Description
This guidance provides recommendations to holders of approved new drug applications (NDAs), abbreviated new drug applications (ANDAs), new animal drug applications (NADAs), and abbreviated new animal drug applications (ANADAs) and holders of drug master files (DMFs) and veterinary master files (VMFs) who want to make a change to the drug substance manufacturing process during the drug product application’s postapproval period.It does not address holders of biologics license applications (BLAs) or holders of any master files cross-referenced in BLAs.
Scope & Applicability
Product Classes
7Guidance applies to synthetic drug substances
Produced by fermentation and synthesis or from natural precursors.
Complex dosage forms that may require one batch per strength for evaluation
Category of dosage forms where physical properties may be critical
Category of dosage forms where physical properties may be critical
Guidance applies to synthetic steps in semisynthetic drug substances
Products with complex active ingredients or formulations
Stakeholders
7Holders of approved applications or master files
Responsible for managing changes and qualifying vendors
Contact the regulatory project manager assigned to the application
When a contract manufacturer is used, a quality agreement should ensure that changes in equipment are reported
outsourced operation provider
Entity responsible for the approved NDA or ANDA; entity responsible for risk assessment
Entity responsible for maintaining the DMF
Regulatory Context
Attributes
10Equivalence of physical properties; Evaluation of physical properties for drug substance; Properties likely to influence drug product manufacturability; Attributes such as physical state, melting point, solubility, and density.
Data on impurities or physical attributes from three or more consecutive batches.
Occurrence of different crystalline forms of the same drug substance.
A measurement of the relative proportion of particles in a sample as a function of size.
commitment to continue the stability study through the retest/expiry date
Property used in the decision tree for in-vitro testing
Physical property of drug substance affecting manufacturability
Physical property of drug substance affecting manufacturability
Physical property of drug substance affecting manufacturability
levels of existing and new impurities; Characteristic of drug substance that may change with starting material redesignation; A comparison of the impurity profile of pre- and post-modification material to establish equivalence; Evaluation of the impurity profile for intermediates or drug substance; Potential to adversely affect drug substance quality; A description of the identified and unidentified impurities present in a drug substance.; The description of identified and unidentified impuritie
Identified Hazards
Hazards
4Risk to identity, strength, quality, purity, or potency
Introduction of impurities that may cause genetic mutations
Risk when the number of steps from the end of the process is reduced
risk affected by particle size changes
Related CFR Sections (7)
- 21CFR314.70§ 314.70 Supplements and other changes to an approved NDA.
(a) Changes to an approved NDA.Read full regulation →
- 21CFR314.3§ 314.3 Definitions.
(a) The definitions and interpretations contained in section 201 of the Federal Food, Drug, and Cosmetic Act apply to those terms when used in this part and part 320 of this chapter .Read full regulation →
- 21CFR210.3§ 210.3 Definitions.
(a) The definitions and interpretations contained in section 201 of the act shall be applicable to such terms when used in this part and in parts 211 , 225 , and 226 of this chapter .Read full regulation →
- 21CFR314.81§ 314.81 Other postmarketing reports.
(a) Applicability. Each applicant shall make the reports for each of its approved applications and abbreviated applications required under this section and section 505(k) of the act.Read full regulation →
- 21CFR514.8§ 514.8 Supplements and other changes to an approved application.
(a) Definitions.Read full regulation →
- 21CFR314.97§ 314.97 Supplements and other changes to an approved ANDA.
(a) General requirements. The applicant must comply with the requirements of §§ 314.70 and 314.71 regarding the submission of supplemental ANDAs and other changes to an approved ANDA.Read full regulation →
- 21CFR314.420§ 314.420 Drug master files.
(a) A drug master file is a submission of information to the Food and Drug Administration by a person (the drug master file holder) who intends it to be used for one of the following purposes: To permit the holder to incorporate the information by reference when the holder submits an investigationalRead full regulation →
Related Warning Letters (5)
- 2025-09-16
False & Misleading Claims/Misbranded
Novo Nordisk Inc.
- 2025-09-16
False & Misleading Claims/Misbranded
Eli Lilly and Company
- 2025-06-10
False & Misleading Claims/Misbranded
Sprout Pharmaceuticals, Inc.
- 2025-05-20
False & Misleading Claims/Misbranded
Sarfez Pharmaceuticals, Inc.
- 2021-02-23
False & Misleading Claims/Misbranded
CooperSurgical, Inc.
See Also (8)
- SUPAC-IR Questions and Answers about SUPAC-IR Guidance (Status: Final)
- Assessing User Fees Under the Generic Drug User Fee Amendments of 2017 Guidance for Industry (Status: Draft)
- Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products: Guidance for Industry (Status: Final)
- Changes to an Approved Application for Specified Biotechnology and Specified Synthetic Biological Products (Status: Final)
- Environmental Assessment of Human Drug and Biologics Applications: Guidance for Industry (Status: Final)
- Q5D Quality of Biotechnological/Biological Products: Derivation and Characterization of Cell Substrates Used for Production of Biotechnological/Biological Products; Availability (Status: Final)
- For the Submission of Chemistry, Manufacturing and Controls and Establishment Description Information for Human Blood and Blood Components Intended for Transfusion or for Further Manufacture and For the Completion of the Form FDA 356h: Guidance for Industry (Status: Final)
- Container Closure Systems for Packaging Human Drugs and Biologics: Guidance for Industry (Status: Final)