US Implementation of ICH Q12

The US Food and Drug Administration (FDA) recently adopted the final ICH Q12 Guideline for post-approval change management. The guideline is intended to complement the existing ICH Q8 to Q11 Guidelines, and is composed of a Core Guideline and two Annexes.

FDA´s ICH Q12 implementation Guideline

ICH Q12 is now in the implementation phase across the ICH regions. However, especially in the EU, revision of local regulations (i.e. the EU Variations Regulation) will have to be performed to fully implement the concepts of Q12 (e.g.: the Post-Approval Change Management Protocol (PACMP) can currently be used in the US and in the EU, whereas Established Conditions (ECs) are not yet used in the EU).

In 2015 the FDA already published a draft guidance "Established Conditions: Reportable CMC Changes for Approved Drug and Biologic Products". Now, the agency issued a draft guidance to help manufacturers implement ICH Q12 by explaining how to submit ECs and prior approval supplements (PASs). The comment deadline for the draft guidance is 19 July 2021. 

ICH Q12 is consistent with FDA regulations and guidance

In contrast to the EU regulations, existing FDA guidances and regulations are fully consistent with the ICH Q12 concepts, including its Scale-Up and Post-approval Changes (SUPAC) guidance, which describe a broad set of post-approval changes and how they should be reported. The draft implementation guidance emphasizes 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 therefore require reporting if changed."

Reporting ECs

  • Applicants should include the specific ECs proposed (or state that specific ECs are not proposed) when submitting an original NDA, a 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 (eCTD).
  • Applicants should propose a specific reporting category for each EC (e.g. PAS, CBE-30, CBE-0 or annual report). Otherwise it should be stated that specific reporting categories for changes are not proposed and therefore will follow the regulations and the recommendations in guidance.
  • A complete list of proposed ECs, their reporting categories (if proposed), and the eCTD locations for their scientific justification should be included in the Product Lifecycle Management (PLCM) document in eCTD section 3.2.R.

Differences in Terminology

The guidance also explains how to interpret ICH terminology for reporting post-approval changes in the US. For example, ICH Q12 describes two categories for post-approval CMC changes: prior approval and notification (low and moderate). While in the US, prior approval means a PAS (prior approval supplement), moderate notification means a CBE-30 supplement, and low notification means a CBE-0 supplement or annual report (AR). As indicated in ICH Q12, the lowest risk changes (NR) are managed and documented within the pharmaceutical quality system (PQS) and do not need to be reported, but they may be verified during a surveillance or inspection.


In Addition to the two ICH Q12 Annexes the draft implementation guideline provides the following three Appendices:

  • A: ECs for combination products with device constituent parts (Appendix A provides guidance about the elements that are generally considered ECs for the device constituent part, e.g. manufacturer, manufacturing process parameters, material attributes, materials of construction, etc.).
  • B: Decision tree for identifying ECs and reporting categories for the device constituent part of a combination product.
  • C: PLCM Document Example (including reporting categories when making changes to the ECs).

For more information please see FDA`s draft guidance ICH Q12: Implementation Considerations for FDA-Regulated Products

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