Pharma groups question enhanced approach in Q14, call for more alignment between Q14 and Q2(R2)

Pharmaceutical industry groups praised certain aspects of the International Council for Harmonisation (ICH) draft Q14 and Q2(R2) guidelines yet had questions on how enhanced knowledge on analytical methods should be conveyed in regulatory submissions and whether smaller companies would have the necessary resources to invest in the enhanced approach in Q14.
 
Other groups had questions related to the use of multivariate modeling in analytical method development. In addition, there were calls for the two guidelines to be better integrated.
 
The comments were submitted in response to European Medicines Agency (EMA)’s call for feedback on the two guidance documents. (RELATED: ICH releases draft guidelines on analytical method development, Regulatory Focus 31 March 2022)
 
The guidelines should make it easier for manufacturers to switch analytical methods for testing medicines postapproval and are aimed to promote more robust analytical processes.
 
In the meantime, the US Food and Drug Administration (FDA) released ICH Q14 and Q2(R2) for public comment on Friday, as well as a slew of other ICH guidance documents.
 
The Q14 guideline would harmonize the scientific approaches for analytical procedures development while the Q2(R2) document covers the validation principles for the use of analytical procedures such as near-infrared (NIR)-based analysis and Raman spectroscopy, which often require multivariate statistical analyses.
 
EFPIA: Q14 framework is reasonable
 
The European Federation of Pharmaceutical Industries and Associations (EFPIA) said the ICH Q14 guidance “provides a reasonable framework for analytical procedures development and method lifecycle management” and that examples provided in the appendices are “very helpful.”
 
However, EFPIA said it is unclear how enhanced knowledge should be conveyed in a submission. “The guidance is short on the expected/anticipated content for communicating enhanced knowledge in a submission. This must be globally accepted for appreciable benefit. Great value will exist in future implementation training case studies to ensure alignment between industry and regulatory agencies on expectations for regulatory change management.”
 
The 64-page ICH Q14 document proposes to harmonize the scientific approaches for analytical procedures development by describing a minimal or an enhanced approach. It also describes the elements on an analytical target profile (ATP) which is incorporated in the enhanced approach.
 
Parexel questions how small regulators will review multivariate approaches
 
Parexel said is unclear how small regulators will review the multivariate models called for in the development of analytical procedures in ICH Q14. The company wrote that using these models “will require specialized review staff. Traditional CMC reviewers are chemists or biologists, not trained in complex analytical math.” The company added that “small agencies may not be able to handle this type of information.”
 
Instead, Parexel suggested that multivariate approaches should be optional, and that summaries of these approaches should be written “in language understandable to non-experts.”
 
EFPIA said the guidance should provide more examples showing how multivariate models can be used for training purposes.
 
Q14 adoption questioned by smaller firms
 
Along the same lines, Jazz Pharmaceuticals questioned whether smaller companies would have the time and resources to implement the enhanced approach to method validation.
 
“The additional time and resource required for applying the enhanced approach is likely to be a greater challenge for smaller biopharma to incorporate, and therefore less likely to be utilized. A risk-benefit assessment of methods will be required to identify where this approach would be most effectively applied and most beneficial to the lifecycle management where resource is limited,” Jazz wrote.
 
More integration with ICH Q2
 
The European Compliance Academy Foundation/European QP Association urged for more alignment between Q14 with ICH Q2, asserting that ICH has “failed to write a single integrated document to provide an encompassing approach to procedure development, validation and operational use Integrate ICH Q2 with Q14.”
 
EFPIA concurred, writing that “improved linkage is required between Q2 and Q14, both in terms of the relationship between the guidelines and the agreement of the terms and concepts utilized.”
 
For example, there should be additional text providing cross referencing to Q14 in the introduction as well as more consistent use of term “performance criteria”.
 
In other areas, the International Society for Pharmaceutical Engineering (ISPE) found several sections in the ICHQ2(R2) draft revision “challenging to follow because information on related validation points is split among different sections, and in some cases the details are not aligned well between sections.”
 
Company offers mixed praise for Q2(R2)
 
Fujifilm Diosynth Biotechnologies Denmark expressed both support and criticism of Q2(R2).
 
The company wrote that “there are a lot of improvements in the guideline with respect to clarifying issues from R1 and making the guidance substantially more unambiguous.”
 
Yet the guidance needs to accommodate advances made in statistical software. “Almost 30 years have passed since the first trio of Q2A was published and among other developments, statistical software to designs and evaluate validation studies has developed tremendously during this time.”
 
FDA begins consultation
 
In the meantime, FDA on Friday announced the release of ICH Q14/Q2(R2) for comment, along with the draft ICH E11A on pediatric extrapolation and ICH M12 guidance on drug interaction studies.
 
The agency also released the final ICH E14 and S7B question and answer guide on the Clinical and Nonclinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential.


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