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.

Elaboration of New USP General Chapter – Analytical Procedure Lifecycle – announced

On June 24, 2016, the USP announced the elaboration of a new general chapter <1220> regarding life cycle management of analytical methods. Read more about the new general chapter  <1220> “The Analytical Procedure Lifecycle“.



On June 24, 2016, the USP announced the elaboration of a new general chapter <1220> “The Analytical Procedure Lifecycle”. Input Deadline is July 29, 2016.

The suggested audience are drug product manufacturers, dietary supplement manufacturers, testing organizations, and drug product related regulatory agencies.

“An analytical procedure must be shown to be fit for its intended purpose. It is useful to consider the entire lifecycle of an analytical procedure when approaching development of the procedure, i.e. its design, development, qualification, and continued verification. The current concepts of validation, verification, and transfer of procedures address portions of the lifecycle but do not consider them holistically. This General Chapter intends to more fully address the entire procedure lifecycle and define concepts which may be useful.”

The approach is consistent with the concepts of Quality by Design (QbD) as described in ICH Guidelines Q8 (R2), 9, 10, and 11 and with the expected new ICH Guideline Q12 (Lifecycle Management).

Preliminary outline:

  • focal point: Analytical target profile (ATP), comparable to the Quality Target Product Profile (QTPP).


  • Procedure design and development,
  • Procedure understanding,
  • Preparing for qualification.



  • Routine monitoring,
  • Analytical control strategy,
  • Knowledge management,
  • Change control.

Anticipated proposed design phase activities:

Two Stimuli articles are scheduled for PF 42(5) [Sep.–Oct. 2016]:

  • Analytical Target Profile: Structure and Application throughout the Analytical Lifecycle,
  • Analytical Control Strategy.

Two stimuli articles have already been published:

  • Lifecycle Management of Analytical Procedures: Method Development, Procedure Performance Qualification, and Procedure Performance Verification. PF 39(5) [Sep.–Oct. 2013],
  • Fitness for Use: Decision Rules and Target Measurement Uncertainty. PF 42(2) [Mar.–Apr. 2016].

Additionally, the USP proposed a revision of general chapter <1225> “Validation of compendial procedures” in PF 42(2) [March-April 2016].
This chapter is being revised to incorporate a section on “Lifecycle Management of Analytical Procedures”. The revision is an attempt to better align the validation concept with the recently (July 2015) issued FDA guidance “Analytical Procedures and Methods Validation for Drugs and Biologics”, which also includes a section on “Life Cycle Management of Analytical Procedures”.

Estimated proposal for the new general chapter <1220> “The Analytical Procedure Lifecycle” is PF 43(1) [Jan.–Feb. 2017].

Furthermore, an USP and ECA Joint Conference and Workshop on Lifecycle Approach of Analytical Procedures will be held November 8-9, 2016 in Prague, Czech Republic.

For more information please visit the USP website – Notices- General Chapter Prospectus – The Analytical Procedure Lifecycle.

//////////The Analytical Procedure Lifecycle, USP, chapter <1220>

Practical Implementation of the Control of Elemental Impurities: EMA’s new Guideline Draft

One and a half year after its publication, the ICH Q3D guideline still raises many questions. The EMA has recently published a guideline draft aiming at clarifying the practical implementation of ICH Q3D. Read more here about what is expected in a marketing authorisation application or in an application for a CEP with regard to risk assessment and the control of elemental impurities in APIs and medicinal products.


The “ICH Q3D Guideline for Elemental Impurities” was published in December 2014 as Step 4 document and released in August 2015 under No EMA/CHMP/ICH/353369/2013 as EMA’s Scientific Guideline. The guideline came into effect in June 2016 for all medicinal products currently underlying a marketing authorisation procedure (new applications).

In the meantime, it became clear that implementing in practice the requirements of this guideline has been so complex and led to some marketing authorisation procedures being delayed. The ICH has already reacted to the situation and published 7 training modules on its website. Moreover, a concept paper announces a question & answer document.

On 12 July 2016, the draft of an EMA’s guideline entitled “Implementation strategy of ICH Q3D guideline” (EMA/404489/2016) was published. The purpose of the document is to provide support for implementing ICH Q3D in the European context.

The draft comprises three chapters addressing the most important elements in relation with the implementation of the ICH Q3D requirements. The chapter “1. Different approaches to Risk Management” starts describing the two fundamental approaches to the performance of a risk assessment and the justification for a control strategy with regard to elemental impurities:

Drug Product Approach
Here, batches of the finished product are scanned by means of analytical (validated!) procedures to develop a risk-based control strategy. If – with this approach – the omission of a routine testing has to be justified, the authority expects a detailed and valid justification though, and not just analytical data from a few batches.

Component Approach
The guideline draft clearly gives its preference to this approach. The respective contribution of the different components of a medicinal product is considered with respect to the potential total impurity profile and compared to the PDE value from the risk assessment. All potential sources of impurity, for example from production equipment or from excipients of natural (mined) origin have to be considered in this assessment. This particularly applies to outsourced APIs; here, all pieces of information available from Active Substance Master Files (ASMFs) or Certificates of Suitability (CEPs) have to be used. Substances with a Ph.Eur. monograph should always comply with the elemental impurities limits of the corresponding monograph.

The chapter “2. Particulars for Intentionally Added Element(s)” deals with the common practice in many organic syntheses to add elements to increase the specificity of the chemical reaction and the yield. It is particularly critical when the last step of an API synthesis just before the end product uses a metal catalyst. In such a case, the authority expects a convincing evidence that the catalyst is purged to levels consistently below the control threshold (<30% of the PDE) by means of appropriate methods. All details about the API synthesis including the fate of the metals intentionally added have to be consistently described and documented in the marketing authorisation application or in the application for a CEP. If the routine testing of an elemental impurity is needed, the API manufacturer may determine a specification. This information will be required by the medicinal product manufacturer for his overall risk assessment.

The chapter “3. ASMF/CEP: dossier expectations and assessment strategy” explains who has to submit the risk assessment necessary for an ASMF or a CEP and how the dossier will be processed by the assessor of the regulatory authority. Basically, two scenarios are possible:

1. The API manufacturer submits a summary of a risk assessment/management for elemental impurities
Such information flows in the overall risk assessment of the medicinal product manufacturer and is assessed by the quality assessor/ CEP assessor within the marketing authorisation procedure. All data and documents used for the risk assessment should also be available for a GMP inspection.

2. The API manufacturer doesn’t perform any risk assessment/ management.
The regulatory authority basically expects a detailed description of the API synthesis including data on all metal catalysts used. This as well as the analytical routine controls on elemental impurities performed by the API manufacturer will also be assessed by the quality assessor/ CEP assessor. Nevertheless, the assessor won’t make a final conclusion in the ASMF or CEP assessment report with regard to the compliance with ICH Q3D. This will be done within the marketing authorisation procedure for the medicinal product.

The guideline draft can be commented on until 12 August 2016.

///////////ICH Q3D, Control of Elemental Impurities,  EMA, control of elemental impurities in APIs

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EMA reviews Medicines manufactured at U.S. Company

Following the issuance of two Non-Compliance Reports for two sites of the US based company, EMA has started a review of medicines manufactured by Pharmaceutics International Inc., USA.

The European Medicines Agency (EMA) has started a review of medicines manufactured by Pharmaceutics International Inc., USA. This follows the issuance of two Non-Compliance Reports for two sites of the US based company after an inspection in February 2016 conducted by the MHRA (the medicines regulatory agency in the United Kingdom) which highlighted several shortcomings in relation to good manufacturing practice (GMP).

Pharmaceutics International Inc. manufactures the centrally authorised medicine Ammonaps (sodium phenylbutyrate) and is also the registered manufacturing site for some other medicines that have been authorised through national procedures in the European Union (EU).

This inspection which was a follow-up to an inspection in June 2015 aimed to assess whether corrective measures agreed previously had been appropriately implemented. It found that shortcomings remained, which included insufficient measures to reduce the risk that traces of one medicine could be transferred to another (cross-contamination), as well as problems with the way data were generated and checked and deficiencies in the systems for ensuring medicines’ quality (quality assurance).

EMA’s Committee for Medicinal Products for Human Use (CHMP) will now review the impact of the inspection findings on the products’ overall benefits and risks and make a recommendation as to whether any changes are needed to their marketing authorisations.

There is no evidence that patients have been put at risk by this issue. However, as a precautionary measure, medicines from this site will no longer be supplied to the EU unless they are considered to be ‘critical’ to public health. Criticality will be assessed by national medicines regulatory agencies for their territories, taking into account alternatives and any impact of shortages on patients. In case where a medicine manufactured at this site is considered not critical in a member state it will no longer be supplied in this member state and any medicine remaining on the market will be recalled.

Source: EMA Press Release

Pharmaceutics International Inc., USA

/////////// EMA,  Medicines,  manufactured, U.S. Company, Pharmaceutics International Inc., USA