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Manufacturers and regulators are working to reach consensus on the harmonization of management of postapproval changes.
After some five years of discussion and debate, manufacturers and regulatory authorities are working hard to reach consensus on the Q12 document to harmonize procedures for managing postapproval manufacturing changes. Agreement is expected later this year on this important quality standard under the auspices of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH).
A large working group of experts from industry and regulatory agencies hope to agree to release a consensus document at an ICH meeting in Minneapolis in June 2017. This would follow an early April session of the Q12 expert working group to review the many comments submitted on the current version 7 document and craft a revised version 8 document for step 1/2A publication. If these efforts are successful, a Step 2B document could be released for public consultation by year-end, setting the stage for formal adoption of Q12 in 2018.
The aim of Q12 is to establish a framework for managing postapproval manufacturing changes in multiple regions. While all postapproval changes must be managed and documented, not all require prior approval by regulatory authorities. Harmonization in this area has the potential to produce a “transformational guideline” that resolves difficult technical and regulatory issues, commented Moheb Nasr, vice-president for CMC regulatory strategy at GlaxoSmithKline at the FDA/PQRI conference on product quality in March 2017. Added important benefits would be to mitigate drug shortages and to encourage the adoption of innovative manufacturing technologies.
The current Q12 document describes a risk-based system for categorizing changes, building on existing policies in the United States, Japan, and the European Union, but not in all regions. A main element of Q12 is to define those “Established Conditions” where chemistry, manufacturing, and control (CMC) changes require regulatory submissions and approval. While everything in product development is subject to change control, Nasr explained, only certain elements need to be reviewed. The new standard also encourages manufacturers to devise post-approval change management protocols (PACMPs) that describe in advance those changes that a firm anticipates it will implement during the product lifecycle and how it proposes to report such changes. PACMPs exist in the EU and US, but have not been widely used; agreement on common approaches to lifecycle management aim to encourage broader adoption of such approaches. This initiative appears particularly important for a company that anticipates shifting production to a new facility, especially when involved in accelerated development of a breakthrough therapy.
To reach final consensus, the experts see a need to more clearly articulate the benefits of developing lifecycle management strategies. They seek further agreement on where this information should go in the common technical document (CTD) and how to present PACMPs, particularly when multiple changes are anticipated for a single product. Future efforts will extend these change-management principles to biotech products and vaccines, and to drugs already on the market.
The recent expansion of ICH to include more regions and product categories promises to extend the reach of Q12 and other ICH standards, but also complicates the process for reaching agreement by all participants. More transparency in lifecycle risk assessment and change-management procedures, though, promise to lead to better regulatory decisions on both new and generic drugs, commented Bob Iser, director of the Office of Process and Facilities (OPF) in FDA’s Office of Pharmaceutical Quality in the Center for Drug Evaluation and Research, at the PQRI conference.
Publication of Q12 will be an important step toward international harmonization, noted Christine Moore, executive director and global head for CMC policy at Merck. A common framework for defining established conditions and change protocols could lead to more uniform risk tolerance among regions, but differences may remain for some time in how regulators define these terms and other specifics. Similarly, Keith Webber, senior director of regulatory affairs at of Perrigo, noted that Q12 faces challenges common to most harmonization efforts due to a range in familiarity with key concepts among different industries and regulators.