Changes to an Approved NDA or ANDA: Guidance for Industry | Guideline Explorer

Description

This guidance provides recommendations to holders of new drug applications (NDAs) and abbreviated new drug applications (ANDAs) who intend to make postapproval changes in accordance with section 506A of the Federal Food, Drug, and Cosmetic Act (the Act) and § 314.70 (21 CFR 314.70). The guidance covers recommended reporting categories for postapproval changes for drugs other than specified biotechnology and specified synthetic biological products. It supersedes the guidance of the same title published November 1999. Recommendations are provided for postapproval changes in (1) components and composition, (2) manufacturing sites, (3) manufacturing process, (4) specifications, (5) container closure system, and (6) labeling, as well as (7) miscellaneous changes and (8) multiple related changes.

Key Topics

Terms and concepts identified from this document

Scope & Applicability

Product Classes

10

Biotechnology products

Specified biotechnology products excluded from certain recommendations in this guidance

Large volume parenterals

Injectable products requiring 100% inspection.

Small volume parenterals

Dosage form category (SVL, SVS, SVT) for profile class codes.

Solid oral dosage form

General category for tablets and capsules discussed in the coating and drilling sections.

Nonsterile drug product

Product category for specific container closure changes.

Sterile drug products

administered parenterally

Natural Protein Drug Substances

Specific category with distinct reporting requirements for scale changes

Drug Product

RTRT and CTD sections apply to drug products

Modified-Release Solid Oral Dosage Form

Drug products with modified rate or extent of availability

Transdermal Systems

Assessment of Adhesion for Topical and Transdermal Systems

Stakeholders

2

applicant

entity submitting marketing applications

Contractor

Contract acceptor for transportation of APIs

Regulatory Context

Regulatory Activities

8

NDA

New Drug Application

Changes Being Effected in 30 Days

CBE-30 reporting category

ANDA

Abbreviated New Drug Application

Prior Approval Supplement

Major changes requiring FDA approval before implementation

Supplement - Changes Being Effected

Reporting category for moderate changes; Moderate potential for adverse effect on drug quality; Reporting category for consolidating testing to a site with satisfactory CGMP status

Annual Report

Reporting category for minor changes; Submission type for low-risk drug product documentation; inclusion of specification changes in an annual report

Supplement - Changes Being Effected in 30 Days

Reporting category for moderate changes requiring 30-day notice; Moderate potential for adverse effect on drug quality

Changes-Being-Effected-in-30-Days Supplement

Reporting category for moderate changes; Subsequent process changes in the same barrier system may be submitted as a CBE-30.

Document Types

6

Comparability Protocol

Prospectively written plan for assessing CMC changes

Inactive Ingredient Guide

FDA resource for information on components used in approved products.

Stability Protocol

Protocol design for formal stability studies; Incorporates information to establish re-test period or shelf life; Design and execution of a stability protocol to support formal studies; Design for supporting drug substance or drug product shelf life; Design of the stability study including frequency and conditions; Written protocol for holding time studies; Design of in-use stability study protocols; Reduced Stability Protocol Design discussed in Annex 1; Including intermediate storage condition

Package insert

labeling artifact containing consumer information

Medication Guide

FDA-approved patient labeling

Official compendium

Reference such as USP or NF

Attributes

8

Adverse Effect

Impact on identity, strength, quality, purity, or potency

Expiration Dating Period

CMC changes after tentative approval; shelf-life period supported by stability data; proposing to extend the expiration dating period for the drug product

Storage conditions

expressed as a numerical value or range

Bioburden

Level and type of micro-organisms present in materials

Impurity Profile

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

Equivalence

Demonstration that pre- and postchange products are equivalent

Potency

Measurement of potency for biological products

Purity

specifications for the purity, strength, and composition of dietary supplements

Technical Details

Substances

7

Drug Substance

Postapproval changes to drug substances; the active pharmaceutical ingredient being modified; Evaluation of physical properties for drug substance; Active ingredient intended to furnish pharmacological activity; The molecule or ion responsible for the physiological or pharmacological action.; The active pharmaceutical ingredient subject to postapproval changes

Active Ingredient

Extent of absorption or other exposure to an active ingredient; Component whose exposure must not be materially affected by dosage change

Desiccant

Addition or deletion in packaging

High density polyethylene

Plastic container material

Adventitious agents

Microorganisms that may have been unintentionally introduced

Master Cell Bank

An aliquot of a single pool of cells used to derive all working cell banks.; Generation of a new master cell bank from a source material

Inactive Ingredients

Requests related to inactive ingredients in generic drugs

Testing Methods

5

Dissolution Profiling

Used to assess effect of change on bioequivalence

HPLC procedure

High-Performance Liquid Chromatography used to distinguish impurities

High Pressure Liquid Chromatography

Instrumental method for analyzing drugs in feeds

Stability Testing

Testing used to justify leveraging data across products

Chromatographic Techniques

Used for profiling impurity or degradant profiles

Processes

10

CMC

chemistry, manufacturing, and controls

Radiation sterilization process

Profile code RSP for manufacturing inspections.

Chemical sterilization process

Profile code CSP for manufacturing inspections.

Steam Sterilization Process

Specific type of operation performed at a site; Profile code SSP for manufacturing inspections.

Aseptic filling

control strategy for assuring the sterility of the product

Dry Heat Depyrogenation

Changes in depyrogenation processes for glass container systems.

Sterilization

Required for contaminated equipment and media before disposal

Aseptic Processing

implied manufacturing process under QS regulation

Lyophilization

Physical modification that does not result in chemical alteration.; A process that does not typically chemically alter an ingredient

Terminal Sterilization

Sterilization method for drug products

Clinical Concepts

2

Adverse event

Safety monitoring concept defined in the protocol

Contraindication

Firms should describe contraindications in the FDA-required labeling

Standards & References

External Standards

4

USP

United States Pharmacopeia standards for compendial drug substances; confirming conformance to the application-approved specification and USP

Official compendium

change to delete the company trademark to comply with the official compendium

USP <61>

Microbial limits tested via USP <61>

USP/NF

Compendial excipients should comply with USP/NF monographs

Specifications

4

Conformance to Specifications

Assessment of the effects of a manufacturing change

Acceptance criterion

Specific limits used to define specified or unspecified impurities.

Approved Specification

Widening of an approved specification.

Acceptance Criteria

limits for solid state form and particle size; Tightening acceptance criteria; Numerical limits or ranges for tests

ICH References (2)

ICH guidances

Principles for standard stability protocols

ICH Q3B

impurities in new drug products; Impurities in new drug products; Recommendations for genotoxicity studies and toxicological qualification; Impurities in New Drug Products; Qualification study(ies) as described in ICH Q3B

Related CFR Sections (2)

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 →
21CFR314.70§ 314.70 Supplements and other changes to an approved NDA.
(a) Changes to an approved NDA.Read full regulation →

Enforcement Impact

Deficiencies cited in Warning Letters referencing the same regulations

Quality control unit failed to exercise its responsibility

101

Failure to conduct at least one test to verify the identity of each component

95

Failure to establish adequate written procedures for production and process control

88

Failure to have appropriate laboratory determination of satisfactory conformance to final specifications

56

Failure to thoroughly investigate any unexplained discrepancy or failure of a batch

56

Failure to establish an adequate quality control unit

49

Failure to test samples of each component for identity and conformity

47

Failure to establish laboratory controls

35

Failure to thoroughly investigate any unexplained discrepancy

28

Failure to test samples of each component for identity

25

Recent Cases

Related Warning Letters (10)

Related MFDS Guidelines

Korean regulatory guidelines covering similar topics