Description
The Food and Drug Administration (FDA, Agency, or we) is announcing the availability of a final guidance for industry entitled “Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs).” This guidance provides applicants and manufacturers of drugs, including prescription and over-the-counter (OTC) drug products, with a recommended framework for predicting the mutagenic and carcinogenic potential of NDSRIs that could be present in drug products and recommends acceptable intake (AI) limits for NDSRIs. NDSRIs, which are a subcategory of nitrosamine impurities that share structural similarity to the active pharmaceutical ingredient (API) in drug products, typically lack compound-specific mutagenicity and carcinogenicity data to inform safety assessments. This guidance provides a recommended methodology for AI determination that uses structural features of NDSRIs to generate a predicted carcinogenic potency categorization and corresponding recommended AI limit that manufacturers and applicants can apply, in the absence of other FDA-recommended AI limits, in their evaluation of potential impurities in their drug products.
Scope & Applicability
Product Classes
3Products combining drug, device, or biological constituents; Generally recommended for Enhanced Documentation; Requires 14971-based framework incorporating ICH Q9; A drug-device combination where the device constituent part detects ingestion.
nitrosamine drug substance-related impurities
Guidance provides a framework for over-the-counter drug products.
Stakeholders
3Facilities compounding drug products pursuant to section 503B.
CDER office to contact regarding potential drug supply disruptions
Drug Master File holders included in the term 'manufacturers and applicants'.
Regulatory Context
Attributes
5Approach used to determine recommended AI limits for NDSRIs.; Methodology to assign AI limits based on structural features
highest potency category with AI of 1500 ng/day
AI limit recommended based on potency category
Calculated value used to determine the potency category in the flowchart.; calculated sum of structural feature scores for NDSRIs; Calculated value used to assign an NDSRI to a potency category.
Five categories (1-5) assigned to NDSRIs based on structural features.; Used to determine the recommended AI limit for NDSRIs; Categories 1 through 5 used to determine acceptable intake limits.
Identified Hazards
Hazards
2The risk associated with NDSRIs that the guidance framework predicts.
Hydrogen peroxide is mutagenic and genotoxic in vitro
Related CFR Sections (7)
- 21CFR10.115§ 10.115 Good guidance practices.
(a) What are good guidance practices? Good guidance practices (GGP's) are FDA's policies and procedures for developing, issuing, and using guidance documents.Read full regulation →
- 21CFR601.12§ 601.12 Changes to an approved application.
(a) General.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 →
- 21CFR314.70§ 314.70 Supplements and other changes to an approved NDA.
(a) Changes to an approved NDA.Read full regulation →
- 21CFR211.100§ 211.100 Written procedures; deviations.
(a) There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Such procedures shall include all requirements in this subpart. These written procedures, inRead 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 →
- 21CFR314.3§ 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 →
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See Also (8)
- IRB Review of Stand-Alone HIPAA Authorizations Under FDA Regulations: Guidance for Industry (Status: Final)
- Acceptability of Draft Labeling to Support Abbreviated New Drug Application Approval; Guidance for Industry (Status: Draft)
- DSCSA Implementation: Product Tracing Requirements for Dispensers — Compliance Policy (Revised) Guidance for Industry (Status: Final)
- Early Clinical Trials With Live Biotherapeutic Products: Chemistry, Manufacturing, and Control Information: Guidance for Industry (Status: Final)
- Determining Donor Eligibility for Autologous Donors of Blood and Blood Components Intended Solely for Autologous Use - Compliance Policy: Guidance for Industry (Status: Final)
- Guidance for Industry: Use of the Term “Healthy” in the Labeling of Human Food Products (Status: Final)
- Revised Recommendations for Determining Eligibility of Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products Who Have Received Human-Derived Clotting Factor Concentrates: Guidance for Industry (Status: Final)
- Guidance for Industry: Application of the Foreign Supplier Verification Program Regulation to the Importation of Live Animals (Status: Final)