Industry 1VQ Solutions: Changes That Bring an Additional Restriction on the Product Compared to Registered Conditions

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 (2), Quality Risk Management, ICH Q10, Pharmaceutical Quality System (3), and ICH Q12, Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management (4) to PACs that bring an additional restriction on the product compared to registered conditions.

The conclusion drawn from this case study is that those changes present a very low risk, and therefore, can be downgraded from a prior-approval to a notification after implementation and managed in the PQS with immediate implementation effect.

Background and context

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 PACs that bring an additional restriction on the product compared to registered conditions,has 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 as a notification after implementation.

This PAC example and the 1VQ for PAC Initiative is sponsored by the Chief Quality Officer’s from more than 20 pharmaceutical companies (5).

Description of current state for changes that bring an additional restriction on the product compared to registered conditions

Putting additional restriction(s) on the drug product or vaccine compared to registered conditions does not affect compliance to the license as it is produced and controlled under more stringent conditions than the ones registered in the approved Marketing Authorization Application (MAA, NDA [new drug application], BLA [biologics license application], or similar, depending on country/region of approval). As a company generates new product and process knowledge during commercial manufacturing and testing, it may decide to tighten or add certain operational parameters to reduce process variation and/or tighten manufacturing and testing controls. Such continual improvement activities should be encouraged.

Specific examples of PACs that add restriction(s) on the product compared to registered conditions are:

• Tightening of acceptance criteria on manufacturing process ranges or test methods performed on the product, materials, or excipients
• Addition of a test method performed on the product, materials, or excipients as long as it is not necessitated by a change in a critical process parameter (CPP)
• Addition or tightening of a validity criterion for an analytical method
• Addition of a CPP in the master batch record of the product, without any change in the manufacturing process.

For any such change mentioned above, the company should provide rationale for the change and supporting documentation in their PQS. These changes do not have a negative impact on the critical quality attributes (CQAs) of the product, and consequently on quality and safety. However, in certain countries, these changes require prior-approval by the regulatory authority.

Table I lists countries requiring prior-approval for PACs to drug product. These additional examples of restriction(s) compared to the registered conditions according to regulations or experience, are based on Sanofi Vaccines experience.

Companies are confronted with the following dilemma: implement continual improvements with no negative impact to patients as soon as possible after gaining new knowledge vs. wait for approval by regulatory authorities requiring prior-approval even though the PAC provides more stringent conditions than those in the approved Marketing Authorization.

By definition, more stringent conditions fall within the registered parameters and thus, comply with the Marketing Authorization.

As part of the company’s change control process, a science and risk-based approach with appropriate justification and documentation must be documented in the PQS when evaluating the changes mentioned in this document.

Scope

This document applies to PACs that bring an additional restriction on the product compared to registered conditions for commercial drug substances and products (chemical and biological/biotechnological products including vaccines).The principles and quality risk management approach described in this document are intended to apply globally to all regulatory authorities.

This risk-based approach applies to PACs which fulfill the following conditions:

• The change brings an additional restriction on the product compared to registered conditions.
• The change does not have any impact on the CQAs of the product, and consequently on product quality and safety.

Industry 1VQ for PAC position for a change that brings an additional restriction on the product compared to registered conditions

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, sound scientific and risk-based approaches (4).

A PACwhich brings an additional restriction on the product compared to registered conditions with the appropriate supporting data (e.g., validation of the analytical method for an additional test, process validation for an additional monitored CPP) can be managed within the PQS, leveraging the principles outlined in ICH Q9, Q10, and Q12. This type of change may only be managed under the PQS and/or be reported to the regulatory authorities within ICH, Pharmaceutical Inspection Co-operation Scheme (PIC/S) and World Health Organization (WHO) member countries through annual reports or notification after implementation.It should not require prior-approval from the regulatory authorities. This will facilitate use of new knowledge and continual improvement efforts to increase the level of control of products in a timely fashion, including the potential to reduce process variability by implementing additional restriction on the product compared to initial registered conditions.

Standard risk-based approach

Figure 1 describes the risk-based approach for assessment of a PAC which brings an additional restriction on the product compared to registered conditions. Such PACs do not increase risks beyond current levels.

Figure 1: Risk-based Assessment of PACs and Determination of Regulatory Reporting Category

Step 1: change proposal. When a PAC that brings an additional restriction on the product compared to registered conditionsis 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 impact can be assessed by using the following risk questions: What might go wrong when changing from the current situation to the proposed one? Why or how could this happen? This initial impact assessment should consider existing product and process knowledge (including process performance and variability) and current control strategies, as follows:

• QSE impact: There is no potential QSE risk associated with a PAC that brings an additional restriction on the product compared to registered conditions given that the product is manufactured and controlled according to restricted specifications, and providing that data supporting the change are assessed and readily available.
• Legal/regulatory impact: If there is a regulatory impact per local/regional regulation, a more detailed risk assessment needs to be performed to define the reporting category of the change. In this example, some countries require prior-approval of the PAC despite there being no potential QSE risk.

Step 2: change evaluation. The initial impact assessment concluded that there is no potential QSE risk associated with this change of additional restrictions on the product compared to registered conditions. In the case, when the change was triggered by recurring events or negative trends arising during manufacture and testing, the assessment should ensure that the relevant PQS requirements have been appropriately followed for managing this change (e.g., appropriate corrective and preventive actions [CAPA], deviation management).

Therefore, no additional risk assessment is required for this low-risk PAC, and the change can be managed within the company’s PQS and implemented immediately without the need for a regulatory prior approval.

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 cumulative effect of the changes.

Demonstrating effective management of a change that brings an additional restriction on the product compared to registered conditions within the PQS

The following risk control elements have been considered for ensuring effective management of such PACs within the PQS:

• No impact on the CQAs of the product, and consequently on quality and safety
• No change to in-place analytical methods or system suitability
• No change to the manufacturing process
• Validation is adequately performed and documented.

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 or through notification after implementation.

The 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.

Conclusion

This 1VQ for PAC 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 that brings an additional restriction on the product compared to registered conditions, 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 approval burden for medium and low-risk changes
• Faster implementation of new knowledge and innovative technologies (e.g., new test).

About the 1VQ for PAC Initiative

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.

Acknowledgements

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:

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), Scott Gunther (Catalent)

The authors wish to acknowledge Mic McGoldrick (Merck & Co, Inc), Leader of IFPMA VSRWG (Vaccines Scientific and Regulatory Working Group) and members of the 1VQ for PAC team who contributed to development of this manuscript.

References

1. E. Ramnarine et. al., "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,”PDA Journal of Pharmaceutical Science and Technology, 74 (4) 456-467 (2020).
2. ICH, Q9, Quality Risk Management (ICH, 2005).
3. ICH, Q10, Pharmaceutical Quality System (ICH, 2008).
4. ICH, Q12, Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management (ICH, 2019).
5. E. Ramnarine and A. Vinther, “Solving the Global Continual Improvement and Innovation Challenge: How an Effective Pharmaceutical Quality System Can Transform Post-Approval Change Management; One-Voice-of-Quality Concept Paper,” PDA Journal of Pharmaceutical Science and Technology, 73 (5) 517-521 (2019).
6. PIC/S Recommendation on How to Evaluate and Demonstrate the Effectiveness of a Pharmaceutical Quality System in Relation to Risk-based Change Management, 2021. Available at: https://picscheme.org/docview/4294

Conflict of Interest Statement

The authors declare no conflict of interest related to the content of the article.