CMC for Phase II and III

Chemistry, Manufacturing, and Controls (CMC) information for Phase II and III supports the continued quality and safety of an investigational drug as clinical development expands. Compared with Phase I, the CMC package generally becomes more detailed as product knowledge increases, manufacturing processes mature and larger numbers of participants are exposed to the investigational product.

The amount and depth of information should remain appropriate to the phase of development, proposed clinical studies and product-specific safety considerations.

For the earlier stage of development, see CMC for Phase I.

Progressive CMC for Phase II and III

CMC development is a progressive process. Information submitted during early clinical development is expanded and refined as the investigational programme advances.

During Phase II and particularly Phase III, greater attention is generally given to manufacturing consistency, analytical procedures, specifications, stability, process understanding and control of materials.

Changes introduced during development should be appropriately evaluated and documented.

Drug Substance

Information concerning the drug substance becomes more comprehensive as development progresses.

Relevant information may include:

• Physical, chemical or biological characteristics
• Manufacturing process and controls
• Starting materials, reagents, solvents and other relevant materials
• Impurity profile and controls
• Specifications and analytical procedures
• Batch analysis information
• Stability data and proposed storage conditions

Specifications and controls may continue to evolve as additional manufacturing and stability experience is obtained.

Drug Product

The CMC package should provide increasingly detailed information concerning the composition, manufacture and control of the investigational drug product.

Information may include:

• Dosage form and composition
• Manufacturing process
• In-process controls
• Drug-product specifications
• Analytical procedures
• Batch analysis data
• Container-closure system
• Stability information
• Storage and handling conditions

Changes in formulation, manufacturing process, manufacturing scale or clinical presentation should be evaluated for their potential impact on product quality and the clinical programme.

Analytical Procedures and Validation

Analytical procedures should become increasingly well characterised as development progresses.

The extent of analytical method validation increases as methods mature and as the programme moves toward late-stage clinical development and eventual marketing submission.

Methods should be suitable for evaluating the identity, strength or potency, quality and purity of the drug substance and drug product and for monitoring relevant impurities and degradation products.

Specifications and Acceptance Criteria

Specifications establish tests, analytical procedures and acceptance criteria used to evaluate the quality of the drug substance and drug product.

During Phase II and III, specifications are progressively refined using accumulated manufacturing, analytical, stability and clinical-development knowledge.

Later-stage specifications should increasingly reflect an understanding of the attributes necessary to ensure consistent product quality.

Stability Programme

The stability programme expands as development progresses.

Additional stability data support appropriate storage conditions, retest periods or shelf life and continued use of clinical materials. Stability studies should consider relevant product characteristics, container-closure systems and intended storage conditions.

By late-stage development, the stability programme should increasingly support the conditions proposed for the eventual marketing application.

Manufacturing Process and Scale-Up

Clinical development commonly involves changes in manufacturing scale, equipment, facilities or processes.

As production progresses from smaller development batches toward larger-scale manufacturing, sponsors should evaluate whether changes could affect the quality or performance of the investigational product.

Process understanding and manufacturing controls should become increasingly robust as development approaches commercialisation.

Comparability During Development

Changes to the formulation, manufacturing process, manufacturing site, analytical procedures or other CMC elements may occur during Phase II and III.

When changes are introduced, appropriate data should demonstrate that material used in subsequent clinical studies remains suitable for its intended use and that changes do not introduce unacceptable risks to participants or undermine interpretation of the clinical-development programme.

The extent of comparability assessment depends on the nature and potential impact of the change.

CMC Information During the IND Lifecycle

CMC information is updated throughout the IND lifecycle as new information becomes available.

Safety-related CMC information or significant changes may require timely submission to FDA through the appropriate regulatory mechanism. Other supporting or corroborating information may be provided through applicable IND reporting processes.

Sponsors should maintain an accurate regulatory history of manufacturing and control information as the development programme evolves.

CMC Development from Phase III to Marketing Application

Phase III CMC development increasingly prepares the product and manufacturing process for an eventual marketing application.

By this stage, greater emphasis is placed on establishing appropriate specifications, validated analytical procedures, manufacturing consistency, process controls, stability information and an adequate understanding of the drug substance and drug product.

The transition toward a marketing application therefore involves progressively reducing uncertainty and demonstrating that the product can be manufactured with appropriate and reproducible quality.

Regulatory Considerations

FDA’s expectations for CMC information during Phase II and III depend on the phase of investigation, the proposed human testing and whether the information is relevant to participant safety.

Product-specific requirements may differ according to factors such as dosage form, route of administration, manufacturing process and characteristics of the drug substance or drug product.

Sponsors should follow applicable regulations and current regulatory guidance and seek regulatory advice when significant manufacturing or control issues arise during development.

For U.S. INDs, the FDA guidance on CMC information for Phase 2 and Phase 3 studies provides additional information on phase-appropriate chemistry, manufacturing and controls expectations during later clinical development.

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