GMP/FDA Requirements on HPLC Systems in the Lab

GMP News No. 391

GMP News
23 February 2004

GMP/FDA Requirements on HPLC Systems in the Lab

1) New AAPS Recommendations on Analytical Instrument Qualification

In July 2003 the Gold Sheet published a Summary Report on AAPS Instrument Qualification Workshop (March 2003). This workshop was co-sponsored by ISPE and the International Pharmaceutical Association (FIP). The aim of this meeting, including FDA representatives, was to establish common terminology for Analytical Instrument Qualification (AIQ).

It was considered appropriate that the DQ, IQ, OQ, PQ terms for qualification – although these terms were found confusing for AIQ – should be continued and that the AIQ process should be defined around them, since these terms have already found their place in the validation (qualification) terminology.

Key requirements for IQ, OQ and PQ were defined. For instance the term Operational Qualification (OQ) is defined and explained as:

  • On-site testing and documentation providing verification that an analytical instrument is functioning as the vendor intended
  • OQ may be performed at some regular interval thereafter
  • OQ is also performed as required by the change control of the instrument, and after major repairs that might affect critical factors of instrument operation
  • OQ tests are not method specific
  • Absorbance detector wavelength accuracy and absorbance linearity, injector precision, pump flow rate accuracy and proper gradient operation are some important tests for HPLC components
  • Holistic tests are acceptable in lieu of modular testing

Performance Qualification is defined as on-site testing that verifies consistent and proper operation of the analytical instrument or system, according to a specification appropriate for its routine use. These tests check the maintenance and calibration of the instrument System. Suitability checks can supplement but not replace the functional checks for PQ!

Furthermore, software validation was probably the most controversial issue handled at this AAPS workshop. A white paper will be published based on the workshop discussions.

Equipment Qualification (including the a.m. AIQ proposals) and Software Validation are two of the main topics of the Conference of the European Compliance Academy Successful HPLC Management in a GMP-/FDA-Regulated Environment. This conference takes place on 31 March and 1 April 2004 in Barcelona, Spain followed by a Post-Conference Workshop on Validation of Chromatography Data Systems. Click here to find the complete programme.

2) HPLC in Human Drug cGMP Notes

In earlier issues of FDA's Human Drug CGMP Notes there were two questions dealing with HPLC, which might be interesting although they are not brand-new:

The first question was in March 1996:
"Does FDA have a CGMP policy on use of recycled solvents for HPLC columns?"

The answer was: "The agency has no specific policy on recycled HPLC solvents…. Therefore it would be acceptable to use recycled solvents which do not interface with analytical results or equipment operation."

The second question was in September 1997:
"When analyzing a sample by HPLC to determine variance within a batch, such as content uniformity or dissolution, and the result for one tablet is out of specifications (OOS), if there is clearly an HPLC malfunction, does the whole test need to be re-run, or only the one solution?"

Russ Rutledge (FDA) answered to this question:
"……if the analytical instrument was clearly shown to give unreliable results by the laboratory investigation, then the test results must all be invalidated and the entire test run again, using the original sample solutions if possible. The new results are substituted for the invalidated results, and only these are used in the batch evaluation. To merely re-run the one sample solution is inadequate because the rejection of data is based on instrument malfunction. Thus, all results from this test should be considered unreliable."

One lecture at the international HPLC Conference Successful HPLC Management in a GMP-/FDA-Regulated Environment in Barcelona will cover Out of Specification HPLC Results. Click here for the complete programme.

3) HPLC in FDA Warning Letters

FDA Inspections often cover HPLC details as you can see from the below listed FDA Warning Letter citations:

  • Procedure for HPLC Calibration Method 013 has no predetermined acceptance criteria for the auto sampler calibration. The auto sampler calibration does not demonstrate that the instrument is capable of accurately assessing 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
  • Data from two of the test runs were voided due to HPLC systems problems, however a review of the chromatograms showed that system suitability was maintained throughout the run
  • No data demonstrating suitability for use could be provided for your firm's HPLC system
  • HPLC chromatograms were found to have poor separation between active ingredient peak and unknown peak, as well as widely different retention times for the active peak between different chromatographic runs
  • HPLC chromatographic data do not always document system suitability requirements

At the ECA Conference Successful HPLC Management in a GMP-/FDA-Regulated Environment, which takes place at 31 March and 1 April 2004 in Barcelona, emphasis will be on latest enforcement issues and current FDA thinking including the revised interpretation of part 11 requirements. The invitation brochure for this conference can be found here.

Dr Günter Brendelberger


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