accuracy of temperature settings for column heater 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 such as system operations, system maintenance, change control, data back-up and archival, system security and disaster recovery have not been evaluated
  • Lack of validation data to support the adequacy of the computer software used to run the HPLC systems
  • It was noted during the inspection that there is an option on the HPLC that allows analysts to delete results after they were processed

Other Findings:

  • Assay peaks with shoulders and unresolved peaks were observed on release and stability for…
  • Your firm did not perform the required standard injection bracketing required 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 used to release…is equivalent to compendial methods
  • The method for integrating HPLC peaks of the same product was inconsistent

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

This topic is the focus of the ECA Conference HPLC in a GMP-/FDA-regulated Environment taking place in Heidelberg, Germany, from 12-13 February 2003. The conference picks up many of the questions arising during FDA inspections, like method validation, equipment qualification, Part-11 compliance or method transfer.

For a whole day, the ensuing Post Conference Workshop will deal with the validation of chromatography data systems (CDS) in compliance with the requirements of 21 CFR Part 11.

Dr Günter Brendelberger


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