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Post-approval changes (PACs) to the control and manufacturing processes of medicines and vaccines are routinely undertaken and critical to enable both innovation and secure sustained supply. In a world of global supply chains, the existence of divergent national PAC requirements (with additional countries introducing new requirements with potential differences) and other factors including document preparation and response timelines, can lead to long delays in approval (of up to 3-5 years) increasing the risk of disruption and shortages.We undertook an Industry survey in 2023 to assess implementation of ICH Q12, PAC procedures (change categorisation and review timelines) and use of reliance mechanisms across different countries (9 selected ICH Members and 19 Observers). Although this survey revealed limited implementation of Q12 in ICH Member countries, when comparing the data collected with those of a previous survey performed in 2020, we observed a broader adoption of risk-based approaches to variation categorisation (in all countries). This, however, was not reflected in improved timelines for approval.With regards to ICH Q12 adoption, the uptake of Post-Approval Change Management Protocols (PACMPs) was unchanged (with only one country reporting in-use) and implementation gaps were evident for Established Conditions (EC) and the Product Life Cycle Management document (PLCM). The survey found greater awareness of ICH Q12 and its tools compared to 2020, potentially illustrating the positive impact of training efforts. This illustrates the challenges being faced to broaden its implementation and use globally.In the same Industry survey, we also assessed PAC processes across different international countries. Long unpredictable timelines were the major concern across the countries surveyed together with limited capacity of the regulators. Four different CMC changes were selected and categorized by the respondents according to current knowledge of national classifications and timelines in the selected countries and compared with a reference classification and timeline from the European Medicines Agency and the World Health Organisation. This highlighted the lack of harmonisation of many countries with EU/WHO requirements, especially within the ICH Observer group.Last, this survey showed that some use of unilateral forms of reliance to Reference Authorities for PACs is starting. This is a mechanism all countries can employ, regardless of convergence of requirements and expertise, to enhance capacity building and reduce duplication of reviews, streamline variations approval, whilst accelerating patient access to innovation and securing supply.

RESUMEN

ICH Q12 asserts that science- and risk-based approaches are applicable to stability studies supporting Chemistry, Manufacturing and Controls (CMC) post-approval changes (PAC) to enable more timely implementation; however, no guidance or specific examples are provided to demonstrate how prior knowledge of the product can inform the risk assessment for the proposed change(s). Ten diverse case studies are presented in this manuscript to demonstrate how science- and risk-based stability strategies were used to support drug substance and product CMC PAC and lifecycle management activities. The accumulated stability knowledge held by original manufacturers of marketed products is substantial, and different elements of this knowledge base were used to assess the risks and impact of the proposed changes for confident change management. This paper provides ways to leverage science- and risk-based stability strategies as part of the post-approval change-management risk-mitigation strategy, which may enable a reduced stability data commitment and/or a reduced reporting category for change implementation.

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RESUMEN

Post-approval changes (PACs) to the registered information of authorised medicinal products are introduced routinely worldwide to enhance the robustness and efficiency of the manufacturing process, ensure timely supply in case of increased demand, improve quality control techniques, respond to changes in regulatory requirements and upgrade to state-of-the-art facilities. These are critical to prevent supply disruption and continuously improve existing medicines and vaccines. Due to the complexity of current PAC systems across markets, a change can take 3 to 5 years to approval globally (Hoath et al in BioProcess Int, 2016) thus hindering innovation and increasing the risk of shortages. The key messages are as follows: 1. Industry believes that global regulatory convergence of post-approval changes to Marketing Authorisations (MAs) using science- and risk-based approaches will enable a more efficient management of quality and supply improvements and will facilitate patients' access to innovative medicines and vaccines of the highest quality. 2. National Regulatory Authorities (NRAs) should establish national or regional guidelines in line with international standards (regarding a risk-based classification of changes and standardisation of requirements) (Guidelines on procedures and data requirements for changes to approved biotherapeutic products, in WHO Technical Report Series, 2018, Guidelines on procedures and data requirements for changes to approved vaccines, in WHO Technical Report Series, 2015), have clear procedural guidance including timelines and implement reliance pathways to accelerate the approval of changes. This paper briefly outlines the challenges for PACs and provides solutions for a more flexible and aligned global system.

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The adoption of Quality by Design (QbD) and Analytical Method Lifecycle Management (AMLM) concepts to ensure the quality of pharmaceutical products has been applied and proposed over the last few years. These concepts are based on knowledge gained from the application of scientific and quality risk management approaches, throughout method lifecycle to assure continuous improvement and high reliability of analytical results. The overall AMLM starts with the definition of the method's intended use through the Analytical Target Profile definition, including three stages: (1) Method Design, taking advantage of the well-known concept of QbD; (2) Method Performance Qualification; (3) Continued Method Performance Verification. This is intended to holistically align method variability with product requirements, increasing confidence in the data generated, a regulatory requirement that the pharmaceutical industry must follow. This approach views all method-related activities, such as development, validation, transfer, and routine use as a continuum and interrelated process, where knowledge and risk management are the key enablers. An increase in method robustness, cost reduction, and decreased risk failures are some of the intrinsic benefits from this lifecycle management. This approach is clearly acknowledged both by regulators and industry. The roadmap of the regulatory and industry events that mark the evolution of these concepts helps to capture the current and future expectation of the pharmaceutical framework.

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RESUMEN

Post-approval changes are inevitable and necessary throughout the life of a drug product-to implement new knowledge, maintain a state of control, and drive continual improvement. Many post-approval changes require regulatory agency approval by individual countries before implementation. Because of the global regulatory complexity, individual post-approval changes usually take years for full worldwide approval even when they reduce patient risk, improve compliance, or enhance the manufacturing process or test methods. This global complexity slows down continual improvement and innovation and can cause drug shortages and current good manufacturing practices compliance issues. Manufacturers that market products globally experience the greatest challenge and risks in their daily operations because of this post-approval change complexity. A global problem needs a global solution. This paper has been sponsored and endorsed by senior quality leaders (Chief Quality Officers/Heads of Quality) from >20 global pharmaceutical companies who have collaborated to speak with "One-Voice-Of-Quality" (1VQ). The paper provides two specific solutions that lay the foundation for an aligned and standardized industry position on the topic of effective management of post-approval changes in the pharmaceutical quality system (PQS). This document represents the 1VQ standard approach for the steps necessary to establish and demonstrate an effective quality system to fully leverage a risk-based approach to post-approval changes as laid out by ICH Q10 Annex 1. Implementation of the solutions presented in this paper can help achieve a transformational shift with faster implementation of new knowledge, continual improvement, and innovation through post-approval changes. The Chief Quality Officers/Heads of Quality are inviting other companies to join the 1VQ (contact either Emma Ramnarine or Anders Vinther) and other stakeholders to join the dialog.

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