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CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports

FinalCenter for Drug Evaluation and Research03/05/2014
CGMP

Description

This guidance provides recommendations to holders of new drug applications (NDAs) and abbreviated new drug applications (ANDAs) regarding the types of changes to be documented in annual reports. Specifically, the guidance describes chemistry, manufacturing, and controls (CMC) postapproval manufacturing changes that we have determined will likely have a minimal potential to have an adverse effect on product quality and, therefore, should be documented by applicants in an annual report.

Key Topics

Terms and concepts identified from this document

Scope & Applicability

Product Classes

6
Positron Emission Tomography Drug Products

excluded from the scope of this guidance

Natural protein drug products

Exception for equipment changes

Natural protein drug substances

Exception for equipment changes

Immediate-release solid dosage forms

Change in coating formulation for immediate-release solid dosage forms

Sterile drug products

administered parenterally

Parenteral drug products

Must generally contain the same inactive ingredients as the RLD

Stakeholders

3
Applicant

Entity submitting development data and knowledge; Entity performing the work process for change

Contract manufacturing organization

transfer to a CMO for the washing, drying, or siliconization

Quality Unit

Oversees reprocess or rework of batches

Regulatory Context

Regulatory Activities

5
NDA

New Drug Application

ANDA

Abbreviated New Drug Application

Prior Approval Supplement

Major changes requiring FDA approval before implementation

CBE-30 Supplement

moderate change supplement submitted 30 days before distribution

CBE-0 Supplement

Changes Being Effected supplement for identical labeling changes; Changes-being-effected supplement required within 15 days of an SLC order

Document Types

7
Annual Report

Reporting category for minor changes like removing a color additive

Manufacturing batch records

Records remain the same except for administrative information

Standard operating procedures

SOPs describing the manufacturing process for CSP

Structured Product Labeling

Standard for exchange of product and facility information

Drug master file

Documentation artifact (DMF) held by stakeholders.

SOP

Standard Operating Procedures for evaluating suppliers; Based on the manufacturer's established SOP for evaluating suppliers.; Standard Operating Procedures for regulatory compliance

Batch Record

Documentation where sterility testing results are added; Documentation of the production of each batch

Attributes

6
Product Quality

Identity, strength, quality, purity, and potency of a product

Potency

Measurement of potency for biological products

Purity

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

Strength

controls in place to maintain the strength, composition, and purity

Identity

assuring and preserving the identity of the new animal drug

Expiration dating period

established based on data from stability studies

Technical Details

Substances

5
Ethylene oxide

Sterilization agent for Class III devices.

Drug substance intermediates

Testing intermediates excluding final intermediate

In-process materials

Testing in-process materials prior to the final intermediate

Raw materials

Specification changes to raw materials

Active pharmaceutical ingredients

The active ingredient in a drug product where NDSRIs could be present.

Testing Methods

4
High performance liquid chromatography

change in the flow rate or sample preparation for a HPLC method

Analytical procedure

The way of performing the analysis including steps necessary to perform each analytical test.

SDS-PAGE

Sodium dodecyl sulphate polyacrylamide gel electrophoresis

Peptide map

discriminating identity test

Processes

7
CMC Postapproval Manufacturing Changes

changes to be documented in annual reports

Granulation

Design space for granulation parameters

Manufacturing processes

Characteristic evaluated for prior knowledge molecule grouping

Process Validation

General principles and practices for manufacturing validation; Summary of batch data for new synthetic procedures

Aseptic manufacturing processes

equipment used in aseptic manufacturing processes

Lyophilization

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

Terminal sterilization

Method used for final sterilization of the device

Standards & References

External Standards

1
Official compendium

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

Specifications

1
Acceptance criteria

Metrics established by developers for each test element.

ICH References (1)

ICH Q7

Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients; Reworking needs more evaluation and testing according to ICH Q7; Good manufacturing practice for API starting materials; Referenced regarding the definition of intermediates.

View on FDA.govDownload PDF

Related CFR Sections (3)

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

See Also (8)