There is currently a lack of harmonisation in technical and regulatory considerations for pharmaceutical product lifecycle management. Implementation of post-approval changes takes time, and the post-approval change system is not harmonised globally. The Common Technical Documentation (CTD) format defines the content of a marketing authorisation application but there is no common agreement about which information in the dossier is binding and therefore requires a post-approval regulatory submission when it is changed. The purpose of the ICH Q12 guideline is to provide a framework to facilitate the management of post-approval CMC changes in a more predictable and efficient manner.
Status and key points
On 21 November 2019, the ICH Q12 Guideline on Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management and its Annexes reached Step 4 of the ICH Process for Guidelines.
The ICH Q12 has been developed to complement the existing ICH Q8 to Q11 guidelines which give guidance on drug substance and drug product development. This new guideline is not mandatory, but it provides a framework for the management of post-approval CMC changes.
Use of the tools described in the ICH Q12 guideline will enhance the transparency between the industry and the regulatory authorities. The goal is to promote innovation and continual improvement, but the adoption of this new guideline is also expected to strengthen quality assurance and reliable supply of product. The ICH Q12 guideline applies to APIs, drug products and drug/device combination products, both chemical and biological.
ICH Q12 tools:
The guideline describes a set of tools and enablers which aim to help enhance post-approval change management. The key tools are ECs, PACMP and PLCM.
Established Conditions (ECs):
ICH Q12 includes a chapter on Established Conditions (ECs), which are the necessary components that assure product quality. There are two categories of ECs in the submissions: implicit and explicit. Implicit ECs are described in regional regulations, e.g. the validation criteria for analytical procedures (ICH Q2). Explicit ECs are identified and proposed by the MAH. An example of an explicit EC would be, for instance, manufacturing process parameters.
The ECs are legally binding and require regulatory submission if they are changed post-approval. The basis for the justification of the ECs is in in-depth pharmaceutical development as well as in expertise of the manufacturing process and the analytical methods related to the product. The guideline describes how ECs could be defined as well as which information could be considered supportive (i.e. information which does not require a regulatory submission if changed). The ICH Q12 also includes a summary table which provides general guidance about the CMC elements that constitute the ECs and their location within the CTD structure.
Post-Approval Change Management Protocol (PACMP):
The PACMP describes the requirements and studies needed to implement a change during the commercial phase of a product. The PACMP describes the CMC change; how the change would be prepared and verified, including assessment of the impact of the proposed change and the suggested reporting category in line with regional regulations and guidance. The MAH submits the protocol to the authority in advance. Consequently, there is an agreement between the MAH and the regulatory authority defining the needed studies and requirements. As the justification and requirements for the change are agreed before the CMC change is submitted, the workload is lighter and the time needed for the review shorter. The PACMP may be submitted with the original MAA or as a standalone submission and can be proposed independent of any prior identification of ECs. The elements of the PACMP document are summarised in the ICH Q12.
Product Lifecycle Management (PLCM) Document:
The PLCM document is an overview that clearly describes how the company (MAH) plans to manage the post-approval changes. It summarises the ECs, presents the reporting categories for changes to the ECs, PACMPs (if used) and any post-approval CMC commitments. The PLCM document can be a part of the original MAA or it can be submitted in a variation for marketed products when defining the ECs. The PLCM document can be located in the CTD Module 3.2.R. The document should be updated throughout the product lifecycle as needed. The elements of the PLCM document are summarised in the ICH Q12 guideline.
Taking the ICH Q12 guideline tools into use can potentially reduce the number of changes that require regulatory approval as well as accelerate regulatory evaluation, implementation and global approval of a change.
The ICH Q12 Guideline and its annexes are available for download on the ICH website.
This summary was compiled by Pharmaceutical Chemical Expert Johanna Paavilainen.
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