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ICH Q12: FDA guidance explains US implementation

Posted 21 May 2021 | By Joanne S. Eglovitch 

ICH Q12: FDA guidance explains US implementation

The US Food and Drug Administration (FDA) has issued draft guidance to help manufacturers implement the International Council for Harmonization’s (ICH) Q12 guideline on postapproval changes by explaining how manufacturers can submit established conditions (ECs) for new drug applications (NDAs) and prior approval supplements (PASs). It also reconciles ICH post-approval changes classification categories with FDA supplement categories.
A Federal Register announcement on 20 May said that the guidance complements ICH Q12 and clarifies “how the ICH Q12 tools and enablers can be implemented within the US regulatory system.”
The Q12 guidance replaces FDA’s 2015 guidance on “Established Conditions: Reportable CMC Changes for Approved Drug and Biologic Products,” said FDA’s Ashley Boam, who is the ICH Q12 rapporteur, at a 15 May ICH regional meeting between the US and Health Canada.
Boam added that the learnings from FDA’s established conditions pilot program in 2019 “informed” the implementation guidance. (RELATED: CDER plots established conditions pilot, Regulatory Focus 14 February 2019). Established conditions (ECs), a core concept of the guideline, is defined as “legally binding information considered necessary to assure product quality,” and any change to ECs necessitates a submission to the regulatory authority.
The ICH Q12 guideline, adopted in November 2020, aims to facilitate the management of postapproval chemistry, manufacturing and controls (CMC) changes for new and marketed pharmaceuticals and drug substances. The FDA made available the ICH guidance on 11 May, which is now being implemented by regulators. (RELATED: FDA issues ICH Q12 final guidance on postapproval changes, Regulatory Focus 11 May 2021).
Q12 consistent with FDA regulations and guidance
The agency said that existing FDA guidances and regulations are consistent with ICH Q12, including its Scale-Up and Postapproval Changes (SUPAC) guidances, which describe a broad set of postapproval changes.
A SUPAC guidance issued in 1997 covered changes to an approved application of specified biotechnology products and a 2004 guidance addressed changes to an approved NDA or abbreviated new drug application (ANDA), while a March 2014 guidance addressed CMC post-approval manufacturing changes to be documented in annual reports.
The ICH concept of ECs is also “consistent” with FDA’s regulations at 21 CFR 314.70(a)(1)(i), 314.97(a), and 601.12(a)(1). While these regulations do not specify what constitutes an EC, they establish a risk-based system for reporting changes. The guidance said that ICH Q12 “helps applicants gain clarity around which elements of the product, manufacturing process, facilities and equipment and control strategy in their applications are considered to be ECs and require reporting changes.”
Reporting ECs
Sponsors should include the specific ECs proposed or which specific ECs are not proposed when submitting an original NDA, biologics license application (BLA), or (ANDA). 
For supplements, applicants should list the ECs in the cover letter, as well as in section 3.2.R of the electronic Common Technical Document.
Applicants should propose a reporting category for each EC; categories include a PAS, changes being effected in 30 days (CBE-30), CBE-0 or annual report.
Terminology differences
The guidance also explains how to interpret ICH terminology for reporting postapproval changes in the US. For example, ICH Q12 outlines two categories for postapproval changes: prior approval and notification. While in the US regulatory system, prior approval means a PAS, moderate notification means a CBE-30 supplement, and low notification means a CBE-0 supplement or an annual report.
FDA is seeking comment on the draft guidance by 19 July 2021.
FDA ICH Q12 implementation guidance


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