ICH Q12 – Where is it at and where do we want it to go?

By Tessa Fiorini-Cohen



Change is constant within the pharmaceutical industry, and requires significant resources to handle. These are further compounded by regional discrepancies and inefficiencies in post-approval change management. It is with this in mind that Q12 is being drafted – a new ICH guideline that promises to streamline post-approval CMC changes (Chemistry, Manufacturing and Controls).

The guideline has not yet been issued, and pharma anticipation is growing.  Pharmaceutical companies are not the only ones that stand to gain; health authorities and ultimately patients will also reap benefits, due to improved medicinal product supply. So what stage is Q12 currently at, what do we know so far, and where do we want it to go?

To date, Q12 has only been published as a Final Concept Paper, although a draft technical document has been circulated among stakeholders.  Four teams are writing the guideline, each focusing on one section, namely: Regulatory Commitments, Knowledge Management, Change Management and Post-Approval Change Management. In the meantime, three regional working groups are tackling issues which are unique to North America, Europe and Asia respectively.  The guideline will apply to chemical, biotechnological and biological products. However, the jury is still out on whether generics will fall under its scope, as this decision has been left up to each regulatory authority. The step four version should be out in June 2017.

Q12 is ultimately about moving from a ‘tell and do’ mind-set, to ‘do and tell’ and ‘understand and do’ mentalities. The guideline is associated with a culture shift, considering lifecycle variations as a proactive evolution of the product, rather than a weakness. Q12 proposes to streamline CMC changes through four main paths.

  • Use of established conditions (specified critical parameters) to reduce the need for approvals for certain changes. Quality Risk Management, Knowledge Management and Quality by Design (Qbd) will all come into play here. Applicants will need to understand their products, know which parameters are critical to product quality, and state these within their original application. The level of notification necessary will then be proportional to the criticality of the change.
  • New dossiers will include a lifecycle strategy subsection, derived from the data submitted within the application. This will enhance transparency and predictability of changes, and promote continuous improvement.
  • The required level of detail within the dossier will be delineated. Reduction of detail will minimise the potential of change from the dossier, and hence reporting requirements. Such changes will instead be controlled within the company’s Quality Management System.
  • Major changes will be managed through Post Approval Change Management Protocols (PACMPs), which will speed up approvals and further reduce required submissions. A PACMP details specific changes that a Marketing Authorisation Holder plans to implement throughout the product’s lifecycle.

Use of PACMPs will involve two steps. The first is submission of the protocol describing the proposed change, rationale, risk management, associated tests and acceptance criteria. This protocol will be approved by regulatory authorities prior to its implementation. The second step is submission of the data generated following the approved protocol. In certain cases, such as non-critical or repetitive changes, this second step may be skipped, and controlled instead through the company’s Quality Management System. Two types of PACMPs have been proposed: protocols documenting specific changes that can be reused (such as a change in analytical method or manufacturing site), as well as expanded protocols potentially covering multiple products or sites.

Tied to PACMPs will be post approval change management plans, which are not submitted to authorities but reviewed upon inspection. However, it has been pointed out by Bryan Silvey from Shire that PACMPs will only be helpful if health authorities review the protocols within 6 months and associated generated data within 30 days.

A high bar of expectation for Q12 has been set, with Anders Vinther from Sanofi Pasteur suggesting a 50% reduction in necessary health authority submissions and, similarly to Silvey, requesting that approval timelines take a maximum of six months. Regardless of the guideline’s final shape, it will have great impact on the pharmaceutical industry, so Real Generics will keep its followers apprised of any developments related to this change in managing change.


Photograph: Change direction by Matt J Newman, CC BY-SA 2.0

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