This article was originally published online on August 19, 2022.
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Change of lot or extension of reference standard shelf-life is considered low risk and should be downgraded from prior-approval to being managed in the Pharmaceutical Quality System (PQS) only based on a science and risk-based approach.
The International Council for Harmonisation’s (ICH’s) Q10, Pharmaceutical Quality System, Annex 1 describes potential opportunities to enhance science and risk-based regulatory approaches to post-approval changes (PACs) as follows: when a company can “demonstrate effective PQS and product and process understanding”, this is an opportunity to “optimize science and risk-based PAC processes to maximize benefits from innovation and continual improvement” (1). Current regulatory mechanisms and guidance for PACs do not consider the company’s latest product and process knowledge when determining the type of filing required to implement the change. Further, the application of ICH Q9, Quality Risk Management (2), or the effectiveness of the company’s pharmaceutical quality system (PQS) to manage PACs is not considered during the assessment of individual PACs, or during inspections. Demonstrating a detailed understanding, effective implementation, and compliance with ICH Q10, will allow companies to overcome barriers to continual improvement and innovation. Additionally, it will help mitigate drug shortages in the global pharmaceutical supply chain by allowing faster implementation of PACs and reduce the burden on both industry and regulators.
This article was originally published online on August 19, 2022.
This specific PAC example of changing a lot or extending the shelf-life of a Reference Standard (RS) has demonstrated the application of the principles outlined in ICH Q9, Q10, Q12 (3) irrespective of current national or regional reporting category and concluded that it could be managed in the PQS only, rather than as a prior-approval change submission when meeting pre-determined criteria.
This position paper is part of a series of industry case studies intended to demonstrate the standard application of the principles outlined in “Effective Management of Post-Approval Changes in the Pharmaceutical Quality System (PQS)—Through Enhanced Science and Risk-Based Approaches: Industry One-Voice-of-Quality (1VQ) Solutions” (4).
This PAC example and the 1VQ for PAC Initiative are sponsored by the chief quality officers from more than 20 pharmaceutical companies (5).
A RS is a material used as a quantitative or qualitative comparator in the release or stability testing of APIs, drug products (pharmaceuticals/ biologicals), or intermediate products. A RS can be a certified reference material (e.g., United States Pharmacopeia [USP] or European Pharmacopoeia [Ph.Eur.]), a commercially supplied material, or a material prepared in-house. Both chemical and biological standards (termed as primary reference standard or a working standard) can be used as RS.
Regulatory authority prior-approval is required in several countries for changes associated with introduction of a new lot of RS or with shelf-life extensions for the RS even when there are no changes to the product quality, patient safety, or drug product efficacy, or to the manufacture of the RS.
Differences in regulatory requirements between countries are observed and range from no requirement to submit the PAC to regulatory authorities, to major variation as type II in the European Union, or prior-approval passing through annual reportable, notification, and minor variations.
The use of approved qualification protocol to downgrade the level of submission is accepted by some regulatory authorities but not all.
Differences in regulatory requirements between countries is shown below in Table I.
Drug shortage situations, in particular for vaccines, caused by stock-out of a RS lot, either because it reached its expiry date, or it was fully consumed, could in many cases be avoided by extending shelf-life using sound scientific and risk-based assessment principles or introducing a new RS lot in a timely fashion. However, for countries requiring regulatory authority approval prior to implementation of such a change, the approval process usually varies between 18 to 24 months from submission at an international level, until the last national regulatory authority has approved the change. This lengthy approval timeline can lead to drug shortages. Although companies are carefully planning the supply and use of each RS lot, they are not always in full control of the rate of consumption particularly when drug product demand suddenly changes or if regulatory authorities make a sudden increase in their request for RS samples for their own testing.
This PAC example demonstrates how applying a science- and risk-based approach using laboratory control strategies including qualification protocol, comprehensive implementation planning, and bundling of changes, can support a faster implementation of this type of PAC.
This position paper describes how ICH Q9, ICH Q10, and Q12 can provide the basis for regulatory relief for the change of lot or the extension of shelf-life of RS when it presents no additional risk to product quality and/or patient safety and minimal regulatory risk.
This practical PAC example applies science- and risk-based concepts from ICH Q9, Q10, and Q12 to the change of lot or extension of the shelf-life of a RS used in a test already registered, so that such changes can be implemented timely utilizing the framework of an effective PQS and without extensive regulatory burden. The scope covers RS used in qualitative assays or quantitative assays.
Industry 1VQ for PAC position for change of lot or extension of shelf-life of reference standard. ICH Q12, Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management, provides regulatory flexibility for post-approval changes to the product or its manufacturing process based on latest product and process knowledge, sound scientific and risk-based approaches (3).
The industry 1VQ for PAC position is that the change of a lot or extension of the shelf-life of a RS can be managed in the PQS only, without prior regulatory authority approval, provided pre-registered acceptance criteria are met. It is recommended for each PAC that the company shares its testing and acceptance criteria for introducing a new lot or extending the shelf-life of a RS with regulatory authorities in the form of a qualification protocol/plan. This document would be the basis for changes of lot or extension of shelf-life of a RS without the need to submit documentation for each specific PAC.
The industry 1VQ for PAC position is that information about the lot reference number or expiry date should not be required in the marketing authorization dossiers. If, for historical reasons, the reference standard lot number or expiry date is mentioned in the dossier for those RSs, this information should not be considered as an “Established Condition” (per ICH Q12 definition) but only informative, and the reference number can be removed in the context of any future variation application impacting the concerned Common Technical Document (CTD) sections.
This will allow faster implementation of this type of change and optimize the testing network for timely and efficient testing and disposition of product. In addition, it will contribute toward meeting the ICH Q10 objectives of achieving product realization, establishing and maintaining a state of control, and continual improvement.
As part of a company’s change control process, a science- and risk-based approach with appropriate justification will be documented in the PQS for each change of lot or the extension of shelf-life of RS.
Figure 1 (4) describes the standard risk-based approach that can be used for assessment of a PAC to change a lot or to extend shelf-life of RS. Application of this risk-based assessment should demonstrate that the change does not increase the risk to product quality and/or patient safety.
The following steps are completed to assess the impact and risks associated with a change of lot or extension of shelf-life of RS as described in the scope section.
Step 1: change proposal. When a PAC to change a lot or to extend shelf-life of RS is proposed, the potential quality, safety, efficacy (QSE), and legal/regulatory impact of the change needs to be considered during the initial high-level impact assessment. This impact can be assessed by using the following risk questions: What might go wrong with the new RS or with the extended shelf-life? Why and how could this happen?
This initial impact assessment should consider an absence of:
Step 2: change evaluation. When the initial impact assessment indicates that there is no additional potential QSE risk and no legal/regulatory impact, no additional risk assessments are needed. The change is managed directly in the company’s PQS only.
Steps 3 and 4: change implementation, review, and closure. Change implementation, review, and closure should be performed according to the change management process. The outcomes of the impact and risk assessments (if needed) will be integrated into the change implementation plan. After implementation of the change, residual risks should be assessed and managed to acceptable levels prior to change closure; any unintended consequences or risks introduced as a result of the change should be evaluated, documented, and handled adequately through effectiveness verification mechanisms. In case several changes are introduced at the same time or related to each other, the company should assess the cumulative effect of the changes.
If ECs are not met (strategy and/or acceptance criteria) or if there is no EC registered, the initial impact assessment should consider a potential QSE and legal/regulatory impact for these changes as well as all the other changes related to RS not included in the scope of the document and managed through a prior-approval submission.
The following risk control elements have been considered for ensuring effective management of the change of lot or extension of shelf-life of RS within the PQS:
The completion of qualification activities and the implementation of this change will be documented and tracked within the change management PQS element.
This change should be included in the annual product quality review and reported to concerned regulatory authorities through the annual or periodic regulatory reporting mechanism as appropriate.
The Pharmaceutical Inspection and Co-operation Scheme (PIC/S) Recommendation Paper on How to Evaluate and Demonstrate the Effectiveness of a Pharmaceutical Quality System in Relation to Risk-based Change Management (6) provides a practical checklist tool that can be used by the company to evaluate the effectiveness of its risk-based change management process.
This position paper provides a standard and enhanced risk-based approach within the framework of an effective PQS that can be utilized by any company to gain regulatory flexibility, reduce the burden and global complexity, and enable faster implementation of a PAC for a new lot of RS or extension of its shelf-life, without increasing risk to the patient and/or product quality, safety, and efficacy.
The benefits of practical application of the principles of ICH Q9, Q10, and Q12 as described in this document are continual improvement with timely (weeks or months vs. years) implementation of such PACs, enhancing product availability and mitigating potential drug shortages, focusing regulatory resources on PACs that may have a potential to impact product quality as it relates to safety and efficacy, reducing the regulatory review and approval burden for medium and low risk changes, and faster implementation of new knowledge and innovative technologies (if applicable).
Many PACs require regulatory agency approval by individual countries before implementation. Because of the global regulatory complexity, individual PACs usually take years for full worldwide approval even when they reduce patient risk, improve compliance, or enhance the manufacturing process or test methods.
Senior quality leaders (chief quality officers and heads of quality) from more than 20 global pharmaceutical companies are speaking with “One-Voice-Of-Quality” (1VQ) to advocate for an effective management of specific PACs that currently are handled as a prior-approval change in some countries, but where a standard science and risk-based approach concludes that these should be downgraded to a notification or handled only in the PQS. This benefit would be a reduction of the implementation timeline from years to months with no increased risk to patient safety.
The authors would like to thank the following chief quality officers (CQOs) for their endorsement of this example and for their continued sponsorship of the 1VQ for PAC Initiative: Kunihiko Kokubo (Astellas, CQO at time of completion of example), Jackie Elbonne (Amgen), Anthony Mire-Sluis (AstraZeneca), Oliver Brehm (Bayer), Melissa Seymour (Biogen), Lothar Halmer (Boehringer Ingelheim), Kerstin Koenig (Bristol-Myers Squibb), Laura O’Brien (CSL Behring), Valerie Brown (Gilead), Paul Daly (GSK), Anil Sawant (Merck Sharp & Dohme Corp.), Dirk Bissinger (Merck Healthcare KGaA), Maria Soler (Novartis, CQO at time of completion of example), Christine Møller-Jensen (Novo Nordisk), Andi Goddard (Roche), Philippe Germanaud (Sanofi), and Scott Gunther (Catalent). The authors also wish to acknowledge Joanna Baszczuk (Global System Owner Change Control, GSK at the initiation of this document) and members of the 1VQ for PAC team who contributed to the development of this manuscript.
Marie-Claire Beckers is global subject matter expert for QC Materials and Samples Management, and Delphine Collete is global subject matter expert for QC Materials Management; both at GSK Vaccines. Julie Barthuet, is head Regulatory CMC&D Vaccines, and Thierry Gastineau is global head quality innovation, Culture & Engagement; both at Sanofi Vaccines.
Vol. 35, No. 9
When referring to this article, please cite it as M. C. Beckers et al., "Industry 1VQ Solutions: Change of Lot or Extension of Shelf-life of Reference Standard," BioPharm International 35 (9) (2022).