Overview

Managing CMC changes after authorization or approval of a vaccine or therapeutic can be challenging, sometimes taking 4 years or more to gain global approval. A more efficient pathway and process are needed for use in a Public Health Emergency.

Marketing Authorization Application Pathway and Process

Many of the recommendations made for original Marketing Authorization Applications also apply to post approval changes (PACs), as detailed in Collaboration and Convergence: Recommendations for Future Public Health Emergencies and Streamlined Global Regulatory Submission Process.

Post Approval Change Management Protocols (PACMPs)

Post Approval Change Management Protocols (PACMPs) may also be used to accelerate authorization and implementation of changes.

A PACMP is a regulatory tool that allows expedited implementation of quality changes during a product’s life cycle. It is restricted to quality changes which do not necessitate complementary nonclinical and/or clinical studies to be conducted when demonstrating comparability, e.g. addition of a new manufacturing site, implementation of a new working cell bank, etc. A PACMP consists of a comparability plan alongside a risk assessment submitted to NRAs well ahead of a quality change taking place.

The Applicant formally informs NRAs on a specific foreseen CMC change as well as how it plans to demonstrate that such a change will have no negative impact on the product’s quality, safety or efficacy. The PACMP can be either included in an initial application or as a standalone post-approval submission. In both cases, NRA approval of the PACMP is required. Subsequently, at the time of the change implementation, a submission with lower categorization and faster procedural timelines will be used for NRAs to assess the change and verify if the comparability strategy applied corresponds with the previously approved plan. If the obtained comparability results are in accordance with PACMP pre-defined expectations, NRAs will approve the change and permit implementation swiftly. A PACMP therefore aims at de-risking while expediting implementation of a quality change.

PACMPs are contemplated in ICH Q12 guideline [1], as well as in WHO guidelines TRS 993 Annex 4 [2], and TRS 1011 Annex 3 [3]. From the time ICH Q12 was released for adoption in November 2019 until now, more and more NRAs have implemented this guideline into their regulatory systems, alternatively some parts thereof, as it is the case of the European Union [4].

Use of PACMPs during COVID-19

The use of PACMPs increased significantly during the COVID-19 public health emergency, and especially during the first wave of vaccine authorizations targeting the initial strain, when applicants were either including management protocols in their initial applications or submitting them post-approval. In both cases, accelerated implementation of quality changes was proven successful, e.g. changes to scale up of DS or DP manufacturing processes; introduction of new production sites serving to higher supply; or changes to analytical procedures.

PACMPs have been demonstrated as an efficient way to introduce quality changes in an expedited manner while adopting a risk-based approach. Prior to use of a PACMP, the user is kindly advised to verify whether a PACMP regulatory mechanism exists in the regulatory jurisdiction where a product is being authorized/licensed.