Implications of the Most Recent Regulatory New Guidance on CMC Drug Development: A Look Ahead Best Practices for Setting Analytical Method Specifications

In recent years, there have been significant regulatory changes and new guidance related to CMC (Chemistry, Manufacturing, and Controls) drug development. These changes and guidance have important implications for pharmaceutical companies, regulatory agencies, and patients. In this article, we will take a closer look at these changes and their potential impact on drug development.

What is CMC Drug Development?

Before we delve into the regulatory changes and new guidance, let’s briefly review what CMC drug development is. CMC is a critical aspect of drug development that focuses on the manufacturing process and quality control of a drug product. The CMC section of a regulatory submission provides detailed information on the chemical structure of the drug, its formulation, manufacturing process, and analytical methods used to ensure its purity and potency.
CMC is an integral part of drug development because it ensures that a drug is safe, effective, and of consistent quality. This is particularly important for biologics and complex drugs that are difficult to manufacture and require specialized equipment and processes.

Recent Regulatory Changes and New Guidance

It is essential to understand the differences between drug substances and drug products when setting analytical methods specifications. Here are some critical differences between drug substances and drug products when setting analytical methods specifications in CMC drug development.

• Definition

In recent years, there have been several regulatory changes and new guidance related to CMC drug development. Some of the most significant changes and guidance are:

• FDA Guidance on Comparability Protocols
  

In November 2018, the FDA issued new guidance on comparability protocols. Comparability protocols are used to demonstrate that changes in the manufacturing process or formulation of a drug product do not affect its safety, efficacy, or quality. The new guidance provides detailed information on the development and submission of comparability protocols, including the types of changes that can be covered by a protocol and the data required to support the protocol.

• FDA Guidance on Quality Agreements

In August 2016, the FDA issued new guidance on quality agreements between drug manufacturers and contract facilities. Quality agreements are written agreements that define the responsibilities of each party in ensuring the quality of a drug product. The new guidance provides detailed information on the content of quality agreements and the types of facilities that require a quality agreement.

• ICH Q12 Guideline on Lifecycle Management

In November 2019, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) issued a new guideline on lifecycle management. The guideline provides a framework for managing the lifecycle of a drug product, including changes to the manufacturing process or formulation of a drug product. The guideline emphasizes the importance of a proactive approach to managing product quality and highlights the use of risk-based approaches to evaluate the impact of changes on product quality.

Implications of the Changes and Guidance

These regulatory changes and new guidance have important implications for pharmaceutical companies, regulatory agencies, and patients. Some of the potential implications are:

• Improved Quality and Consistency of Drug Products
  

The new guidance on comparability protocols and quality agreements can help to ensure the quality and consistency of drug products. By providing detailed information on the development and submission of comparability protocols and quality agreements, the guidance can help to standardize the approach to these important aspects of drug development.

• Increased Collaboration Between
  Manufacturers and Contract Facilities
  

The new guidance on quality agreements can help to increase collaboration between drug manufacturers and contract facilities. By defining the responsibilities of each party in ensuring the quality of a drug product, quality agreements can help to ensure that the product is of consistent quality regardless of where it is manufactured.

• Greater Flexibility in Managing the Lifecycle of Drug Products
  

The new ICH Q12 guideline on lifecycle management can help to provide greater flexibility in managing the lifecycle of drug products. By emphasizing a proactive approach to managing product quality and the use of risk-based approaches to evaluate the impact of changes on product quality, the guideline can help to streamline the regulatory process and reduce the time and cost of bringing new drugs to market.

Most Recent and Potential New CMC Guidance in Draft

It is common for regulatory agencies such as the FDA to periodically release draft guidance documents for public comment before finalizing them. These draft guidance documents may provide insight into potential new guidance on CMC drug development.

It is important to note that draft guidance documents are subject to change, and their contents may not reflect the final guidance released by the regulatory agency. Nonetheless, some recent draft guidance documents related to CMC drug development include:

• FDA Draft Guidance on Gene Therapy Products

In August 2020, the FDA released a draft guidance document on the development of gene therapy products. The guidance provides recommendations on CMC considerations for gene therapy products, including viral vector production, analytical methods, and stability testing. The guidance also addresses issues related to product characterization and comparability, as well as the use of manufacturing controls to ensure product safety and consistency.

• FDA Draft Guidance on Elemental Impurities

In November 2019, the FDA released a draft guidance document on the control of elemental impurities in drug products. The guidance provides recommendations on the selection of analytical methods for detecting and quantifying elemental impurities, as well as the establishment of acceptable limits for these impurities. The guidance also addresses the use of risk assessments to determine the potential impact of elemental impurities on product quality and safety.

• ICH Q13 Guideline on Continuous Manufacturing

In November 2020, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) released a draft guideline on continuous manufacturing. The guideline provides recommendations on the development, validation, and regulatory approval of continuous manufacturing processes for drug products. The guidance also addresses issues related to product quality, process control, and change management for continuous manufacturing.

It is important for stakeholders in the pharmaceutical industry to stay up-to-date with the latest regulatory guidance and changes related to CMC drug development, as these can have important implications for the development and approval of new drugs.

Some challenges faced by pharmaceutical and emerging biotech companies in implementing new CMC Guidances

Implementing new CMC guidance can pose several challenges for pharmaceutical and emerging biotech companies. Some of the challenges include:

1. Cost of implementing changes: Implementation of new guidance can require significant investments in new equipment, processes, and personnel. This can be particularly challenging for small emerging biotech companies that may have limited resources.
2. Regulatory uncertainty: Regulatory agencies are constantly updating their guidance documents, which can lead to uncertainty about what will be required for the approval of a drug. Companies may need to invest in new processes or equipment to meet current guidance, only to find that new guidance is released that requires further changes.
3. Timelines: Developing and validating new processes can be time-consuming and may cause delays in the development timeline. In some cases, companies may need to re-do experiments or conduct additional testing to meet new guidance, which can also cause delays.
4. Technical expertise: Implementing new guidance may require technical expertise that is not readily available within the company. Companies may need to hire new personnel or engage consultants to help implement new guidance.
5. Supply chain issues: Changes in manufacturing processes or equipment can impact the supply chain for a drug. Companies may need to work with their suppliers to ensure they can provide materials that meet the new guidance.
6. Patents: Changes to the manufacturing process or equipment can impact the validity of existing patents or result in the need for new patents. Companies may need to conduct a patent analysis to ensure they have the appropriate intellectual property protection.

Conclusion

In recent years, there have been significant regulatory changes and new guidance related to CMC drug development. These changes and guidance have important implications for pharmaceutical companies, regulatory agencies, and patients. The new guidance on comparability protocols, quality agreements, and lifecycle management can help to ensure the quality and consistency of drug products, increase collaboration between drug manufacturers and contract facilities, and provide greater flexibility in managing the lifecycle of drug products. Some recent draft guidance documents related to CMC drug development include the FDA’s draft guidance on gene therapy products and elemental impurities, as well as the ICH Q13 guideline on continuous manufacturing. It is important for stakeholders in the pharmaceutical industry to stay up-to-date with the latest regulatory guidance and changes related to CMC drug development.In summary, implementing new CMC guidance can be a challenging process for pharmaceutical and emerging biotech companies. It requires careful planning, investment, and technical expertise to ensure that the drug development process remains on track while meeting the regulatory requirements.