Implementation of an effective pharmaceutical quality system (PQS) is essential for a company to achieve product realization, establish and maintain a state of control, and facilitate continual improvement (1). According to ICH Quality Guideline Q10: Pharmaceutical Quality System, companies that apply the principles and concepts of ICH Q8: Pharmaceutical Development, ICH Q9: Quality Risk Management or ICH Q10 should be eligible for reduced regulatory oversight once it has been demonstrated that a PQS is in place. In this regard, ICH Q10 makes specific reference to changes made during the commercial lifecycle of a product (i.e., post-approval changes, or PACs) (1). With sufficient product and process understanding and the use of quality risk management (QRM), certain PACs should be covered in the PQS (or only as a regulatory notification) with little to no prior approval by regulators. This should be the case as long as a comprehensive risk assessment concludes that a proposed change introduces no additional risk to patient safety, product quality or product efficacy. This includes downgrading the reporting category for established conditions (ECs) on a case-by-case basis as supported by the risk assessment.
Elements for Effective PAC Management
At the time of first license or approval, manufacturing process knowledge is limited. The regulatory framework should facilitate timely improvements to manufacturing processes and controls as commercial production experience and knowledge grows. Regulators should accept that the PQS is capable of an appropriate degree of self-governance in ensuring product quality and safety. Building an effective PQS is the responsibility of the company—one that extends beyond having a license or a GMP certificate to manufacture medicines. Essential elements of a PQS for effective PAC management include the following:
- Management Responsibilities. Senior management is ultimately responsible for ensuring that an effective PQS is in place for managing PACs. This includes defining and communicating roles and responsibilities, providing adequate resources and ensuring a comprehensive and objective science- and risk-based approach to decision-making. Internal audit and self-audit mechanisms should enable proactive assessment and mitigation of compliance risks in the PQS, including any issues that might be introduced by a PAC. Management is also responsible for developing the desired quality culture at all levels throughout the company.
- Process Performance and Product Quality Monitoring (PPPQM). Systems should be in place for the early detection of process drifts and unexpected variability and trends, as well as for the effective handling of adverse events, complaints and defects. Systems should identify PACs needed to ensure an ongoing state of control and product availability that drives continuous improvement.
- Change Management. An effective change management system for internal as well as outsourced operations is characterized by a data-driven, science- and risk-based approach to the assessment and management of changes that takes into account the potential impact on all relevant aspects of the product and process, established conditions and any unintended consequences. It ensures improved product quality, process performance, a state of control and/or product availability, and it lowers residual risks. Changes should be managed in keeping with the product lifecycle management strategy (with plans and protocols).
- Corrective and Preventive Actions (CAPA). An effective CAPA program monitors and manages unintended risks and consequences of PACs for internal and outsourced operations, and should enable identification of root cause(s) so that appropriate actions can be taken to correct problems and prevent their recurrence. The program should also monitor and verify the effectiveness of any CAPAs associated with PAC initiatives.
- Knowledge Management (PQS Enabler). An effective knowledge management system leverages existing and newly achieved/newly identified product and process knowledge, including innovation and technology advancements, as well as knowledge gained from PPPQM, deviations, trends, complaints, recalls, annual product review/product quality review and management reviews. Effective knowledge management ensures that the right knowledge is used by the right people at the right time, allowing for effective decision-making.
- Quality Risk Management (PQS Enabler). An effective QRM system provides a risk-based decision-making framework and ensures that systematic and proactive risk-based and data-driven decision-making is used for all PACs. Such a system should facilitate faster implementation of changes that reduce the risk of quality failures and manufacturing problems and improve process capability. It should also be used to determine the appropriate level of regulatory oversight, i.e., distinguish changes that require regulatory reporting or notification from changes (ECs as well as non-ECs) that can be managed solely within the PQS.
Demonstrating PQS Effectiveness
The effectiveness of a PQS can be demonstrated by management review activities that monitor the performance of the key elements outlined above. Appropriate performance indicators, based on the use of data and trends, should be in place for each of those elements; they should be meaningful, simple, and not subject to interpretation (2).
Management review activities should also include a review of all PAC initiatives, their intended objectives, their implementation, and a verification of their expected outcomes. Where the objectives of PAC initiatives are not achieved, formal CAPA action plans should be developed and implemented, and lessons learned should be captured and incorporated into future PAC activities.
For sustained effectiveness, the PQS needs to be embedded within the company’s quality culture—a set of shared values, beliefs and behaviors that support product quality- and patient-centric decision-making. Senior management should demonstrate and communicate to the entire organization their commitment to achieving and maintaining an effective PQS. It should also share a common vision, fostering transparent, open and “no-blame” communication throughout the company based on trust and investing in employee education and training to ensure a proficient and knowledgeable workforce.
- ICH Q10: Pharmaceutical Quality System, International Conference on Harmonisation, 2008
- Ramnarine, E., et al. “PDA Points to Consider: Technical Product Lifecycle Management- Pharmaceutical Quality System Effectiveness for Managing Post-Approval Changes.” PDA Journal of Pharmaceutical Science and Technology 71 (2017):252–258.