Approaches to Design an Efficient, Predictable Global Post-approval Change Management System that Facilitates Continual Improvement and Drug Product Availability.

The complexity and inter-connectedness of operating in a global world for drug product supply has become an undeniable reality, further underscored by the COVID-19 pandemic. For Post-Approval Changes (PACs) that are an inevitable part of a product's commercial life, the impact of the growing global regulatory complexity and related drug shortages has brought the Global PAC Management System to an inflection point in particular for companies that have their products marketed in many countries.This paper illustrates through data analyzed for the first time from 145,000 + PACs for 156 countries, collected by 18 global pharma companies over a 3-year period (2019-2021), how severe the problem of global regulatory complexity is. Only PACs requiring national regulatory agency (NRA) approval prior to implementation were included in the data set. 1 of the 156 country NRAs approved all submitted PACs within a period of 6 months. The 6-month timeline was chosen because it is the recommended review timeline for major changes in the WHO guidance for vaccines and biotherapeutic products. 10 out of the 156 (6%) countries had no more than 10% of the PACs reviewed and approved in > 6 months. In 33 (22%) countries more than half of the PACs took > 6 months for approval. It is rare that the same PAC is approved globally within 6 months as individual NRAs take from a few months to years (in some cases > 5 years) for their review.The global PAC management complexity has steadily grown over the past 20 years. Attempts thus far to solve this problem have not made any meaningful difference. Senior leaders and decision-makers across the interdependent components of the complex Global PAC Management System (industry and regulators) must come together and collaboratively manage the problem holistically with the objective of ensuring global drug product availability instead of continuing with distinct stakeholder or country-focused solutions, which can tend to worsen the problem.In this paper, the Chief Quality Officers (CQOs) from 18 of the largest innovator pharma companies (see Acknowledgements) are speaking with One-Voice-of-Quality for PACs (1VQ for PACs Initiative). They are recommending a set of 8 approaches to activate a holistic transformation of the Global PAC Management System. This article presents their view on the problem of global regulatory complexity for managing PACs, it's impact on continual improvement and the risk to drug product supply, as well as approaches that can help alleviate the problem.

Industry One-Voice-of-Quality Solutions Management Review of Post-Approval Changes Guide.

Post-approval changes (PACs) are inevitable and necessary throughout the life of a drug product. Because many PACs require prior approval by individual regulatory agencies each having their own reporting requirements and approval timelines, this results in companies having to manage several versions of a manufacturing process at the same time. The global regulatory complexity increases risk of drug shortages. Chief quality officers and heads of quality from more than 20 global pharmaceutical companies have come together to speak with One-Voice-of-Quality (1VQ) and develop solutions to this problem by developing a science and risk-based approach to manage more PACs in the pharmaceutical quality system (PQS) rather than submitting these as prior approval supplements. Pharmaceutical companies already conduct management review (MR) according to the International Conference on Harmonization (ICH) Q10. This One-Voice-Of-Quality paper is a practical guide on how companies can expand the MR to also evaluate and demonstrate the effectiveness of their PQS in specifically managing PACs to achieve regulatory flexibility as stated in ICH Q10, Annex 1. Examples of PQS key performance indicators (KPIs) that may be used to assess, plan, implement, and monitor PACs are described. The intent is to provide assurance through MR that PACs can be managed effectively in the PQS, thereby resulting in a reduced need for regulatory prior approval of certain low risk changes that enhance product availability, reduce the risk of drug shortages, and/or facilitate timely innovation and continual improvement in the pharmaceutical industry. This document is endorsed by 1VQ chief quality officers and heads of quality.

Industry One-Voice-of-Quality (1VQ) Solutions: Effective Management of Post-Approval Changes in the Pharmaceutical Quality System (PQS)-through Enhanced Science and Risk-Based Approaches.

Post-approval changes are inevitable and necessary throughout the life of a drug product-to implement new knowledge, maintain a state of control, and drive continual improvement. Many post-approval changes require regulatory agency approval by individual countries before implementation. Because of the global regulatory complexity, individual post-approval changes usually take years for full worldwide approval even when they reduce patient risk, improve compliance, or enhance the manufacturing process or test methods. This global complexity slows down continual improvement and innovation and can cause drug shortages and current good manufacturing practices compliance issues. Manufacturers that market products globally experience the greatest challenge and risks in their daily operations because of this post-approval change complexity. A global problem needs a global solution. This paper has been sponsored and endorsed by senior quality leaders (Chief Quality Officers/Heads of Quality) from >20 global pharmaceutical companies who have collaborated to speak with "One-Voice-Of-Quality" (1VQ). The paper provides two specific solutions that lay the foundation for an aligned and standardized industry position on the topic of effective management of post-approval changes in the pharmaceutical quality system (PQS). This document represents the 1VQ standard approach for the steps necessary to establish and demonstrate an effective quality system to fully leverage a risk-based approach to post-approval changes as laid out by ICH Q10 Annex 1. Implementation of the solutions presented in this paper can help achieve a transformational shift with faster implementation of new knowledge, continual improvement, and innovation through post-approval changes. The Chief Quality Officers/Heads of Quality are inviting other companies to join the 1VQ (contact either Emma Ramnarine or Anders Vinther) and other stakeholders to join the dialog.

Managing Excipient Supplier Name and Address Changes in the Pharmaceutical Quality System.

It is important to identify, assess, and address current barriers to implementation of post-approval changes that are intended to ensure continued (uninterrupted) operations and drive innovation and continual improvement in a maximally efficient, agile, and flexible pharmaceutical manufacturing sector. Leveraging the International Conference for Harmonisation Quality Guideline Q10 provides regulatory relief when it comes to addressing changes related to excipients, specifically excipient supplier's name and address changes, which will ensure a sustainable, reliable global supply and the availability of high quality product to patients through the entire commercial lifecycle of a product without extensive regulatory oversight.

Solving the Global Continual Improvement and Innovation Challenge: How an Effective Pharmaceutical Quality System Can Transform Post-Approval Change Management.

Post-approval changes are inevitable and necessary throughout the life of a drug product-to implement new knowledge, maintain a state of control, and drive continual improvement. Many of these post-approval changes require regulatory agency approval by individual countries before implementation. Because of the global regulatory complexity, individual post-approval changes usually take years for full worldwide approval even when they reduce patient risk, improve compliance, or enhance the manufacturing process or test methods. This global complexity slows down continual improvement and innovation and can cause drug shortages and current good manufacturing practices compliance issues. Manufacturers that market products globally experience the greatest challenge and risks in their daily operations because of this post-approval change complexity. A global problem needs a global solution. Quality leaders speaking globally with "One Voice of Quality" are essential for solving this difficult problem. This concept paper has been developed under the sponsorship of a group of Chief Quality Officers (Heads of Quality) from >25 global pharmaceutical companies and has been endorsed by the Parenteral Drug Association. The intent of this concept paper is to develop and implement aligned, standard solutions within the industry, leveraging the core foundation of the pharmaceutical quality system, such that a transformational shift can be achieved with faster implementation of new knowledge, continual improvement, and innovation through post-approval changes.LAY ABSTRACT: Pharmaceutical manufacturers must make changes to their products and manufacturing processes over time as they incorporate new technology and new information. Because drug products are highly regulated in every country, the manufacturer must often contact national drug regulators before making these changes, even if the manufacturer is confident, based on testing and process controls, that the change will not have a negative impact on product quality or patient safety. For a product that is globally marketed, the manufacturer may have to contact dozens of regulators before making a change. This paper suggests that industry work together to identify ways to demonstrate to regulators that product and process knowledge as well as pharmaceutical quality systems are strong enough that the manufacturers should be allowed to manage some post-approval changes themselves.

Demonstrating Pharmaceutical Quality System Effectiveness and Driving Continual Improvement: Evidence-Based Risk Reduction.

Product knowledge grows and evolves during the life of a product. In order to maintain a state of control and deliver product with consistent quality throughout its commercial life, continuous improvement and product lifecycle management become essential. The practical link between product and process knowledge, risk-based control strategies, and continual improvement and innovation can be made stronger through evidence-based risk reduction. This paper introduces the concept of evidence-based risk reduction within the continual improvement framework. It presents how regulatory relief and flexibility in post-approval change management and overall product lifecycle management can likely only be achieved via (1) effective application of science and risk-based concepts and (2) demonstrated effectiveness of the pharmaceutical quality system in assuring a state of control.

2015/2016 Quality Risk Management Benchmarking Survey.

This paper investigates the concept of quality risk management (QRM) maturity as it applies to the pharmaceutical and biopharmaceutical industries, using the results and analysis from a QRM benchmarking survey conducted in 2015 and 2016. QRM maturity can be defined as the effectiveness and efficiency of a quality risk management program, moving beyond "check-the-box" compliance with guidelines such as ICH Q9 Quality Risk Management, to explore the value QRM brings to business and quality operations. While significant progress has been made towards full adoption of QRM principles and practices across industry, the full benefits of QRM have not yet been fully realized. The results of the QRM Benchmarking Survey indicate that the pharmaceutical and biopharmaceutical industries are approximately halfway along the journey towards full QRM maturity.LAY ABSTRACT: The management of risks associated with medicinal product quality and patient safety are an important focus for the pharmaceutical and biopharmaceutical industries. These risks are identified, analyzed, and controlled through a defined process called quality risk management (QRM), which seeks to protect the patient from potential quality-related risks. This paper summarizes the outcomes of a comprehensive survey of industry practitioners performed in 2015 and 2016 that aimed to benchmark the level of maturity with regard to the application of QRM. The survey results and subsequent analysis revealed that the pharmaceutical and biopharmaceutical industries have made significant progress in the management of quality risks over the last ten years, and they are roughly halfway towards reaching full maturity of QRM.