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CMC for Phase I

Updated

Chemistry, Manufacturing, and Controls (CMC) information for Phase I supports the quality and safety of an investigational drug during early clinical development. The amount and level of detail expected should be appropriate to the stage of development, the characteristics of the investigational product and the potential risks to clinical trial participants.

For first-in-human Phase I studies, the objective is not necessarily to establish the complete commercial CMC package. Instead, sufficient information should be available to support the identity, quality, strength or potency, purity and appropriate control of the investigational product for its proposed clinical use.

Drug Substance

CMC information for the drug substance should provide sufficient understanding of the material used to manufacture the investigational product.

Information may include:

  • Nomenclature, structure and relevant physical, chemical or biological characteristics
  • Manufacturer information
  • A description of the general manufacturing method
  • Relevant starting materials, reagents, solvents or other materials
  • Appropriate tests and acceptance criteria for identity, quality, purity and strength or potency
  • Available batch and stability information

The extent of characterization and process-control information should be appropriate to the development stage and product-specific risks.

Drug Product

Information about the investigational drug product should describe the dosage form and how it is manufactured and controlled for clinical use.

Relevant information may include:

  • Dosage form, presentation and strength
  • Composition of the drug product
  • Manufacturing process
  • Appropriate in-process controls
  • Tests and acceptance criteria for release and stability
  • Container-closure or packaging information
  • Available stability information

Particular attention should be given to attributes that could affect participant safety or the reliable administration of the investigational product.

Analytical Procedures

Appropriate analytical procedures are needed to evaluate important quality attributes of the drug substance and drug product.

During early development, analytical procedures should be suitable for their intended purpose and capable of supporting appropriate control of the investigational material.

For an original first-in-human Phase I IND, full analytical method validation data are generally not expected at the time of initial submission. Analytical methods and their validation typically evolve as product and process knowledge increases during development.

Stability Information

Stability information supports the proposed storage conditions and the period during which the investigational product will be used in the clinical study.

For first-in-human Phase I development, stability expectations are phase-appropriate. The available data should provide adequate assurance that the investigational product will maintain acceptable quality during its intended use.

The stability programme can be expanded as clinical development progresses and additional manufacturing experience becomes available.

Manufacturing and Quality Controls in Phase I

Manufacturing controls should be appropriate to the investigational product and its stage of development.

The emphasis during Phase I is on controls necessary to support product quality and participant safety. Some process controls that are not directly related to safety may be developed or refined later as manufacturing knowledge increases.

Manufacturing practices should also comply with the applicable requirements for investigational products.

Phase-Appropriate CMC for Phase I

CMC requirements increase as a drug progresses through clinical development. Information that may not be necessary for an initial first-in-human Phase I IND can become important during later clinical phases and before marketing approval.

Examples include more extensive process understanding, analytical method validation, tighter specifications, expanded stability data and greater demonstration of manufacturing consistency.

This phase-appropriate approach allows early clinical development to proceed with sufficient controls for participant safety while enabling the CMC package to mature alongside increasing product and process knowledge.

As development progresses, the required level of manufacturing and control information increases. See CMC for Phase II and III for the later-stage requirements.

Regulatory Considerations

CMC expectations depend on factors such as product type, manufacturing process, route of administration, clinical population and potential safety risks.

Sponsors should therefore consider the requirements of the relevant regulatory authority and obtain regulatory advice when product-specific issues require clarification.

For U.S. INDs, FDA provides specific information concerning CMC expectations and regulatory flexibilities for first-in-human Phase I development.

For U.S. INDs, the FDA guidance on CMC information for Phase I investigations provides current information on phase-appropriate CMC expectations and regulatory flexibilities for first-in-human development.

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