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A Post Approval Change (PAC) in size of thermal shipping solution used for transport of product is considered a low risk provided it has been qualified and temperature monitored, and therefore can be downgraded from a prior approval to a notification to health authorities, and managed in the PQS with immediate implementation effect.
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 in thermal shipping solution size used for transport of product.
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 burden on both industry and regulators.
This specific example of a PAC in the size of a thermal shipping solution used for transport of productdemonstrates the application of the principles outlined in ICH Q9, Q10, and Q12 irrespective of current national or regional reporting category and concludes that this change could be managed as a notification after implementation instead of a prior-approval submission.
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 for PACs associated with changing the size of the thermal shipping solution for cold chain products to be shipped worldwide, even when there are no changes to the product quality and/or patient safety and the shipping and transportation controls remain the same. Adjusting the size of shipping solutions increases the efficiency and flexibility without increasing any risk to product quality and/or patient safety.
The complexity of the submission level in different countries represents the primary challenge. In many countries, this PAC is not considered regulatory relevant; reporting levels in other countries where it is considered regulatory relevant are listed in Table I.
This position paper describes how ICH Q10 and Q12 can provide the basis for regulatory relief for this specific change in the size of the thermal shipping solution for cold chain products, as it presents no additional risk to product quality and/or patient safety and minimal regulatory risk.
The position paper applies science- and risk-based concepts from ICH Q9, Q10, and Q12 such that a change in the size of the thermal shipping solution for cold chain products can be implemented globally utilizing the framework of an effective PQS, and without extensive regulatory burden. All cold chain products (+2 to +8 °C) that are shipped in small volumes to affiliates and third-party customers worldwide are in scope of this PAC.
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 and proactively engaging with health authorities that are known to require notification or prior approval can enable this low-risk change to be managed solely in the PQS, and speed up implementation of the PAC.
The pharmaceutical industry’s position is that changing the size of the thermal shipping solution for cold chain products should not need to be assessed as regulatory impacting. Adjusting the size of the thermal shipping solution to the volume of product being shipped increases the efficiency and flexibility for small-volume shipments. In addition to the higher flexibility in delivering small volumes worldwide, it reduces packaging material, transport costs, and CO2 emissions by using the right packaging solution related to the individual order volume while maintaining a state of control. Transport validation should be performed prior to implementation of the PAC.
This change presents no increased risk to product quality and/or patient safety, allowing for faster implementation of the change. In addition, it will contribute towards 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 and transport validation will be documented for a change in the size of the thermal shipping solution.
Figure 1 (1) describes the risk-based approach for assessment of a PAC to the size of the thermal shipping solution used for transport of product. Application of this risk-based assessment, based on current controls including shipping/transport validation, should demonstrate that at a minimum 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 the change.
Step 1: change proposal. When a PAC in the size of the thermal shipping solution used for transport of product is proposed and entered into the change management system, the potential quality, safety, and 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 changing from the current size to the proposed one? Why or how could this happen? This initial impact assessment should consider existing product and process knowledge (including current shipping validation) and current control strategies.
Due to the availability of data and experience, the initial impact assessment indicated that the impact on product quality is low. Transport validation activities will be completed to confirm. An assessment to determine potential regulatory impact needs to be performed.
Step 2A: change evaluation: quality risk assessment. A quality risk assessmentis performed when assessing potential risks of the change. Any potential impact (direct or indirect) on the identity, strength, quality, purity or potency of the product should be considered, based on current product/process knowledge and the control strategy. Some examples of risk questions that should be considered to assess the risks associated with a change to size in thermal shipping solution used for transport of product include:
Existing knowledge was leveraged to determine the risks and controls that need to be tested during shipping qualification. Potential impact on product quality was assessed as low due to the available data and experience.
The qualification was successful and the risk to product quality confirmed to be low. Temperature monitoring is performed according to requirements in the PQS.
Step 2B: assignment of regulatory reporting category: In an assignment of regulatory reporting category, consistent with ICH Q12 (4), it is recommended that:
Based on the outcome of the risk assessment (performed in step 2A), a change in size of the thermal shipping solution used for transport of product can be managed either as low risk or as prior-approval depending on the country. In many countries, such a change is considered as ‘not regulatory relevant’ provided there are no high risks for instance, due to inadequate risk controls. It is recommended to share the risk assessment with the regulatory agency and discuss the reporting category.
Steps 3 and 4: change implementation, review, and closure. Change implementation, review, and closure should be performed according to the change management process. Outcomes of the impact assessment and risk assessment 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.
After change closure, relevant risk assessment tools and documents should be updated post-effectiveness assessments and documented in the PQS. Product quality monitoring and periodic product quality review should be performed post-closure for the ongoing review/monitoring of the risks associated with a change in size of the thermal shipping solution used for transport of product.
The following risk control elements have been considered and documented within the PQS for ensuring effective management a change in size of the thermal shipping solution for transport of product:
The Pharmaceutical Inspection and 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 in the size of the thermal shipping solution used for transport of product, 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. The 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 for PAC Initiative:
Sean McEwen (Abbvie), Jackie Elbonne, (Amgen), Kunihiko Kokubo (Astellas, CQO at time of completion of example), 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), 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 the 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.
Marie Schommer is Quality Manager at Roche.
Federico Colombari is Quality Risk Management Specialist at Roche.