What is the ICH Q2(R2) guideline?

Written by Anindya Ghosh Roy Posted in Method validation

“Validation of Analytical Procedures” (ICH Q2(R2)) published by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human (ICH) is a tripartite harmonized guideline that identifies validation parameters needed for variety of laboratory methods to analyze drugs. The three parties involved in this harmonization are the US, EU and Japan. There are quite a lot of other ICH guidelines, which are categorized into 4 major groups:

  1. Quality Guidelines (e.g. GMP, Pharmaceutical development, Analytical validation etc.)
  2. Safety Guidelines (e.g. Toxicity studies)
  3. Efficacy Guidelines (e.g. Pharmacovigilance, Clinical trial reports, GCP etc.)
  4. Multidisciplinary Guidelines (e.g. Electronic standards, Gene therapy etc.).

Here again we meet the basic pharmaceutical terms of the German Medicinal Products Act (Arzneimittelgesetz – AMG): quality, safety and efficacy (AMG §1).

These guidelines are formed to bridge any differences that may occur and may affect the quality of the overall drug product, while applying for market authorization by any of the corresponding authorities. They should ensure the same quality of the drug irrespective of the country to be released on. Additionally, they should help the authorities getting the same documents in the application in a good quality facilitating approval as all information required are known to the applicants. Although, the US is part of the ICH tripartite, there are additional guidelines published by its own regulatory body, the US Food and Drug Administration (FDA), which also need to be respected in case of marketing drugs in the USA.

As mentioned earlier, the ICH Q2(R2) is a part of the ICH quality guidelines and is responsible for the validation of analytical methods. This guideline is directed towards three main categories of analytical tests:

  1. Identification tests
  2. Quantitative tests for impurities' content and limit tests for the control of impurities
  3. Assays as quantitative content determinations of the active pharmaceutical ingredient as well as for potency.

Apart from compendial test methods, which need to be verified, these test categories are to ensure the quality (e.g. by identification of the active ingredient), safety (by demonstrating impurities being below acceptable limits) and efficacy (by showing the drug possess the right amount of active ingredient and its potency). For each analytical method, it is required to prove the method’s suitability to analyze a specific drug substance and / or drug product. The performance characteristics required for validation according to the ICH Q2(R2) are Specificity / Selectivity, Range, Trueness and Precision. The validation tests Response (Linearity) and the lower range limits (Limit of detection (LOD) as well Limit of quantification (LOQ)) belong to the (reportable) Range. The parameter "Robustness" should have been examined during the method development and doesn’t fall under the ICH Q2(R2) performance characteristics and validation tests. Not all parameters are required for each method category; thus, it is very important to identify the type of analytical method to be able to prove its intended use by the validation respecting the correct parameters.

The ICH Q2(R2) method validation guideline allows an understanding to the application and limitations of the test method. During method development no validation is yet needed but the principles noted in the ICH Q2(R2) should already be kept in mind as after final method development the method needs to be validated. In addition, the parameter “robustness” (as mentioned above) must be evaluated during development, just like the system suitability test criteria. If the method validation has not been performed or has been performed in an inadequate manner, the method is not considered to provide reliable data and will not be accepted by the authorities for the upcoming drug product batch release and stability testing.

 

Update 12/16/2018:

A revision of the validation guideline ICH Q2(R1) is planned

As announced in summer this year and now in more detail in November, ICH's guideline on validating analytical methods will be revised. The content of this guideline comes from two previously separate guidelines merged in 2005, which were published more than 20 years ago. The decision to revise the validation guideline ICH Q2(R1) was made at the ICH meeting in June, together with the decision to create a new analytical procedure development guideline (ICH Q14). Currently, it is unknown whether these will be two separate documents, or whether a combined guideline will result as a possible combination should be examined by the Expert Working Group.

The revision will provide validation characteristics for more advanced spectroscopic / -metric techniques such as Near Infrared (NIR), Raman or Nuclear Magnetic Resonance (NMR) spectroscopy and various mass spectrometry combinations such as GC-MS or CE-ICP-MS. Some of these methods are used as real-time in-process controls (keyword "Process Analytical Technology" (PAT)) and can be associated with multivariate statistical data analysis. Accordingly, this aspect will also be taken into account in the ICH Q2(R2). In the course of the lifecycle approach, which is currently being developed for analytical methods too (see, for example, the stimuli paper for the new USP chapter <1220>), considerations for continuous method performance verification will also be included in the revision.

According to the concept paper published in November, it is expected that the revised ICH Q2(R2) guideline will be issued in spring of 2021. We can be curious!

 

Update 01/04/2022:

According to the work plan published in June last year, the ICH Q2(R2) guideline should now be in Step 2a/b and public consultation should start in January of this year. Step 4 is expected for November 2022...

Update 03/25/2022:

And finally, the next step has been reached: on March 24, 2022, the consensus draft of the revised ICH Q2(R2) guideline has been endorsed to Step 2b, i.e. it is under public consultation by the relevant stakeholders, such as the European Commission, the Korean MFDS, the Chinese NMPA and Taiwanese TFDA with deadlines of mid- and late-July, respectively. In the Q2(R2) / Q14 Step 2 presentation published on the ICH homepage, Step 4 is announced for May 2023...

Update 11/15/2023:

As announced in the ICH press release of November 8, 2023, Step 4 has been reached for both guidelines and next up, training materials can be developed.

 

Update 12/07/2023:

The text above was written at the time of its creation based on the previous version (ICH Q2(R1)) and has now been updated accordingly.

When comparing the current ICH Q2(R2) and the former ICH Q2(R1), the main differences can be summarized as follows:

  • The detailed description of the method categories in ICH Q2(R1) has been omitted in ICH Q2(R2), but can still be found in Table 1, as the scope of application of ICH R2(R2) is broader. In this context, ICH Q2(R2) also contains completely new information for the validation of multivariate analytical methods.
  • In addition to the individual evaluation of accuracy and precision, ICH Q2(R2) also allows for their combined evaluation, e.g., with the help of a tolerance interval.
  • ICH Q2(R2) includes requirements for specificity / selectivity for stability-indicating methods, which were previously only listed in the 2015 FDA Guideline, as well as for the use of stressed samples, and allows the elimination of specificity experiments for certain methods based on technology inherent justification.
  • Regarding response (linearity), the meaningless RSS declaration required by ICH Q2(R1) has finally been omitted from ICH Q2(R2), but a residual plot is explicitly mentioned in ICH Q2(R2) instead...
  • New is the requirement of ICH Q2(R2) regarding the limit of quantification, which must be ≤ the reporting limit for impurity methods.
  • Partially revised wording + several new chapters and appendices based on underlying concepts (e.g., “reportable range,” life cycle concept), often clearer (alphabetically sorted glossary, tables instead of continuous text, reduction of redundancies), etc.