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A Post Approval Change (PAC) to replace identity (ID) testing of incoming liquid drug substance with ID by visual inspection is considered a low risk provided questioned listed in this example have been answered favorably. In that case the PAC 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 for replacing identity (ID) testing of incoming liquid drug substance (DS) with ID by visual verification.
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 (EU Type 1A/US Annual Reportable/Canada Level III) 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 to replace ID testing of incoming liquid DS with ID visual verification demonstrates the application of the principles outlined in ICH Q9, Q10, and Q12 irrespective of current national or regional reporting category and concludes that it could be managed as a minor variation (EU Type 1A/US Annual Reportable/Canada Level III).
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 with long waiting periods is required in most countries for PACs associated with changing ID testing for incoming liquid DS, even when there are no changes to the product quality and/or patient safety, and the product and laboratory controls remain the same. This PAC is an example of aligning an ID verification strategy of incoming liquid drug substances across several manufacturing sites. Such an approach can be used, for instance, when a company wants to align, harmonize, and simplify testing procedures across their network.
The execution phase for such a PAC can be quite complex and challenging if it impacts several drug substances or drug products that are marketed worldwide. Regulatory relevance and reporting category may typically vary from product to product and country to country. Regulatory relevance ranges from prior-approval submission to annual reportable for each regulatory relevant product. Therefore, the PAC cannot be implemented for all impacted products across all countries at the same time.
The planning phase for such a PAC should include regulatory assessments and a quality risk assessment specifically for the PAC. Based on the quality risk assessment the PAC can be managed as a minor variation (for EU Type 1A/US Annual Reportable/Canada Level III) instead of a prior-approval (refer to section “Standard Risk-Based Approach”).
Due to differences in regulatory relevance of products, implementation of this type of change is performed via a transition phase. This leads to an execution phase of up to minimum 10 months, depending on when the green light is received for each specific regulatory relevant product.
Differences in regulatory relevance between countries is shown below in Table I.
This position paper describes how ICH Q10 and Q12 can provide the basis for regulatory relief for this specific change from ID testing to ID visual verification for incoming liquid DS, 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 from ID testing to ID visual verification for incoming liquid DS can be implemented proactively using the framework of an effective PQS, and without extensive regulatory burden. The following are in scope for this PAC:
Out of scope for this PAC are:
Definition and baseline criteria include:
In companies with several manufacturing sites, the implementation of PQS over time might have led to a misaligned approach on defining certain processes and procedures. Especially, when mergers or acquisitions take place, processes and procedures need to be aligned to ensure application of the same standard across the company. Having an aligned approach allows establishing and maintaining a state of control and supporting continuous improvement across the lifecycle.
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, including risk-based implementation planning, appropriate bundling of changes, and proactively engaging with health authorities that are known to require long prior-approval timelines, can enable this low-risk change to be managed through annual reports or notifications without prior regulatory approval, and speed up implementation of the PAC.
Current ID testing involves thawing of the DS prior to DP manufacture. The DS is thawed and then sampled (unless side samples are provided). Biologics DS are temperature-sensitive with limited stability in unfrozen states. Additionally, allowed number of freeze-thaw cycles are limited for product stability reasons. Testing is a holding step, as confirmed test results are the prerequisite to start with DP manufacture.
Visual ID verification is performed as verification of the documented identity as well as assessment of discrepancies during transport or interim storage. After thawing, the DS can be used immediately for production.
The visual ID verification is aligned with the quality concept to focus on ensuring adequate preventive controls such as correct delivery instead of establishing additional detection controls. A quality risk management approach is leveraged to determine the adequateness of the prevention controls to ensure the correct DS is delivered at the DP site.
The pharmaceutical industry’s position is that a change from ID testing to ID visual verification for incoming liquid DS as described in the Scope section, should not need to be assessed as a prior-approval submission. This will allow faster implementation of this change, and alignment of a company’s network.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 will be documented for this PAC.
Figure 1 (1) describes the risk-based approach for assessment of a PAC to replace ID testing of incoming liquid DS with ID visual verification. Application of this risk-based assessment, based on current product control strategy, 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 to replace ID testing of incoming liquid DS with ID visual verification 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 is the potential impact on QSE for implementing this change? What is the potential risk on QSE during the process of 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.
The problem statement highlighted that:
The initial impact assessment indicated a potential QSE risk and a potential legal/regulatory impact. Therefore, a more detailed risk assessment was performed to define the reporting category of the change.
Step 2A: change evaluation—quality risk assessment. The initial impact assessment concluded that there might be a potential impact associated with the change, or the potential impact is unclear, therefore, a quality risk assessment should be performed for the PAC. As the risk assessment covers development, commercial manufacturing, quality control (QC) testing and release, subject matter experts (SMEs) from each of these areas should be involved. 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 potential risks associated with a change to replace ID testing of incoming liquid DS with ID visual verification include
An end-to-end assessment should be conducted starting with the bulk filtration/filling step into the primary container at the DS site up to the in-bound check of the material identity at the DP manufacturing site. The Table II provides a possible risk assessment template for a change to replace ID testing of incoming liquid DS with ID visual verification. Other risk assessment tools may be used as appropriate.
A potential hazard considered in this risk assessment example is ‘wrong (mixed up) DS is used at a DP manufacturing site’. Possible failures leading to the hazard and relevant controls are assessed to determine the overall risk level.
Some examples of failures are:
To manage the risk of this hazard the already established prevention (P) and corresponding detection (D) controls for each process step were considered. The set of controls implemented need to be able to securely prevent the use of a mixed up (wrong) DS for a DP manufacture. Additional controls should be identified as needed, as shown in the example. The risk assessment should be completed for all applicable failures.
Upon completion of the risk assessment, it should be determined if sufficient controls are in place to deem the change as low risk and if the residual potential risk (in this example of contamination and mix up) is acceptable.
Step 2A: change evaluation—Assignment of Regulatory Reporting Category:Consistent with ICH Q12 (6), it is recommended that:
Based on the outcome of the risk assessment (performed in step 2A), a change to replace ID testing of starting material/DS with ID visual verification can be managed as a minor variation (Type 1A), provided there are no high risks for instance, due to inadequate risk controls. Where several sufficient prevention and detection controls are already in place and additional controls, implementation plans, and procedures for these controls were defined to control the identified risk (e.g., mix up), the level of risk can be determined to be low. It can therefore be managed as a notification with immediate effect for implementation through the company’s PQS. It is recommended to share the risk assessment and risk controls with regulatory agencies and discuss a downgrade from a prior-approval to a notification 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 and based on the regulatory assessment outcome. Activities that can be bundled should be considered to increase overall speed of the PAC. 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 to replace ID testing of incoming liquid DS with ID visual verification.
The following risk control elements have been considered and documented within the PQS for ensuring effective management of a change to replace ID testing of incoming liquid DS with ID visual verification:
Comprehensive implementation planning of change is documented and managed in the PQS as part of the change control process.
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 (7) 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 utilized by any company to gain regulatory flexibility, reduce the burden and global complexity, and enable faster implementation of a PAC to replace ID testing of incoming liquid DS with ID visual verification, 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. This 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 development of this manuscript.
The authors declare no conflict of interest related to the content of the article.