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

Action Proposed

Determine an aligned and standardized industry approach to overcome barriers to proactive continual improvement and innovation and to help reduce drug shortages in the global environment.

1. Define and demonstrate effective management of post-approval changes (PACs) in the pharmaceutical quality system (PQS) (during review and inspections) so that more changes can be managed in the PQS and be reported via notification pathways (e.g., annual report or changes-being-effected) instead of via prior approvals provided that they do not negatively impact patient risk and drug product efficacy and quality.

2. Develop a standard risk-based assessment of PACs that incorporates latest product and process knowledge.

3. Pilot the proposed solutions for PACs with a limited number of companies. Seek input from regulatory agencies on outcomes.

Statement of the Perceived Problem

Today many PACs to regulatory filings require prior approval by the regulatory authority of every country individually—this can be >100 countries for globally marketed products. The global approvals for a change often take years because of the varying requirements and timelines across different regulatory authorities. This severely hinders and disincentivizes continual improvement, innovation, and timely implementation of knowledge gained during commercial operations, even when the PAC can result in patient risk reduction, process and technical improvements, or closure of compliance gaps. PACs of the following are required: facilities age, routine operations require updates to maintain current good manufacturing practices (cGMP) compliance and state of control, regulatory requirements change, technology evolves, suppliers change, findings from regulatory agencies during inspections may require changes, and the company generates new knowledge about products and processes. Some PACs are generated by the company, but some are not.

The global PAC complexity leads to challenging product life-cycle management and product supply logistics, including opportunities for serious errors because of multiple versions of a process/product at the same time. Companies that maintain the status quo may realize an immediate or short-term financial advantage over those that continually improve and innovate because the cumulative global cost of change can appear to outweigh the long-term benefit. Unfortunately, a decision to not implement continual improvements can eventually result in drug shortages (and impact public health) because of aged facilities, equipment, and processes, outdated product control systems, or changes in regulatory requirements (1, 2).

Drug shortages are a global problem for most product types (including small molecules, biologics, vaccines, and combination products) and are not localized to certain countries or regions; therefore, local solutions will not sustainably resolve this global problem.

The concept defined in ICH Q10 Annex 1—which discusses the potential for risk-based regulatory oversight for companies that demonstrate an effective PQS—has not been implemented, although this would reduce the PAC complexity. Additionally, no regulatory guidance is available on what the measures for an effective PQS are and how to demonstrate effectiveness of a PQS such that more PACs can be managed only within the PQS without prior approval. Such PACs would be reported to regulatory agencies via notification pathways such as an annual report or a changes-being-effected supplement. Current regulatory mechanisms and guidance for PACs also do not fully take into account the company’s latest knowledge about the product and process when dictating the type of filing required to implement the change. Further, the effectiveness of the company’s PQS to manage PACs is not considered during the assessment of individual PACs nor during inspections. Currently, companies already share significant information with individual regulatory agencies. Examples of this include annual product reports, product issues reporting, post-approval change management protocols (PACMPs) in certain countries, and information obtained through regulatory inspections. There is an opportunity for regulatory agencies to use this information further when assessing the effectiveness of a company’s PQS.

Although the industry is globalizing, the regulatory authorities are becoming increasingly regionalized (3), and the global regulatory burden of PACs continues to increase (1). The full impact of this global complexity is experienced by only pharma companies, as they provide their drug products globally, whereas national or regional agencies only see a part of the problem related to their country or region. ICH Q12 is working toward addressing this topic to a certain extent by introducing common terminology. However, it does not address mutual reliance between agencies for PAC assessments. It also only covers ICH countries.

All of this makes continual improvement, innovation, and drug shortages a difficult problem that is highly resistant to solutions. The current situation is contrary to what every stakeholder wants (an uninterrupted supply of safe quality medicines to patients, and an industry that continually improves and innovates its operations) despite the best intentions and the highest commitment to provide a sustainable supply of safe, efficacious, high-quality drugs to patients.

Strategic Importance of the Topic

The objective of this concept paper is to enable implementation of ICH Q10 Annex 1 in the industry to facilitate continual improvement and innovation without extensive regulatory oversight and with no added risk to patient safety or drug product efficacy and quality. An additional expected outcome of this concept paper is to encourage a dialog among regulators to provide guidance on measures of an effective PQS and how to demonstrate its effectiveness during PAC reviews and inspections—thus creating a global framework for managing PACs.

Risk-based approaches that consider prior product and process knowledge within the frame of an effective PQS are not widely understood and used today when assessing individual PACs. Any PAC that can be demonstrated, via a robust risk assessment and appropriate data, to reduce risk to patients should have a pathway available that allows immediate implementation within the structure of an effective PQS without requiring prior approval. The same should apply when PACs are intended to avoid drug shortages as long as this does not increase risks to patients or to product quality.

The complexity of the PAC global regulatory framework causes a significant time delay between new product and process knowledge is gained and when it can be implemented into daily operations. Maintaining the status quo rather than continually improving and innovating operations can be financially advantageous for companies in the short run but causes a lack of state of control and drug shortages in the long run. Today there is no regulatory incentive as defined in ICH Q10 Annex 1 to proactively continually improve and innovate product and processes—even when it reduces risk to patients. PAC categorization is generally the same irrespective of level of product and process knowledge and whether the company demonstrates an effective PQS for managing PACs.

Although regulators, industry, and patients alike strive for an uninterrupted supply of high-quality products, and all favor innovation and continual improvement, local solutions or solutions independently designed by one stakeholder population will not resolve this global problem. Therefore, the industry and regulators must co-develop solutions and implement relevant aspects across their respective domains.

The aspiration is increased innovation and faster implementation of new knowledge through a transformational shift in PAC implementation timelines with at least 50% reduction in prior approval PACs.

Issues to Be Resolved

ICH Q9 and ICH Q10 have not been utilized as intended for PACs to obtain the regulatory flexibility described in ICH Q10 Annex 1 and the upcoming ICH Q12 (4, 5, 6). This has contributed to the following issues:

1. No guidance or practical definition on how to demonstrate effective management of PACs in the PQS: ICH Q10 and soon ICH Q12 provide a framework and directional guidance on how a PQS should support product realization, maintain a state of control, and drive continual improvement. However, these guidelines do not articulate what the elements of and the measures/attributes for an effective PQS are and how to demonstrate effective management of PACs in the PQS such that more PACs can be managed only within the PQS without requiring prior approval. Lack of utilization of current product and process knowledge further limits the potential to downgrade a change and implement it faster. This concept paper intends to align the industry on how a company can demonstrate effective management of PACs in the PQS. The outcomes will be discussed with regulators globally to enable development of guidance.

2. Delayed implementation of knowledge and lack of risk-based assessment of PACs: During the commercial life of a product, new knowledge is continuously acquired through routine operations. Continual improvement of routine operation is desired and expected to maintain cGMP compliance and state of control. However, it takes years to implement even simple changes in daily operations because of the complexity and high cost of global PAC management processes. This concept paper will develop a standard, structured, and data-driven risk-based approach and tool(s) for companies to determine if a change can be effectively managed only in the PQS or if it needs to be submitted as a prior approval. Examples demonstrating the approach will be developed.

3. High PAC management burden for both industry and regulators: The current global regulatory framework provides no incentive for companies to proactively continually improve or innovate within the framework of an effective PQS. This leads to companies maintaining the status quo even when it could adversely impact product quality, product availability, and patient safety. The regulatory approval effort is not always proportional to the value gained from regulatory review. Risk tolerance needs to increase to ensure that PACs that result in improved patient safety are not delayed because of lengthy global regulatory approvals. There is an opportunity for agencies to leverage each other for scientific and technical assessment of PACs. When companies demonstrate an effective PQS including a sound risk-based approach for managing PACs based on latest product and process knowledge, they should be able to gain trust from the regulators. Regulators in turn can reduce their level of control and oversight and allow the company to manage more changes in their PQS or as notifications versus prior approvals.

These issues apply across all product types (small molecules, biologics, vaccines, combination products).

Type of Working Group Recommended

This work will be performed under the sponsorship of the Chief Quality Officers (CQOs) from individual pharma companies who have decided to speak with One-Voice-Of-Quality. The CQOs will allocate time and resources to this topic including their Head of Quality Management System (QMS) and other senior leaders as relevant.

The outcomes will be discussed with regulators globally to enable development of guidance on elements and measures/attributes of an effective PQS and how to demonstrate it for PACs during review and inspections.

Deliverables

1. Demonstrate how PACs can be effectively managed in the PQS so that more changes can be managed in the PQS or via notification pathways instead of by prior approvals.

   • Identify PQS elements specifically for PAC management within only the company’s PQS that must be described further.

   • Develop an approach for how these PQS elements can be assessed to demonstrate effective management of PACs in the PQS (leverage PDA Quality Culture/Metrics, St. Gallen Quality Metrics Research as appropriate).

   • Obtain input from the Pharmaceutical Inspection Convention (PIC), Pharmaceutical Inspection Cooperation Scheme (PIC Scheme), World Health Organization (WHO), Food and Drug Administration (FDA), and other regulatory agencies, and notified bodies on the approach.

   • Establish the standard industry position on how to demonstrate effective management of PACs in the PQS.

2. Create a standard risk-based assessment of PACs that incorporates latest product and process knowledge.

   • Develop a standard risk-based approach for PACs including templates and tool(s).

   • Obtain input from PIC/S (QRM Expert Circle) on the risk-based approach and the integration of risk management into the change control system.

   • Develop specific PAC examples with application of the standard risk-based approach.

   • Obtain input from regulatory agency reviewers/assessors [e.g., Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), European Union (EU), National Competent Authorities (NCAs), Health Canada, Pharmaceuticals and Medical Devices Agency (PMDA), World Health Organization (WHO), Swissmedic] on the risk-based approach.

3. Survey to collect industry examples of changes that can be managed in the PQS only.

4. Pilot the effective PQS and standard risk-based approach at a limited number of companies.

5. Make updates to the risk-based approach and PQS elements based on input from regulators and industry.

6. Obtain endorsement of the standard PQS effectiveness and risk-based approach from senior leadership of regulatory health authorities (including FDA, Health Canada, EMA [NCAs], WHO) by June 2020.

A detailed workplan with timelines has been developed.