California Separation Sciences Society (CaSSS) holds a two-day, highly interactive meeting with attendance from the biotechnology industry and global regulators each summer in the Washington, DC area (i.e., the CMC Strategy Forum).  This year the title of the forum was “The Future of Post-Approval Changes is Coming – Are You Ready for ICH Q12?” and it focused on the draft International Conference on Harmonization (ICH) Q12 guideline (here) which addresses the technical and regulatory aspects of reporting post-approval changes to the regulatory bodies.  This was a very timely meeting, given that the Q12 guideline is expected to reach Step 4 at the next ICH meeting this coming November.

Speakers at the meeting represented the USA, Japan, Europe, and Canada, and included regulators from the U.S. FDA (CBER and CDER) and Health Canada.

The speakers from CBER were skeptical about the applicability of the enhanced approach (as defined in the Q12 guideline) to the products CBER regulates and to changes for analytical methods.  However, CDER’s outlook was a bit more positive and it has received the nine applications and supplements that it solicited via the “Established Conditions” pilot program (here).

The industry speaker from Japan gave an overview of how the Japanese regulatory system has utilized Establish Conditions (ECs) in the country’s Marketing Authorization Applications (MAA) for at least the past five years.  In an MAA for Japan, the ECs are presented in a textual section called “Approved Matters” in Module 1 of the eCTD.  In this section, those process parameters that require prior approval from the regulators if changed are enclosed in double-carats (i.e., <<parameter>>) and those that can be changed with only notification to the regulators (considered key process parameters) are enclosed in brackets (i.e., [parameter]).

Although Post-Approval Change Management Protocols (PACMPs) have not historically been a part of the Japanese regulatory system, subsequent to the drafting of the Q12 guideline, Japan has initiated a pilot program for these.  Similarly, discussions are underway in Japan to determine how to incorporate the Product Lifecycle Management (PLCM) document into the Marketing Authorization Application (MAA).

Health Canada’s representative said that the agency is fully supportive of downgrading the submission categories of manufacturing changes when such downgrades are justified.  However, some challenges to implementation of Q12 were mentioned, including how to manage regulatory complexity when ECs differ from expectations in current guidance documents, maintaining decisional consistency among the various evaluators, and training of evaluators and regulatory affairs officers regarding how to apply ICH Q12 concepts.

With regard to PACMPs, Health Canada is not yet ready to implement them and may consider a pilot program like the Japanese have done.  Also, Health Canada is partially aligned with the utilization of PLCM documents in that the agency already has within its system the Certified Product Information Document (CPID) that incorporates some, but not all, of the information envisioned for the PLCM.

A number of industry speakers addressed the potential challenges of implementing the use of Established Conditions in their applications and there is clearly a good deal of uncertainty with regard to the costs vs. benefits.  Among the concerns raised were the complexities of managing multiple applications in a global regulatory environment if each regulatory body approves a different set of ECs, challenges in knowledge management related to justification of ECs and non-ECs, the need for efficient IT systems to track ECs for different applications in different countries, the need to establish standards within the company for justifying ECs and non-ECs and how to document them in applications, and how to utilize ECs in Accelerated Development situations.

In spite of these challenges and uncertainties, representatives from several companies spoke about how their firms are moving ahead with preparing for the finalization of Q12.  In particular, one company has established a core Q12 team and sub-teams to address ECs, PACMPs, PLCMs, and Change Management, and PQS that are developing EC assessment tools, templates for PACMPs and PLCMs, and principles for presentation of these in the dossier.  Several other companies at the meeting are participating in the FDA’s pilot program for the use of Established Conditions in their applications.

All in all, this CMC Strategy Forum provided a valuable and current view of the progress and concerns regarding the planning and preparation of both the industry and the regulators for the coming release of the final ICH Q12 Guideline on Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management.