ICH Q14: Pharma groups want clarity on benefits of enhanced approach

Regulatory NewsRegulatory News | 04 October 2022 |  By 

Pharmaceutical industry groups questioned whether following the enhanced approach in International Council for Harmonization (ICH) Q14 guidance will confer regulatory relief for manufacturers that follow this method in developing an analytical procedure.
They also asked for recommendations for when an enhanced approach should be followed, called for greater alignment with the ICH Q2(R2) guideline and requested more examples showing multivariate approaches to analytical method development.
The comments were made in response to the US Food and Drug Administration’s (FDA) call for feedback on the two ICH draft guidelines, and echo earlier comments submitted to the European Medicines Agency (EMA). (RELATED: Pharma groups question enhanced approach in Q14, call for more alignment between Q14 and Q2(R2), Regulatory Focus 29 August 2022)
The Q14 guideline would harmonize the scientific approaches for analytical procedures development, while the Q2(R2) document covers the validation principles for using analytical procedures such as near-infrared (NIR)-based analysis and Raman spectroscopy, which often require multivariate statistical analyses.
The two guidelines are meant to make it easier for manufacturers to switch analytical methods for testing methods post approval and are aimed to promote more robust analytical processes. The guidelines were released in March 2022. (RELATED: ICH releases draft guidelines on analytical method development, Regulatory Focus 31 March 2022)
Groups question benefits of using enhanced approach in Q14
The Pharmaceutical Research and Manufacturers of America (PhRMA) and the Biotechnology Innovation Organization (BIO) wanted ICH to spell out the advantages of following the enhanced approach in ICH Q14, and whether using this method would accord manufacturers more regulatory flexibility in making post approval changes to their analytical methods.
The 64-page ICH Q14 document proposes to harmonize the scientific approaches for analytical procedures development by describing a minimal or an enhanced approach; a comprehensive analytical target profile (ATP) is incorporated in the enhanced approach.

“While PhRMA welcomes the option to use an enhanced approach on a voluntary basis, we emphasize the need to ensure that the provision of additional information results in increased efficiency for Industry’s regulatory submissions and post-approval changes. Although Industry has generally followed the enhanced approach for many years, it has withheld the additional information in submissions due to the minimal benefit and added burden to maintain this information,” the group wrote.
BIO similarly wanted more information on the benefits of following the enhanced approach. It urged ICH to “clarify if the enhanced approach will afford the flexibility to make changes within the design space with minimal or no post approval changes … is there or will there be dialog with any Health Authorities to discuss this topic and a possible commitment to honor the benefits of the enhanced approach to method development.”
BIO also wants ICH to provide clarity on when an enhanced approach is recommended. The group states that “we like the direct statement that the minimal approach remains acceptable; is there potential to provide either examples or further detail on when the enhanced approach may be more highly recommended?”
The International Society for Pharmaceutical Engineering (ISPE) suggested ICH provide additional examples and training materials to illustrate the minimal approach and how a minimal approach could be supplemented to have the same features as the enhanced approach.
More alignment between two guidelines
Similar to the comments made to EMA, groups called for better alignment between ICH Q2(R2) and Q14.
ICH Q14 states that "once a technology has been selected, the ATP [Analytical Target Profile] serves as a foundation to derive the appropriate analytical procedure attributes and acceptance criteria for analytical procedure validation (ICH Q2). However, ICH Q2 does not mention the concept of an analytical procedure attribute,” said PhRMA.
BIO also urged for better alignment on terminology between the two guidelines. As an example: ICH Q14 states that “the range of an analytical procedure is the interval between the lowest and the highest reportable results in which the analytical procedure has a suitable level of precision, accuracy and response.”
Yet ICH Q2 states that “the reportable range is confirmed by demonstrating that the analytical procedure provides results with acceptable accuracy, precision and specificity.” BIO questioned whether “response” should be replaced with “specificity” to better align with the ICH Q2 guideline.
Delete region specific requirements in PACMP
PhRMA also objects to the region-specific examples in ICH Q14’s Annex A showing how post-approval change management protocols (PACMPs) should be described in ICH Q14. PACMPs are agreements between applicants and regulators on a prospective change to be implemented and outline the studies and acceptance criteria to support the change.
The guideline states that “a PACMP may be required for some cases (e.g., a change between technologies) depending on region.”
“PhRMA strongly recommends avoiding the use of terminology such as “depending on region” as this would not result in an internationally harmonized approach, does not provide clear guidance for companies, and is not consistent with the approach taken in other internationally harmonized guidelines developed by FDA and ICH.”
PhRMA wants more clarity on multivariate approaches in Q2
In other areas, PhRMA said that more clarity and examples are needed to demonstrate the use of multivariate procedures in analytical method development.
“PhRMA appreciates the draft guidance’s discussion of multivariate analytical procedures, including how such procedures are conducted and best practices for performing them. At the same time, PhRMA would value additional examples of multivariate analytical procedures that use different models (e.g., principal component analysis, partial least squares, etc.) to help readers better understand validation and lifecycle management of multivariate analytical procedures.”
Industry comments on ICH Q2(R2) and Q(14)


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