Regulatory CMC: Enhancing Biologics Development

Gabriel Bohl, PharmD, FTOPRA, Director, Regulatory Affairs, ICON plc

In the rapidly evolving field of biologics, strategic chemistry, manufacturing, and controls (CMC) play a crucial role. In particular, the specialized expertise in regulatory CMC can truly move the needle to facilitate accelerated development timelines. Regulatory CMC ensures that every aspect of the product’s composition, manufacturing, and quality control aligns with stringent regulatory standards, paving the way for faster and more efficient drug development by avoiding regulatory-based delays. This expertise is especially important for the evolving fields of advanced therapeutic medicinal products (ATMPs) and cell and gene therapies (CGTs), where the unique development complexities require precise regulatory navigation. In these areas, sponsors stand to gain the most from strategic, regulatory-focused CMC support.

Understanding regulatory CMC compared to traditional CMC

While all CMC includes the comprehensive management of the technical aspects of drug development, regulatory CMC focuses on compliance with regulatory requirements. This includes ensuring that every step of the manufacturing process and quality control meets the necessary standards set by regulatory authorities in preparation for registration.

Regulatory CMC professionals not only manage the technical details but also ensure that all documentation, data, and processes align with the expectations of regulatory bodies, thereby reducing the risk of delays during the approval process. These experts also address regulatory inquiries, which are more frequent in ATMP and CGT programs, and interpret CMC guidelines to ensure clear alignment with regulatory intention.

A guiding hand for charting new courses

As regulation and experience evolve along with these therapeutic areas, regulatory CMC challenges for ATMP and CGT also include:

• Fewer regulatory CMC guidelines, ambiguity in existing guidance
• More regulatory authority queries and longer review timelines
• More CMC amendments
• Special IMP management
• Complexity of genetically modified organisms (GMOs) requirements
  Complex manufacturing and testing methods
• Dietary supplement current good manufacturing practice
  

Gap analysis and risk assessment

A thorough regulatory CMC gap analysis and risk assessment, as part of a wider regulatory strategy, are fundamental to identifying potential gaps and risks in the development process that equate to costly wrong turns or dead ends along the journey.

This analysis involves a comprehensive review of the current development status, identification of areas that require further work, and assessment of potential risks that could impact the development timeline.

The regulatory CMC team can assess each gap and allocate a risk. The risk assessment work can help anticipate a specific question from the regulatory authorities before submission and identify its associated risk (e.g., no impact, medium, low, high, very high). Based on their bank of experience and expertise, the team could likely identify from 60% to 80% of the authority’s CMC questions.

Key focus areas include:

• Manufacturing process. Ensuring that the manufacturing process is robust and meets regulatory standards.
• Control strategy. Implementing a control strategy that guarantees the quality and safety of the product.
• Product characterization. Comprehensive characterization of the product to meet regulatory requirements.
• Stability data. Providing stability data to demonstrate the product’s shelf life and potency.

By addressing these gaps and risks early, regulatory CMC experts ensure that the development process aligns with regulatory requirements, minimizing the chances of unexpected delays. However, there may be CMC changes during development. Regulatory CMC experts play a critical role in assessing the impact and substantiality of these changes and ensuring that comparability assessments are conducted appropriately. Detailed planning and early engagement with regulatory authorities are essential to avoid significant delays.

By proactively managing CMC changes, regulatory CMC experts ensure that the clinical development process remains on track and compliant with regulatory requirements.

Interconnections with other teams

The successful development of biologics relies on seamless collaboration between regulatory CMC teams and other groups, such as clinical operations, regulatory operations, and manufacturing teams. These interdependencies are crucial in meeting regulatory requirements and ensuring that all aspects of the development process are efficiently aligned. For example, clinical teams must work closely with regulatory CMC experts to ensure that the manufacturing process and product composition meet regulatory standards. This collaborative effort ensures that the development process is smooth and efficient, minimizing the risk of regulatory setbacks, e.g., on GMO submissions and approvals.

Interactions with regulatory authorities

Early interactions with regulatory bodies through their dedicated channels provide invaluable guidance for sponsors with advanced biologics in development. The European Medicines Agency can provide scientific advice with early meetings while the US offers the INTERACT meeting program and pre-investigational new drug meeting processes to provide clear communication pathways. Regulatory CMC teams can support sponsors in these meetings for global submissions to ensure clarity and alignment in mapping next steps. Similar support can be provided for the marketing stages and lifecycle management with focus on comparability protocols and
risk assessment.

Real-world benefits

Every biologics program and sponsor team is different. The overall approach to CMC strategy should be tailored to the needs of the project, the applicable regulation, and the knowledge and experience of the sponsor teams to optimize the benefits of the regulatory CMC approach.

When implemented early, this approach prepares sponsors more thoroughly for the potential setbacks and authority requirements along the development journey.

Thorough preparation and clarity through detailed gap analysis and compliance assessments improves the likelihood of authority approval, and a regulatory CMC team’s presence in meetings can bolster the case made within dossiers that may otherwise have been too weak.

Successful management of any CMC changes and comparability protocols will align new processes with regulatory standards to prevent significant delays and allow development to proceed smoothly. Smoother routes mean avoiding delays, improving timelines, and ultimately benefitting the sponsor’s return on investment.

Indispensable efficiency for biologics

The role of regulatory CMC expertise in the development of biologics, especially for complex and innovative therapies such as ATMPs and CGTs, is indispensable. Engaging regulatory CMC professionals early and maintaining close collaboration throughout the development process can produce compounding benefits, namely through ensured compliance, minimized risk, and accelerated timelines.

Establishing robust regulatory CMC practices is essential for stakeholders seeking to streamline development processes and bring innovative therapies to market efficiently.

Gabriel Bohl, PharmD, FTOPRA, Director, Regulatory Affairs, ICON plc