Regulatory CMC Considerations – Developing Modified Versions of Immediate Release Oral Solid Dosage Forms

STEP 1- Identify critical strategic decisions and essential information that a development team will need to be successful.

When developing modified-release versions of immediate-release oral solid dosage forms, critical strategic decisions that a development team will need to consider include the following:

• Determining the appropriate modified release mechanism: There are various modified release mechanisms available, such as sustained release, controlled release, and extended release. The development team must choose the one that best suits the product and its intended use.
• Establishing the appropriate release profile: The development team will need to determine the optimal release profile for the product based on its intended use and the chosen modified release mechanism.
• Understanding the regulatory requirements: The development team must be familiar with the regulatory requirements for modified release products, as they can vary between countries and regions.
• CMC Considerations: The development team will need to consider the formulation, manufacturing process, and analytical testing methodologies used for the modified release product, as these will need to be demonstrated to be suitable for the intended use and regulatory requirements.
• Biopharmaceutical classification system (BCS) and Biowaiver: The development team will need to consider the BCS classification of the active pharmaceutical ingredient (API) and the applicability of biowaiver, as it will have a significant impact on the regulatory pathway.
• Clinical development plan: Clinical development plan with appropriate study designs will be needed to demonstrate the safety and efficacy of the modified release product.
• Intellectual property protection: The development team will need to consider the intellectual property protection for the modified release product, including patents and trademarks.

STEP 2 – Understand the benefits of appropriate API characterization and pre-formulation work with Regulatory and CMC Considerations that a development team will need to be successful.

API characterization and pre-formulation work can provide significant benefits regarding regulatory and CMC considerations when developing modified-release versions of immediate-release oral solid dosage forms. These benefits include:

• Improved understanding of API properties: API characterization provides essential information on the physical and chemical properties of the API, such as solubility, stability, and polymorphism, which can help guide the development of the modified release product.
• Identification of potential formulation challenges: Pre-formulation work can help identify potential formulation challenges, such as API-excipient interactions, that may need to be addressed during development.
• Support for regulatory submissions: API characterization and pre-formulation data can support regulatory submissions, such as demonstrating that the modified release product is suitable for its intended use and that the API is of suitable quality.
• Improved process understanding: API characterization and formulation work can help the development team better understand the API and the formulation process, leading to more efficient and effective development.
• Biopharmaceutical classification system (BCS) and Biowaiver: API characterization and pre-formulation work can help determine the BCS classification of the API and the applicability of biowaiver, which can have a significant impact on the regulatory pathway.
• Better control of the manufacturing process: API characterization and pre-formulation work can help the development team better control the manufacturing process, leading to a more consistent and reliable product.
• Better prediction of the product’s performance in the human body: API characterization and pre-formulation work can help the development team better predict the product’s performance in the human body, leading to more accurate and efficient clinical development.

STEP 3 – Recognize the key CMC development data that health authorities expect to see to evaluate submissions properly.

Health authorities expect to see critical CMC development data to evaluate submissions properly when developing modified-release versions of immediate-release oral solid dosage forms. These data include:

• Formulation development data: This includes information on the composition of the modified release product, including the API, excipients, and other components, as well as details on how the formulation was developed and optimized.
• Manufacturing process data: This includes information on how the modified release product is manufactured, including details on the equipment, facilities, and procedures used, as well as any process controls in place to ensure product quality.
• Analytical method development and validation: This includes information on the analytical methods used to test the modified release product, including methods for the API and any excipients, and validation data demonstrating the accuracy, precision, and specificity of the methods.
• Stability data: This includes data on the long-term stability of the modified release product, including information on storage conditions, testing frequency, and any changes in product quality over time.
• In-vitro release studies: This includes data from in-vitro release studies designed to simulate the product’s performance in the human body and demonstrate that the modified release product meets the intended release profile.
• Biopharmaceutical classification system (BCS) and Biowaiver: If the development team plans to seek biowaiver, the CMC data will need to prove that the product is BCS class I or III and meets the criteria of the FDA or EMA guidance.
• Clinical development plan and data: This includes the clinical development plan and data from studies that demonstrate the safety and efficacy of the modified release product in human subjects.
• Comparative data: This includes data from comparative studies that demonstrate the superiority of the modified release product over the immediate release product, if applicable.

All of these data will be needed to demonstrate that the modified release product is suitable for its intended use and that it is of suitable quality for regulatory approval.