Alignment in post-approval changes (PAC) guidelines in emerging countries may increase timely access to vaccines: An illustrative assessment by manufacturers

Abstract

A comparison of the regulations and guidelines from 33 countries, across different regions, on the requirements and procedures for the management of chemical, manufacturing and control (CMC) changes for vaccines, also known as post- approval changes (PACs), reveals significant variability and lack of predictability of timelines for regulatory review and approval. These shortcomings imply that multiple data packages have to be prepared for submission to different authorities, generating a complex regulatory environment. Moreover, the timelines for approval by individual national regulatory authorities are variable, which results in manufacturers keeping various stocks of vaccines produced in accordance with the various approved specifications and procedures, in the different countries. This can seriously affect timely availability of vaccine in those countries. The World Health Organization (WHO) guidelines on procedures and data requirements for changes to approved vaccines provide a consensual framework for alignment, but are still underused. Reliance on both the review and approval by the regulatory authority in the country of manufacturing, or on the review performed by other national regulatory authorities, recognized by WHO as stringent, or on WHO prequalification dossier, offer alternative ways forward. These and other options to improve the management of post-approval changes during the product lifecycle of vaccines are discussed in this report, and aimed at improving guidelines alignment and regulatory convergence to advance immunization equity and coverage.

Keywords: Changes classification; Post-approval changes; Regulatory convergence; Regulatory science; Vaccine access; Variations guidelines.

Fig. 1

PACs classification of common CMC changes. The chart summarizes the proportion of most common types of chemistry, manufacturing and controls (CMC) introduced changes to vaccine products at post-approval stages. It illustrates four groups: 1. Brown: Routine changes include new standards, new working seed or cell banks, shelf life extension, manufacturing site discontinuation, compendial alignment, material replacement. 2. Blue: Continuous Improvement changes include assay modifications, new assays introduction, process improvement and revisions of specifications. 3) Yellow: Supply changes include introduction of a new site, site name change/discontinuation, capacity increase, presentation discontinuation, product discontinuation. 4) Green: Innovation changes include assay replacement, specific process improvements. Feedback from the field can drive changes like the need to discontinue a presentation, increase capacity, or specific changes linked to usage of the product. The data focuses on CMC changes only; it doesn’t contain clinical effectiveness and safety updates. The chart shows in average the percentage of changes that fall under each of these groups or categories based on 175 dossiers reviewed according to a large multinational vaccine manufacturer’s international experience, as to CMC changes only. The figure is a courtesy of GSK vaccines. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Availability of PACs guidelines in a selected group of 33 emerging countries and 3 economic blocks. The map shows the status of post-approval changes for selected 33 emerging countries and 3 economic blocks with respect to the availability of national guidelines on post-approval changes. It classifies them in 4 colour-coded groups: a) in yellow, emerging countries that have published own national guidelines which do not state to be based on any other international guideline including those recommended by WHO (Brazil, Colombia, Cuba, Ghana, India, Philippines, Singapore, South Africa, Venezuela); b) in blue, countries that rely or adopt WHO recommended guidelines or that have developed national guidelines based on those recommended by WHO (Egypt, Indonesia, Liberia, Malaysia, Mexico, Nigeria, Pakistan, Senegal, Tanzania, Thailand, The Gambia, Vietnam); c) in red, countries that do not have national guidelines but include guidance as to the management of PACs in their general registration regulations (Bolivia, Chile, Costa Rica, Ecuador, El Salvador, Guatemala, Honduras, Nicaragua, Panama, Paraguay, Peru, Uruguay); and d) in green, blocks of countries with guidelines, the difference in the tone of green indicates that the guidelines of different blocks are not necessarily similar (European Union = dark green; Eurasian Economic Union = green; Gulf Cooperation Council = light green). Singapore and The Gambia territory are so small that are not visible on a world map, therefore are represented as a circle. Countries in grey were not included in this assessment. The asterisk indicates countries that state in their guidelines, or in other published materials or documents, specific timelines to review and approve variations. The schematic representation therein does not imply the expression of any opinion whatsoever on the part of the authors concerning the legal status of any country, area or territory or of its authorities, or concerning the delimitation of its borders. The depiction and use of boundaries, geographic names and related data shown on maps and included in lists, tables, documents, and databases on this report do not imply any endorsement or acceptance. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Timelines for approval of PACs recommended in guidelines from 3 economic blocks and WHO. The figure shows the classification of changes and the timelines taken for their review and approval for three regional economic blocks and for WHO based on the respective published guidelines. The Gulf Cooperation Council (GCC), classifies variations in minor of types IA or IB and in major or type II variations. It states timelines for review of minor variations only. The Eurasian Economic Union (EEU), classifies variations also in minor of types IA or IB and in major variations of type II, and provides timelines for review for all of them. In addition to the timelines defined for review of minor variations of type IA and IB and the major variations of type II, the European Union (EU), establishes timeframe for review of extensions to the marketing authorization and for urgent safety restriction. Variations of type IA have minimal or no impact at all on the quality, safety or efficacy of the medicinal product, variations of type IB are those that do not fall under a Type IA variation nor a Type II variation nor an Extension. Variations of type II are those that may have a significant impact on the quality, safety or efficacy of a medicinal product. In addition, an extension in EU and in EEU is defined as a variation which is listed in Annex I and fulfils the conditions laid down therein , . Annex I lists three main categories, only two of which apply to human vaccines: 1. Changes to the active substance(s) 2. Changes to strength, pharmaceutical form and route of administration. An urgent safety restriction is defined as an urgent regulatory action triggered by the marketing authorisation holder or a national regulatory authority in the event of, or to prevent, a risk to human or animal health or to the environment. Both EU and EEU consider extensions and urgent safety restrictions in their variations guidelines, although only EU defines timelines for review.