Elemental Impurities in Drug Products Guidance for Industry | Guideline Explorer

Description

This guidance provides recommendations regarding the control of elemental impurities of human drug products marketed in the United States consistent with implementation of International Council for Harmonisation (ICH) guidance for industry Q3D Elemental Impurities (ICH Q3D).

Key Topics

Terms and concepts identified from this document

Scope & Applicability

Product Classes

3

Drug products

Guidance is applicable to drug and biological products

Radiopharmaceuticals

Guidance does not specifically provide recommendations addressing dosage optimization for radiopharmaceuticals

Compendial Drug Products

Drug products recognized in official pharmacopeias

Stakeholders

1

Manufacturer

Entity responsible for submitting NDINs

Regulatory Context

Regulatory Activities

3

BLA

Biologics License Application

ANDA

Abbreviated New Drug Application

NDA

New Drug Application

Document Types

2

USP Monograph

Official standards for specific drug products

Annual Report

Reporting category for minor changes like removing a color additive

Attributes

2

Permitted Daily Exposure

Defined as a pharmaceutically acceptable intake of residual solvents; The maximum acceptable intake per day of residual solvent.

Dosage Form

Field B.2.2.2 describing the physical form of the VMP

Technical Details

Substances

4

components

Drug product components subject to compliance expectations

Excipients

Differences in excipients may affect product stability

Active Pharmaceutical Ingredient

examples of such components include but are not limited to the active moiety (API)

Elemental Impurities

Analytes tested by ICP-OES or ICP-MS

Testing Methods

1

Quantitative Analytical Procedures

Procedures for measuring elemental impurities; Methods used to determine the amount of elemental impurities

Standards & References

External Standards

6

USP <233>

Elemental Impurities – Procedures; Instrumental methods for elemental impurities

USP <232>

Elemental Impurities – Limits

USP <231>

Heavy Metals test previously described in USP; Non-specific heavy metals test method

USP General Chapter <231>

Former chapter on Heavy Metals replaced by <232> and <233>

USP General Chapter <233>

Elemental Impurities—Procedures; Describes analytical procedures for elemental impurities

USP General Chapter <232>

Elemental Impurities Limits

Specifications

3

Control Thresholds

Levels used to decide if routine testing is required

Control Threshold

Defined as 30% of the established PDE; Defined as 30% of the PDE; compare the measured or predicted levels in the drug product to the control threshold

Permitted Daily Exposure

Chronic PDE values derived for BHT and Erucamide.

ICH References (2)

ICH Q2(R1)

Validation of Analytical Procedures: Text and Methodology

ICH Q3D

Elemental impurities and interaction with storage containers

Related CFR Sections (3)

21CFR211.165§ 211.165 Testing and release for distribution.
(a) For each batch of drug product, there shall be appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release. Where sterility and/or pyrogen testing are conducted on sRead 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 →
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