WHO Draft on Analytical Method Validation

The World Health Organization (WHO) recently published a draft document on analytical method Validation for comment. Read more about the draft “Guidelines on Validation – Appendix 4 Analytical Method Validation“.


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.
  • (…)

3. Pharmacopoeial methods
4. Non-pharmacopoeial methods
5. Method validation
6. Method verification (New):

  • 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.


////////WHO Draft, Analytical Method Validation

MHRA GxP Data Integrity Definitions and Guidance for Industry: New Draft Version for Consultation

In January and March 2015, the U.K. Medicines and Healthcare Products Regulatory Agency (MHRA) published a “GMP Data Integrity Definitions and Guidance for Industry”. The agency has recently published a new version of the Guidance. Please find here a short overview of the new features in the “GxP Data Integrity Definitions and Guidance for Industry: Draft version for consultation”.


In recent years, regulatory authorities have been struggling with data integrity issues. In particular the U.S. American FDA has tightened the awareness regarding the topic in many Warning Letters. In the meantime, data integrity has also become a focus of European regulatory authorities’ inspections. One of the first regulatory authorities to publish a “GMP Data Integrity Definitions and Guidance for Industry” in January and March 2015 was the U.K. Medicines and Healthcare Products Regulatory Agency (MHRA). More information can be found in “MHRA revises its Guideline on Data Integrity in the short Term“. The contents of this Guidance led to a number of discussions and activities within the industry. Not all the requirements were considered appropriate. Just recently, the Agency has published a new version of the document entitled “GxP Data Integrity Definitions and Guidance for Industry: Draft version for consultation July 2016”.

The basic structure of the Guidance has been largely maintained both in the introduction and the definitions part. Primarily, the changes made concern new formulations and a few new term definitions. The following terms have been newly added:

7. Data transfer / migration.
8. Data processing.
9. Recording data.
10. Excluding data.
14. Electronic signatures.
20. Cloud providers and virtual service / platforms (also referred to as software as a service Saas / platform as a service (PaaS / infrastructure as a service (Iaas).

A News about the detailed content differences will be issued soon.

Source: MHRA GxP Data Integrity Definitions and Guidance for Industry: Draft version for consultation July 2016.

/////////GMP Data Integrity Definitions, Guidance for Industry, MHRA, MHRA GxP Data Integrity

Written Confirmation expired: Can an API still be imported when produced earlier?

What needs to be considered if an API is produced in the time period of a valid written confirmation but imported after this confirmation has expired? This is answered in a revised Q&A Document of the EU Commission.


The EU Commission has updated its Question and Answers Document “Importation of active substances for medicinal products for human use” (now version 7). In this updated version, the question “Can an API batch manufactured during the period of validity of a written confirmation be imported into the EU once the written confirmation is expired?”

In the answer it is referred to Article 46(b)(2)(b) of Directive 2001/83/EC, where it is defined that APIs can only be imported if they are manufactured in accordance with EU GMP or equivalent, and accompanied by a written confirmation from the competent authority of the exporting third country certifying this.

But what if an API is produced in the time period of a valid written confirmation but imported after this confirmation has expired?

In the respective answer the EU Commission states that “it is legitimate to consider that the guarantees of equivalence provided by the written confirmation apply to any API batch in the scope of the written confirmation which was released for sale within the period of validity of the written confirmation, even if not exported in that time period.”

So the answer is ‘yes’, it still can be imported. But it needs to be accompanied by the expired written confirmation together with appropriate documentation which proves “that the whole consignment has been manufactured and released for sale by the quality unit before the expiry date of the written confirmation” and “provides a solid justification of why a valid written confirmation is not available.”

An import without any written confirmation is not possible.

///////////API, produced, time period of a valid written confirmation, imported, confirmation has expired, revised Q&A Document of the EU Commission.