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Addition of a testing lab to an existing testing site as a Post Approval Change (PAC) is considered low risk when there is no change to testing procedure, specifications, equipment, and the additional lab is already approved by health authorities for other testing activities. Such PACs should be managed in the Pharmaceutical Quality System (PQS) only rather than requiring prior approval.
Post-approval changes (PACs) are inevitable and necessary throughout the lifecycle of pharmaceutical products—to implement new knowledge, maintain a state of control, and drive continual improvement.
This One-Voice-Of-Quality (1VQ) for Post-Approval Changes (PAC) position paper is part of a series of industry case studies intended to demonstrate the standard application of the principles outlined in the publication, “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” (1).
Furthermore, this 1VQ for PAC position paper provides a practical application of the concepts described in International Council for Harmonisation (ICH) Q9, Quality Risk Management (2), ICH Q10, Pharmaceutical Quality System (3), and ICH Q12, Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management (4), to a PAC for adding a testing lab to an existing testing site.
The conclusion drawn from this case study is that this change presents a low risk and, therefore, can be downgraded from a prior-approval to a notification, and managed in the PQS with immediate implementation effect.
ICH Q10, Pharmaceutical Quality System, Annex 1 describes potential opportunities to enhance science and risk-based regulatory approaches to 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” (3). 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, or the effectiveness of the company’s 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 burdenon both industry and regulators.
This specific example of a PAC to add a testing lab to an existing testing sitehas demonstrated the application of the principles outlined in ICH Q9, Q10, and Q12 irrespective of current national or regional reporting category and concluded that it could be managed with fast-track approvals for countries that require prior approval.
This PAC example and the 1VQ for PAC Initiative is sponsored by the Chief Quality Officers from more than 20 pharmaceutical companies (5).
Regulatory authority notification or prior approval is required in several countries, with long waiting periods, up to 21 months, for addition of a testing lab, even when the testing and laboratory controls remain unchanged and there are no additional risks to product quality and/or patient safety. This PAC is an example of how applying a risk-based approach using current product and laboratory control strategies, comprehensive implementation planning, and bundling of changes can support a faster implementation of PACs.
As an example, Table I is an assessment for addition of an adventitious agent testing lab for several biologics products in scope of this change.
This position paper describes how ICH Q10 and Q12 can provide the basis for regulatory relief for the addition of a testing lab to an existing testing site when the testing and laboratory controls remain unchanged, it presents no additional risk to product quality and/or patient safety, and carries minimal regulatory risk.
Scope. The position paper applies science- and risk-based concepts from ICH Q9, Q10, and Q12 to a PAC for the addition of a testing lab to an existing testing site, so that such changes can be implemented proactively utilizing the framework of an effective PQS, and without extensive regulatory burden.
The scope of this PAC is the addition of a new testing lab to an existing site, which is already approved for specific testing activities and/or for the same testing activities for other products.
The evaluation of existing controls, such as availability of trained personnel, procedures, existing controls for the monitoring of procedure performance, equipment as well as products already tested at the site, is the basis for the determination of the risks associated with the change.
ICH Q12, Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management provides regulatory flexibility for PACs to the product, or its manufacturing process, based on latest product and process knowledge and sound scientific- and risk-based approaches (4).
Applying the principles in ICH Q9, Q10, and Q12, including risk-based implementation planning, bundling of several changes, and proactively engaging with health authorities that are known to require long prior-approval timelines, can enable this low-risk change to be managed through annual reports or notifications without prior regulatory approval and speed up implementation of the PAC.
The pharmaceutical industry’s position is that addition of a testing lab to an existing testing site as described in this paper’s Scope section should not need to be assessed as regulatory impacting, especially if this is only to update the dossier to include a new testing lab. The new lab can be added in future significant filing updates to the dossier. This will allow faster implementation of this change and optimize the testing network for timely and efficient testing and release of products.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 for the addition of a new testing laboratory to an existing approved testing site.
Figure 1 describes the risk-based approach for assessment of a PAC to add a testing lab to an existing approved testing site (1). Application of this risk-based assessment, based on current laboratory controls, should demonstrate that at a minimum, the addition of a new lab 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 addition of a new testing lab to an existing testing site.
Step 1: change proposal.When a PAC to add a testing lab to an existing testing site is proposed and entered into the change management system, 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 can be assessed by using the following risk questions: What might go wrong when adding a new lab? Why and how could this happen? This initial impact assessment should consider existing product control strategies and laboratory controls, including the review of whether the testing to be conducted in the new laboratory is comparable to the current testing for factors such as complexity, experience with same or comparable testing, or equipment.
The initial impact assessment indicated that there is no additional potential QSE risk. This is because the site is already approved for performing various testing activities for certain products with adequate laboratory controls such as trained personnel, qualified equipment, approved testing procedures, existing controls for the monitoring of procedures, performance, etc. Furthermore, the availability of fully trained personnel, established testing procedures, as well as known qualified testing equipment supports the initial assessment. There is a potential regulatory impact due to the divergent local, national, and regional requirements from regulatory authorities for the reporting category of the change. Therefore, the focus is on smart planning of change activities, early engagement, and transparent communications with the countries that require long prior-approval timelines.
Step 2: change evaluation. As the initial impact assessment indicated that there is no additional potential QSE risk, no additional risk assessments are needed.
Due to the potential regulatory impact, the focus is on smart planning of change activities, early engagement, and transparent communications with the countries that require long prior-approval timelines.
Steps 3 and 4: change implementation, review, and closure. Change implementation, review, and closure should be performed per the change management process. Outcomes of the impact and any risk assessments (if needed) should be integrated into the overall 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 cumulative effectiveness of the changes.
The following risk-control elements have been considered and documented within the PQS to ensure effective management of a PAC to add a new testing lab to an existing approved testing site:
Comprehensive implementation planning of change is documented and managed in the PQS as part of the change control process.
The Pharmaceutical Inspection Cooperation 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 1VQ for PAC position paper provides a standard and enhanced risk-based approach within the framework of an effective PQS that can be used by any company to gain regulatory flexibility, reduce the burden and global complexity, and enable faster implementation of a PAC for addition of a testing lab to an existing testing site, 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:
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 product quality or patient safety.
Thank you to the following Chief Quality Officers (CQOs) for their endorsement of this example and for their continued sponsorship of the 1VQ on PAC Initiative:
Sean McEwen (Abbvie), Jackie Elbonne (Amgen), Kunihiko Kokubo (Astellas, CQO at time of completion of example), Anthony Mire-Sluis (Astra Zeneca), 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), Flemming Dahl (Novo Nordisk, CQO at time of completion of example), Andi Goddard (Roche), Philippe Germanaud (Sanofi), Jerry Greco (Takeda), Edith Koller-Dette (Teva).
The authors wish to acknowledge members of the 1VQ for PAC team who contributed to development of this manuscript.
The authors declare no conflict of interest related to the content of the article.
Manuela Gottschall is Head of Risk and Project Management, Global Quality at Roche. Federico Colombari is Quality Risk Management Specialist, also at Roche.