ICMRA gives early readout on collaborative assessment, hybrid inspection pilots

Background on the ICMRA Pharmaceutical Knowledge Management Project

• Changes to how a pharmaceutical product is made throughout its lifecycle will often trigger multi-national submissions. These changes could include updates to the manufacturing process, changes in suppliers and other changes to implement technological innovations and expanding knowledge. However, these changes will most likely need approval from regulatory agencies in countries where the product is being developed or marketed. Hence, developers will have to make multiple submissions to regulatory agencies before changes can be made. Submissions to multiple authorities with potentially diverging regulatory requirements and approval timeframes can lead to inefficiencies and potential delays in implementing the change. These changes are tracked by companies through their pharmaceutical quality systems (PQS).
• A guideline from the International Council for Harmonisation (ICH), ICHQ10, highlights knowledge management as a way to enable compliance with PQS requirements. The guideline recommends that “product and process knowledge should be managed from development through the commercial life of the product and including product discontinuation.” It goes on to explain that “knowledge management is a systematic approach to acquiring, analyzing, storing, and disseminating information related to products, manufacturing processes, and components.” Sources of knowledge include continual improvement and change management activities.
• The ICH has issued several other guidelines supporting quality management, but the International Coalition of Medicines Regulatory Authorities (ICMRA), a group of regulators that cooperate to provide strategic direction in medicines regulation, highlighted three (in addition to ICH Q10) that are of particular interest. These include ICH Q8, Pharmaceutical Development, which provides the contents of the pharmaceutical development section in Module 3 (Quality information) as used in the common technical document (CTD); ICH Q9 on Quality Risk Management, which provides tools to manage risks to medicine quality and can be applied to development, manufacturing, distribution and inspections; and ICH Q12 on product lifecycle management, which provides a framework to manage post-approval changes to chemistry, manufacturing and controls more efficiently and predictably.
• In a 2022 reflection paper, the ICMRA noted that the “current operating environment,” which requires prior approval from multiple regulators, “presents regulatory complexity that can significantly constrain manufacturer agility.” This hinders manufacturers in responding to supply chain issues, scaling up manufacturing to address urgent needs, or even continuously supplying an authorized medicine in all marketed regions. Not only does it affect the manufacturers, but regulatory agencies also need greater agility to keep pace with the dynamic operating environment.
• The ICMRA’s 2022 reflection paperF proposed that information- and process-sharing through a pharmaceutical quality knowledge management system (PQ KMS) could increase regulatory efficiency. According to ICMRA, “ the envisaged PQ KMS aims at strengthening international collaboration” which could enable reliance for inspections and lead to convergence of the regulatory quality requirements of chemistry, manufacturing and control (CMC). Together, these aligned processes can increase efficiency in implementing changes and responding to manufacturing challenges such as supply chain issues through reduced duplication of effort and, potentially, more efficient evaluations by regulators. Earlier discussions at a July 2021 workshop highlighted the need for flexibility and a more harmonized regulatory approach to change management, which led to the development of two pilot programs. [See AgencyIQ’s analysis of the reflection paper.]
• In June 2022, the ICMRA initiated two pilots to test how information-sharing and collaboration impact regulatory efficiency and the burden on the pharmaceutical industry. The first pilot focused on collaborative assessment of CMC for post-approval change applications. The second pilot implemented hybrid facility inspections for pre-approval/licensing inspections. In 2023, the coalition released updated expectations for applicants wanting to participate the collaborative hybrid inspection pilot (CHIP). [See AgencyIQ’s analysis of the pilots and update on hybrid inspection pilot.]
• Last week, the ICMRA announced that in May, the PQKM project “reached a major milestone”: the completion of both pilots. The coalition provided a brief update on both pilots.

Pilot one on collaborative CMC assessments for post-approval changes led to alignment of assessment outcomes

• The collaborative CMC assessment pilot aimed to increase regulatory capacity during the Covid-19 pandemic. It therefore focused on products addressing the public health emergency, with a potential expansion to other products as the regulators gained experience. The pilot aimed to identify best practices for assessments, identify areas of misalignment across regions, and enable collaboration and dialogue among regulators and pharmaceutical companies interested in filing global submissions.
• During the pilot, multiple regulators collaboratively assessed the selected CMC submissions supporting post-approval changes. Applicants submitted a single dossier for the proposed CMC post-approval changes that was assessed by three to five participating regulators who met to align their approaches as best possible. Additionally, the regulators aimed to align requests for information, with the understanding that some region-specific difference might occur.
• The aim was to share any responses from applicants among participating regulators and then provide applicants with a common response to streamline communication, and achieve faster implementation of changes given the near-simultaneous approval across regions. The pilot was to assess a maximum of three applications over the course of one year.
• The ICMRA ultimately accepted five applications due to the “ early successes and high level of interest” in the pilot, according to a June 12, 2024 update. The coalition notes that the applications covered a “varied range of products” as well as proposed post-authorization changes. These focused on high priority medicines with public health in mind. The last assessment was concluded in May 2024.
• The result? Regulators were able to issue approvals within days of each other across the involved regions. Regulators “ made every effort to ensure alignment and harmonization” to achieve the near-simultaneous approvals within the normal assessment timelines for the participating regions. The ICMRA also noted that industry participants didn’t experience an increased regulatory burden.

Pilot two using collaborative hybrid inspections resulted included three inspections

• This pilot aimed to streamline on-site inspections that are of interest to regulators from multiple regions. However, this pilot was limited to pre-approval/licensing inspection. The inspections would be conducted as a hybrid using a combination of virtual platforms and on-site inspectorates. The aim was to identify best virtual and information technology platforms and best practices for the preparation and conduct of those inspections, and to establish a framework supporting inspections across multiple time zones. Like the assessment pilot, this pilot also aimed to identify any misalignment between regulatory expectations and to provide a platform for collaboration and dialogue between regulators and the industry.
• The hybrid approach combined on-site inspections by the local inspectorate with remote participation of other regulators with common interest in the inspected facilities and products. The on-site inspectorate would be the one single voice for all regulators participating remotely and conduct the inspection according to local requirements. The goal was to make “ one regulatory decision,” though each regulatory agency had region-specific regulatory requirements, which could result in divergent inspection findings. Hybrid inspections differ from joint inspections where all regulators are present on-site, since they eliminate the need for all authorities to travel to the site. This pilot was also set to run one year, with regulatory agencies conducting three to five inspections.
• Hybrid inspections address problems posed by travel restrictions during an emergency like the Covid-19 pandemic, when international travel was significantly restricted, leaving inspectorates unable to inspect international facilities. The hybrid approach also spared the limited inspector travel budgets of most agencies since only the inspectorate closest to the facility needs to be present on site, while the remaining inspectors participate remotely.
• Applicants also benefit from reduced administrative burden. Additionally, pilot participants would ordinarily receive just one request for information, comments and questions, if regulators participating in the inspection agree. Multiple regulators could potentially reach an agreement of compliance at the same time, accelerating access to medicines. However, industry noted concerns about how these inspections would be implemented in practice and what would happen if the regulators weren’t able to align the focus of the particular inspection and had different priorities, questions and observations.
• The inspectors participating in the hybrid inspections generally aligned the focus area for each of the three inspections completed. Narrowing down the focus of the inspection allowed a streamlined inspection process, minimizing burden on the inspected facilities.

What’s next

• According to the report, both pilots actually increased resource requirements for regulators, but the pilot implementation group is still gathering feedback. Some of the additional burden might be attributed to the learning curve of learning to collaborate and develop protocols for hybrid inspections, so time and experience – and updated technology platforms – might erase the initial cost in time and effort. The group is still exploring the “ best path forward” and implementing lessons learned. Feedback thus far is overall positive, according to ICMRA, but the pilots also highlighted some challenges, especially with practical aspects of information sharing.
• Technological requirements pose challenges for international collaboration between regulators. Each regulator uses a unique, proprietqry platform for regulatory submission assessments, requiring cumbersome information exchange. Ideally, a unified and commonly accessible platform would allow industry and regulators to submit and retrieve the required documents. During a workshop discussing the pilots, regulators identified such a shared platform with secure access as an area for improvement. An example of such a platform would be the Clinical Trials Information System, which allows all E.U. national competent authorities to access industry-submitted clinical trial applications, which are a national competency.
• A cloud-based platform could provide a solution, allowing regulators and industry to access computing resources as needed without having to manage the information technology platform locally. Servers could be stored at a trusted and appropriately secured site. One example of such as system was recently test-driven by Roche: the Accumulus cloud platform. In February 2024, Roche became the first company to submit a post-approval change to 48 global regulators at the same time. Potential concerns for cloud technology include how they would accommodate data protection requirements by global regulators. The Good Data Protection Regulation, for example, restricts the movement of data to countries outside the E.U. However, these issues would need to be addressed once a technological solution has been identified, since the challenges will likely be specific to the particular specifications. [See AgencyIQ’s analysis of the use of Accumulus.]
• Faster access to medicines is a clear benefit of increased harmonization and alignment of regulatory assessments through collaboration. Industry noted during the workshop that their motivation to participate in the joint assessment pilot stemmed from factors that included the joint review and consolidated list of questions. This in turn allows for faster implementation of any necessary post-approval changes which ensures medicine supply, with the eventual promise of reducing regulatory burden and avoiding duplication of effort for both industry and regulators. Future tweaking of procedures can address the challenges that come with working across time zones, translations and technology.
• Achieving harmonization and convergence of regulatory requirements has recently become a universally sought-after goal, allowing medicine candidates to fulfill requirements in more jurisdictions simultaneously without the need of additional studies. Other groups working on international harmonization include the International Council for Harmonization (ICH), the International Medical Device Regulators Forum (IMDRF), the Pharmaceutical Inspection Co-operation Scheme (PIC/S), and International Pharmaceutical Regulators Programme (IPRP). Project Orbis and the Access Consortium are two of the newer initiatives to share work and have mutual reliance in assessments, to reduce the workload on the individual regulators – and sponsors. The Access Consortium implemented mutual reliance on good manufacturing practices in addition to work-sharing on regulatory assessments in 2022. [See AgencyIQ’s analysis of the reliance program.]
• The pilot implementation group plans to release summary reports on the experience with both pilots later in 2024. It seems from the ICMRA statement that for the time being, both pilots are closed and won’t accept any new applications. The absence of any future outlook for these pilot programs raises many questions: Will there be a new phase of these pilots or an implementation of these two processes in general, or will the efforts die with the pilots? If these collaborative processes are implemented, how do regulators plan to overcome challenges identified (e.g., technology, time zones, translations)? How many will be admitted for the next phase? Since the program arose to address challenges during the Covid-19 pandemic and aimed to enable access to critical medicines addressing the public health challenge, will the program be widened to include a wider range of products? Inspections were limited to pre-approval/licensing; would those be extended to post-approval inspections? Would acceptance criteria significantly change from those during the pilot? How soon after the summary reports are published would the next phase start? The summary reports will hopefully address some or all of these questions, and provide a detailed overview of the learnings from the pilot and translation into the next phase.

To contact the author of this item, please email Kirsten Messmer ( kmessmer@agencyiq.com).
To contact the editor of this item, please email Kari Oakes ( koakes@agencyiq.com).

Key Documents and Dates

• ICMRA press release – Update on the status of the ICMRA PQKM pilot programmes, June 2024, published June 12, 2024
• Reflection paper – A regulatory pharmaceutical quality knowledge management system (PQ KMS) to enhance the ability of quality medicines, published July 21, 2022