ICH Q2(R2) & Q14 Aim to Promote More Robust Analytical Processes, Greater Ease for Switching Analytical Methods Post Approval

Currently effective International Conference on Harmonization (ICH) guidance for analytical procedures, Validation of Analytical Procedures: Text and Methodology, Q2(R1), contains content that was approved in 1994. Reflect on that for a moment. Think about the evolution that has occurred within our industry over the last approximately three decades. We have new forms of manufacturing, new modalities employed for therapeutic benefit, and new technologies incorporated into analytical procedures that are still guided by Q2(R1). On a related noted, ICH guidance has continued to evolve over this same timeframe with the publishing of ICH Q8, Q9, Q10, Q11, Q12, and Q13 (draft-Step 2).

ICH recently published drafts of ICH Q2(R2) Validation of Analytical Procedures and ICH Q14 Analytical Procedure Development. These documents have been signed off as Step 2 documents (24 March 2022) to be issued by the ICH Regulatory Members for public consultation. The documents were developed based on a Concept Paper (15 November 2018) and a Business Plan (15 November 2018). ICH is targeting finalization as Step 4 documents to be implemented in the local regional regulatory system in May of 2023.

The key principles of these documents as defined by ICH are the following:

• Together ICH Q14 and ICH Q2(R2) describe the development and validation activities suggested during the lifecycle of an analytical procedure used for the assessment of the quality of drug substances and drug products.
• ICH Q14 describes the scientific principles for development, change management and submission requirements of analytical procedures for the minimal and enhanced approach.
• ICH Q2(R2) provides guidance for establishing, submitting, and maintaining evidence that an analytical procedure is fit for purpose (assuring drug quality).

The new guideline in this pair, ICH Q14, describes science and risk-based approaches for development and maintenance of analytical procedures, in line with approaches suggested in previous ICH guidelines (e.g., ICH Q8 and Q11). For the first time in detail, two approaches to analytical procedure development are articulated, a minimal (or traditional) approach and an enhanced approach (originally mentioned at a high level in ICH Q12). There also is information for the development of multivariate analytical procedures and the use of these tests for real time release testing (RTRT). In addition, principles are provided to facilitate change management of analytical procedures based on risk management, and comprehensive understanding of the analytical procedure via adherence to predefined criteria for performance characteristics. Lastly, there is guidance on the submission of analytical procedure development and related lifecycle information in the Common Technical Document (CTD).

ICH Q14 describes the benefits of using elements of the enhanced approach to analytical procedure development. The key elements of the enhanced approach are:

• Evaluation of the sample properties
• Defining an analytical targe profile (ATP)
• Conducting risk assessment (ICH Q9) and evaluating prior knowledge
• Conducting uni- or multi-variate experiments (MODR)
• Defining an analytical procedure control strategy
• Defining a lifecycle change management plan

The benefit of this information-rich approach is better understanding of which analytical procedure attributes are essential for robust procedure performance (e.g., Established Conditions (ECs)), and by employing predefined performance characteristics and their associated acceptance criteria, there is a path that enables the evolution of the analytical procedure over its lifecycle. All of this should reduce the amount of effort required for analytical procedure lifecycle maintenance, including regulatory approval or notification (if required).

It is important to note that there is a continuum of options between the categories of minimal (traditional) and enhanced approaches for analytical procedure development. More specifically, it is possible to apply elements of the enhanced approach (e.g., Analytical Target Profile (ATP), ECs, risk assessment, prior knowledge, uni- or multi-variate experiments, analytical procedure control strategy or lifecycle change management plan) to minimal (traditional) analytical procedures. We can anticipate that the benefits of using elements of the enhanced approach during development will be clarified as the documents are finalized, or through training information as we have experienced with other ICH guidelines (e.g., ICH Q12).

ICH Q2(R2) a revision to ICH Q2 also has been released for public consultation. Key changes to this guideline are the following:

• Incorporation of guidance for validation of a more diverse set of analytical procedures including those for biotechnological products, multivariate based procedures, and more diversity in synthetic molecule examples
• Inclusion of expectations of multivariate based analytical procedure validation
• Connection to principles described in ICH Q8, Q9, and Q10
• Connection to Q14, and outlining that some validation parameters should be evaluated as part of method development, e.g., method robustness

This is an exciting time within the community of practitioners that work with analytical procedures. What was started in many other ICH guidelines is now being incorporated into the guidance for analytical procedures.

ISPE’s Analytical Method Strategy/ICH Q2(R2) & Q14 team will continue to be active across multiple platforms as we look to influence the content and support implementation of these guidelines. In particular, we plan to develop content related to practical applications of these guidelines. For more information, please plan to attend our session “New Paradigm for Analytical Methods: ICH Q2(R2) and Q14” on 1 November 2022 at the ISPE Annual Meeting & Expo in Orlando, FL, USA.