In June 2016 the World Health Organization (WHO) published a draft document "Guidelines on Validation - Appendix 4 Analytical Method Validation". Comments on the text should be sent to WHO until July 30, 2016.
The appendix 4 of the published Supplementary guidelines on good manufacturing practices: validation (WHO Technical Report Series, No. 937, 2006, Annex 4) has been revised in view of current trends in validation. The appendix presents some information on the characteristics that should be considered during validation of analytical methods. Approaches other than those specified in the Appendix may be followed and may be acceptable.
The new Appendix 4 is structured as follows (New and revised):
1. Principle (revised):
1.5 The recommendations as provided for in good laboratory practices and guidelines for transfer of technology (WHO Technical Report Series, No. 961, 2011, Annex 7) should be considered, where applicable, when analytical method validation is organized and planned.
2. General (revised):
2.6 The procedure should become part of a continuous verification procedure to demonstrate that it meets the predefined criteria over the life of the procedure.
2.7 Trend analysis and risk assessments should be considered at intervals to ensure that the method is appropriate for its intended application.
2.8 Changes to methods should be managed in accordance with the authorized change control procedure.
2.9 The scope of verification or degree of revalidation depend on the nature of the change(s) and the outcome of risk assessment.
2.11 The data obtained during method validation and verification should be considered covered by good anything practices (GxP) requirements and are expected to follow the principles of good data and record management practices. Their associated metadata are also expected to be retained and subjected to good data and record management practices (WHO Technical Report Series, No. 996, 2016, Annex 5).
2.12 When computerized systems are used to obtain and process data relating to method validation and verification, they should comply to the principles enunciated in Appendix 5 – Validation of computerized systems.
2.13 Adequate attention should be paid to the method of sample preparation.
6.1 Method verification should be performed for already validated analytical methods, for example, when it is used on a product for the first time (e.g. in case of a change in API supplier, change in method of synthesis or after reformulation of a drug product).
6.2 Method verification may include only the validation characteristics of relevance to the particular change.
7. Method revalidation (New):
7.1 Methods should be maintained in a validated state over the life of the method. Revalidation (see also ICH Q2) should be considered whenever there are changes made to the analytical method (e.g. changes to mobile phase, column, column temperature, detector).
7.2 In case of repeated SST failures or when obtaining of doubtful results. In such cases an investigation of the root cause should be performed, the appropriate changes made and the method revalidated.
7.3 Periodic revalidation of analytical methods should be considered according to a period that is scientifically justifiable.
8. Method transfer (New)
8.1 During method transfer, documented evidence should be established to prove that a method has equivalent performance when used in a laboratory different from that where it has been originally validated.
8.3 The two sets of results should be statistically compared and the differences between the two sets of test results should be within an acceptable range.
8.4 Method transfer should be performed before testing of samples for obtaining critical data for a dossier, such as process validation or stability studies or applied for routine use.
9. Characteristics of analytical procedures (revised), 9.3 System suitability testing:
9.3.1 The suitability of the entire system should be confirmed prior to and during method validation tests as well as during the test of samples.
9.3.2 System suitability runs should include only established standards or reference materials of known concentration to provide an appropriate comparator for the potential variability of the instrument.
9.3.3 Where a sample is used for system suitability or a trial run, written procedures should be established and followed and the results of all such trial runs be included in the results and data review process. A sample can be used only if it is a well characterized material. Characterization in such a case should be performed prior to the use of this sample as part of system suitability testing. The sample material or product under test should not be used for trial run purposes or to evaluate suitability of the system (see WHO guidelines on good data and record management practices).
The revised version of appendix 4 parallels certain considerations of the current USP lifecycle approach for analytical method validation. However, QbD concepts and the Analytical Target Profile (ATP) - which is equivalent to the Quality Target Product Profile (QTPP) - have not yet been introduced in the WHO draft.
According to WHO the draft of Appendix 4 will also be placed on the WHO Medicines website under "Current projects".
Members of the ECA Academy are able to access the new WHO Guidelines on Validation - Appendix 4 Analytical Method Validation in the ECA Members Area.