04.02.2025 | LOGFILE Feature 03/2025

Regulatory Requirements for the Validation of Analytical Methods – Part 1

Regulatory Requirements for the Validation of Analytical Methods – Part 1

7 min. reading time | by Joachim Ermer

Proof of the suitability of analytical test methods is a general GMP requirement. While the EU GMP Guideline Part I generally requires "validated test methods", Part II refers to the ICH guidelines with regard to the content of method validation. 21 CFR Part 211 also requires in §194(a)(2) that the suitability of the test methods must be verified.

The ICH Guideline Q2A on validation of analytical procedures published in 1994 was very important for the standardization of terms and definitions as well as for establishing the basic requirements for analytical method validation. The guideline was adopted by the EU in 1995 as a scientific guideline in the Notice to Applicants (EudraLex Volume 3) and is therefore binding for new authorizations. In 2005, the guidelines ICH Q2A and Q2B were merged under the name Q2(R1) with the new title Validation of analytical procedures: Text and Methodology, without changes to their content.

Since the 1990s, significant developments have occurred, particularly in the area of pharmaceutical production, such as quality-by-design tools, risk analysis and lifecycle. The ICH validation guideline Q2(R1) focuses mainly on chromatographic test methods. Due to the lack of acceptance criteria, the basis to prove the required suitability is diffuse, and the chapter on "Linearity" confuses the response function (calibration model) with the linearity of the analyte in the sample, i.e. with the precision. The latter has led to problems with analytical techniques which display non-linear response functions, especially with biological methods and products.

In November 2018, the ICH therefore published a concept paper on the revision of the validation guideline and the introduction of a new guideline Q14 on analytical procedure development. After a period of almost two years, the drafts of the two guidelines were published for public consultation in March 2022 in step 2 and each received more than 3,000 comments. At the ICH meeting in Prague on 31 October - 1 November 2023, the finalized guidelines in Step 4 were adopted by the regulatory ICH members, but were not published on the ICH website until 20 December 2023 (valid since June 2024).

Some of the shortcomings were rectified, but as expected, the international coordination process also led to various compromises and inconsistencies. The following table summarizes the significant changes and shortcomings from the author's perspective.


 
   Improvements, additions & clarifications
 

 
   Ambiguities, lack of information, lack of context, errors
 

  Extension of the scope of application:

  •   Intermediates, IPC (product control strategy)
  •   Phase-dependent validation


  Lifecycle aspects

  •   Limited to transfer activities
  •   No discussion of level 3 activities (monitoring)
  •   No discussion of the analytical control strategy (in Q14)
     

 
  Basis of demonstrating suitability:

  •   Performance characteristics with corresponding
      acceptance criteria

  Analytical Target Profile (ATP) is not mentioned (only in  
  Q14)


  Use of existing knowledge:

  •   Development data
  •   Abbreviated validation for platform methods
     

  No description how to derive acceptance criteria (neither in 
  text nor in examples)


  Product-related range (reportable range):

  •   Extrapolation of the experimental range if necessary
     

  Conflation of the validation study design with the final
  result (reportable result)


  Extensions regarding techniques:

  •   Multivariate and bio(techno)logical test methods
     

 


  Specificity/selectivity

  •   Technology inherent justification (instead of
      experimental  studies)

 

  "Linearity" replaced by "Response (calibration model)"

  •   Non-linear & multivariate models added
  •   Residuals plot to confirm the calibration model (at
      least for linear response)

 

  Response and calibration model are not
  necessarily identical

  •   Various calibration models possible with linear response

  Non-linear response:

  •   Residuals plot is not mentioned, only coefficient
      of determination

  Area% method:

  •   Linearity from reporting limit to 120% content:
      nonlogical, not possible with unweighted regression
     


  Lower range limit

  •   QL must be equal to or below the reporting threshold
     

 


  Accuracy:

  •   Focus on routine conditions (e.g. in the presence of
      the sample matrix and using the described
      reprocessing steps)
     

 

  Precision

  •   Prioritization of authentic samples

 

  •   The precision levels for the system, the measurement,
      the injection and precision of the end result are missing
  •   Aim of the precision studies not discussed:
      Understanding the factors contributing to variance in
      order to determine the replication strategy
     


  Consideration of uncertainty:

  •   Comparison of the confidence interval (or alternative
      statistical ranges) with the acceptance criteria
  •   Missing context of statistical equivalence tests: always
      expected, or dependant on risk?

  Combined assessment of accuracy and precision

  •   Combined confidence, forecast or tolerance ranges

 

  •   Prerequisite is routine or at least
      representative  processing of the spiked samples
      ("regular test conditions")
  •   Number of repetitions (9) may not be sufficient for
      extrapolation and tolerance ranges
     

  Illustrative examples for more detailed orientation

 

  •   Often not much more information than in
      the guideline text,
  •   Intermediate precision: number of series (only for qPCR)
      lacking, calculation method not discussed,
  •   Without acceptance criteria (but given in Q14),
  •   In part, reflecting out-of-date "linearity" (separation 
      techniques, release), residuals plot only discussed in
      NIR example

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


In the next LOGFILE, you can read about important aspects of putting the regulatory requirements into practice.

 
Joachim Ermer

Author

Joachim Ermer, PhD
Consultant at Ermer Quality Consulting
E-Mail: info@ermer-quality-consulting.com

 
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