The ICH Q8 Guidelines – What the R2 Revision means for Pharma

  • The ICH Q8 Guidelines – What the R2 Revision means for Pharma

    Posted by Frank Davis on October 24, 2022 at 4:39 pm

    What is ICH Q8 (R2)?

    This guidance is a revision of the ICH guidelines Q8 Pharmaceutical Development (Q8 parent guidance) that published in May 2006. In June 2009, the Q8 parent guidance was revised to add an annex, which provides further clarification of the key concepts outlined in the May 2006 guidance and describes the principles of quality by design (QbD). The Q8(R1) document issued in June 2009 includes the Q8 parent guidance and the annex. This second revision, Q8(R2), provides corrected captions for figures 2a and 2b in Appendix 2, section C.

    At the July 2003 ICH meeting in Brussels an arrangement was reached on a common vision and approach for developing an international plan for a harmonized pharmaceutical quality system that would be applicable across the life-cycle of a product. Among other actions that were outlined to implement this vision, an expert working group was established to develop guidance for pharmaceutical development, which will cover the life-cycle of a product.

    The ICH Q8 guideline is intended to provide guidance on the contents of Section 3.2.P.2 (Pharmaceutical Development) for drug products as defined in the scope of Module 3 of the Common Technical Document (ICH topic M4). The aim of pharmaceutical development is to design a quality product and the manufacturing process to deliver the product in a reproducible manner. Information from pharmaceutical development studies is a basis for risk management. It is important to recognize that quality cannot be tested into products.

    Therefore, “Reviewers should ensure that applications contain at least the minimum information on pharmaceutical development described by ICH Q8(R2) as at a minimum, those aspects of drug substances, excipients, container closure systems and manufacturing processes that are critical to product quality should be determined and control strategies justified,” the policy states.

    Reviewers should check applications to ensure that certain minimal elements described in the Annex of ICH Q8(R2) are included in all applications, namely:

    • Quality target product profile (QTPP),
    • Critical quality attributes (CQAs) of the drug product,
    • CQAs of the drug substance and excipients,
    • Selection of an appropriate manufacturing process,
    • Control strategy.

    However, analytical methods are not explicitly mentioned in the document and the introduction of, for example, the Analytical Target Profile (ATP) -equivalent to the QTPP- has not yet been established.

    Additionally, FDA says its reviewers should be making sure the applications demonstrate that the manufacturer has enhanced knowledge of the development and manufacturing processes they have identified in their applications. If necessary, quality reviewers should “confer with CMC (chemistry, manufacturing and controls) subject matter experts and members of the extended review team (e.g., medical officer, pharmacology/toxicology reviewer) to establish the relevance of CMC information that supports the drug’s safety, efficacy, and performance.

    Additionally more flexible regulatory approaches can be proposed in applications. As described in ICH Q8(R2), manufacturers can justify the use of flexible regulatory approaches in areas where the demonstration of greater understanding of pharmaceutical and manufacturing sciences can create a basis for flexible regulatory approaches. When an application includes information supporting a flexible regulatory approach, the reviewers should determine whether the application “includes sufficient enhanced knowledge that demonstrates the applicant’s understanding of material attributes, manufacturing processes, and controls for product quality to support the proposed flexible regulatory approaches.”

    FDA gives the following examples of potential flexible regulatory approaches a manufacturer can take:

    • Manufacturing process improvements without regulatory notification (e.g., movement within a design space),
    • Approaches to reduce post-approval submissions through submission of change protocols (“Comparability Protocols”),
    • In-process tests in lieu of end product testing, including real time release testing approaches (PAT, RTRT),
    • Mathematical models (e.g., multivariate models) as surrogates for traditional end product testing.


    Frank Davis replied 1 year, 7 months ago 1 Member · 0 Replies
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