Adjustment versus Modification - Interpretation of the Ph.Eur. Requirements

The possibilities for adjusting an analytical technique as described in the Ph.Eur. Monograph are quite generous: in HPLC e.g., the column length may vary by +/-70%, as may the flow rate, and the inner column diameter may deviate by +/-25% without any need to consider this as a modification relevant to change control.

Strictly speaking, the regulations laid down in this monograph apply exclusively to analytical methods listed in pharmacopoeial monographs. So they cannot simply be transferred to other analytical techniques, e.g. within the framework of drug product analysis. On the other hand, it is generally recognised that such a monograph represents the state of the art and knowledge.

It has been discussed whether one can orientate one's own, self-developed chromatographic methods towards the Ph.Eur. Monograph. There has been agreement on the fact that one should validate the method and prove by means of an appropriate robustness test that this method remains in fact valid over the whole adjustment range of the individual parameters. The robustness test is meant to ensure that slight changes in the method parameters will not influence the test result during routine operation.

Furthermore, the adjustment of a method has to be checked immediately before an analytical sequence through a product-specific system suitability test. By means of this test it has to be proven that the chromatographic separation technique is really suitable for the analysis in hand under the current conditions and settings of the day.

From a formal point of view, it remains to say that no revalidation is necessary in case of a method adjustment, nor is any further internal or external analysis or approval. In contrast to this, the modification of an analytical technique is subject to the change control procedure: the method has to be revalidated, and a notification of change has to be sent to the registration authorities.

Owing to large demand, the Conference "Successful HPLC Management in a GMP-/FDA-Regulated Environment" is repeated in Barcelona on 31 March - 1 April 2004 together with the ensuing Post-conference Workshop "Validation of Chromatographic Data Systems" to be held on 2 April 2004. If you would like to view the conference programme, please click here.

Author:
Dr Günter Brendelberger
CONCEPT HEIDELBERG