Biotech Values

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B. When is an amendment classified as major?

Responses to the following examples of deficiencies would result in a major amendment. This should not be considered an all-inclusive listing.

1. Manufacture of a new batch of drug product (with supporting information) for any reason; for example:

• Composition change or reformulation

• Change in the source of a drug substance

• Change in manufacturing site

• Need for a new bioequivalence study (21 CFR 320.21)

• New in vitro study for a specific product (e.g., metered dose inhalers)

• Change in major manufacturing process

• New strength of the product

• Unacceptable impurities or impurity levels (21 CFR 314.94(a)(9))

• Unacceptable excipients found during the review (21 CFR 314.94(a)(9))

• Failed stability data

• Change in the container-closure system (other than solid oral dosage forms)

2. New bioequivalence study (21 CFR 320.21) that is not related to manufacture of a new batch of the drug product

3. New analytical methods and full validation data (21 CFR 314.94(a)(9))

Any other circumstances that might be considered to be a major amendment should get division level concurrence, including an assessment that the application is of such overall poor quality that substantive review is not possible.

Many of the deficiencies that would be categorized as a major amendment for chemistry would also pertain to the sterility assurance and/or microbiology review (i.e., change in facility or container-closure system). Generally, the microbiology review would not affect the designation determined through the CMC review. However, in rare instances, the sterility assurance and/or microbiology reviews, rather than chemistry, may determine the major amendment designation. This could occur, for example, when extensive validation work is necessary (21 CFR 314.94(a)(9)).


C. When is an amendment classified as minor?

Except for those amendments that are classified as major or telephone, amendments will be designated as minor. Minor amendments often consist of deficiencies that are outside the control of the applicant or deficiencies that are more easily addressed than those in a major amendment. Though most amendments will likely be minor, some examples include, but are not limited to:

1. Deficiencies in the drug master file (DMF)

2. Problems regarding good manufacturing practices (GMPs)

3. Incomplete dissolution data

4. Labeling deficiencies that have not been adequately addressed

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072888.pdf