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  6. Investigational New Drug (IND) Application
  7. IND Applications for Clinical Investigations: Chemistry, Manufacturing, and Control (CMC) Information
  1. Investigational New Drug (IND) Application

IND Applications for Clinical Investigations: Chemistry, Manufacturing, and Control (CMC) Information

Streamlining First in Human Phase 1 INDs

FDA provides regulatory flexibility to support bringing innovative treatments to patients as quickly as possible. The Agency has observed that some sponsors provide more CMC information than is necessary for the First in Human (FIH) Phase 1 IND. To spare sponsors unnecessary time and effort, FDA has clarified the minimum CMC information that sponsors of FIH Phase 1 INDs should submit and what information can generally be submitted at later stages of development. This clarification enables sponsors to provide the information necessary to support FDA’s assessment of quality to ensure patient safety. By focusing on minimum requirements to ensure phase-appropriate CMC information is provided, FDA estimates that sponsors of FIH Phase 1 INDs can reduce application development time by up to 12 months.

Examples of FIH Phase 1 IND requirement clarifications and flexibilities include that: 

  • Stability data from the specific clinical lot to be used may not be required.
  • The initial stability data may not need to cover the full duration of the proposed clinical studies.
  • Analytical method validation data are not expected. 
  • Process controls that are not directly related to product safety are not expected to be specified.

For full lists of these clarifications and regulatory flexibilities, see: 

Contents

This component of an IND application includes the Chemistry, Manufacturing, and Control information for: (1) drug substance; (2) drug product; (3) placebo formulation, if applicable; (4) labeling information for the labeled products relevant to the investigational drug; and (5) an environmental analysis for assessment of the effects of the investigational new drug or biological product on the environment. Throughout the life cycle of an IND application and in each phase of the investigation, sufficient information should be submitted to assure the proper identification, quality, purity, and strength of the investigational drug. The amount of information needed to make that assurance will vary with the phase of the investigation, the proposed formulation, and duration of the investigation.

Suggested references

Available information in a published scientific literature may be referenced, if appropriate. The current edition of the United States Pharmacopeia—National Formulary may be referred in this section.

Safety perspective 

In addition to the contents described below, the CMC component is expected to address whether any information regarding the chemistry and composition of the drug substance, drug product, or the manufacture of either might suggest any possible human risks. If so, such risks should be described along with explanation on how these safety issues will be addressed. Any differences between the drug product planned for use in clinical studies and that used in animal toxicology studies should also be described.

Drug Substance

This section is expected to contain the following:

  1. Description of physical, chemical, or biological characteristics and evidence supporting structure and identity of the active pharmaceutical ingredient(s).
  2. Name and address of manufacturer.
  3. Description of the general method of preparation of the drug substance, including a list of the reagents, solvents, and catalysts used. A detailed flow diagram is suggested as the most effective presentation. More information may be needed to assess the safety of biotechnology-derived drugs or drugs extracted from human or animal or plant sources.
  4. The acceptable limits and analytical methods used to ensure the identity, strength, quality, and purity of the drug substance, with a brief description of the test methods used (e.g., Nuclear Magnetic Resonance, Infrared, UV spectra to prove the identity, and High Performance Liquid chromatograms to support the purity level and impurities, etc). Submission of certificates of analysis is also suggested.
  5. Information to support stability of the drug substance during storage in the intended container closure and during the toxicological and clinical studies.
Drug Product

This section is expected to contain the following:

  1. A list of all components and composition used in manufacturing process, including reasonable alternatives for inactive compounds used in the manufacture of the investigational drug product. This list is expected to include both those components intended to appear in the drug product and those which may not appear, but which are used in the manufacturing process.
  2. Summary of quantitative composition of the investigational new drug product, including any reasonable variations that may be expected during the investigational stage.
  3. Brief general description of the manufacturing process (in the form of a flow diagram is suggested) and packaging procedure, as well as other relevant tests, as appropriate for the product. Final specifications for the drug product intended to be used in toxicological and clinical studies should be included. For injectable products, sterility and pyrogenicity tests, endotoxin levels and particulate matter should be included. Submitting a copy of the certificate of analysis of the clinical batch is also suggested.
  4. The acceptable limits and analytical methods used to ensure the identity, strength, quality, and purity of the drug product.
  5. Information to support stability of the drug product during the planned clinical studies.
Placebo formulation, if applicable

This section is expected to include a brief general description of the composition, manufacture, and control of any placebo formulation to be used in the proposed clinical study. The description may be structured similarly to the description of the drug product recommended above.

Note: For placebo, the Quality Control test will include the absence of the active pharmaceutical ingredient(s). The physical characteristics of the placebo formulation should be comparable to the actual drug product to enable effective blinding.

LabelingCopies of labeling for the investigational product are expected to be provided in this section, when applicable. Investigator’s Brochure is considered the current and most up-to-date label of the investigational new drug. IB may be obtained from the IND product’s manufacturer or referenced from an existing IND application.
Environmental Assessment

This section is expected to include an assessment of effects of the investigational product on the environment. Environmental Assessment may be obtained from the IND product manufacturer or referenced from an existing IND application.

Most products qualify for a categorical exclusion from such an assessment. In general, exclusion is based upon a variety of considerations, including the following:

  1. Environment compartment (soil, air, water) into which the material will partition;
  2. Degradation of the material and degree;
  3. Safety margin between expected environmental concentration and effect level, for materials that slowly degrade.

Granting of a categorical exclusion will also depend upon the size of study population and amount of active moiety manufactured for the study.

For additional information on environmental assessments consult Guidance for Industry: Environmental Assessment of Human Drug and Biologics Applications (PDF - 188KB) .

 Additional FDA Guidances Related to CMC Section of IND Application

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