Q3 ICH Guidelines for Impurities

Q3 ICH Guidelines for Impurities:

Q3A (R2): Impurities in New Drug Substances:

First recommended for adoption at Step 4 of the ICH Process on 30 March 1995, the guideline was revised under Step 2 of the ICH Process on 7 October 1999 and finalized under Step 4 on 7 February 2002 (Q3A(R1)).

The Guideline addresses the chemistry and safety aspects of impurities, including the listing of impurities in specifications and defines the thresholds for reporting, identification and qualification. The revision of the Guideline has allowed for clarifying some inconsistencies, revising the decision tree, harmonizing with Q3B and addressing some editorial issues.

Attachment 2 of this Guideline has been revised under Step 4 without further public consultation on 25 October 2006 (Q3A(R2)).

Data of Step 4: 25 October 2006

Status of Step 5: Implementation

Q3B (R2): Impurities in New Drug Products:

This Guideline has been first revised and finalized under Step 4 in February 2003. It complements the Guideline on impurities in new drug substances and provides advice in regard to impurities in products containing new, chemically synthesized drug substances. The Guideline specifically deals with those impurities which might arise as degradation products of the drug substance or arising from interactions between the drug substance and excipients or components of primary packaging materials. The Guideline sets out a rationale for the reporting, identification and qualification of such impurities based on a scientific appraisal of likely and actual impurities observed, and of the safety implications, following the principles elaborated in the parent Guideline. Threshold values for reporting and control of impurities are proposed, based on the maximum daily dose of the drug substance administered in the product.

Attachment 2 of this Guideline has been revised under Step 4 without further public consultation on 2 June 2006 (Q3B(R2)).

Date of Step 4: 2 June 2006

Status of Step 5: Implementation

Q3C (R8): Guideline for Residual Solvent:

The Q3C ICH Guideline was finalized under Step 4 in July 1997, providing recommendations on the use of less toxic solvents in the manufacture of drug substances and dosage forms, and setting pharmaceutical limits for residual solvents (organic volatile impurities) in drug products. A Maintenance process for the Q3C Guideline was set up to enable the revision and inclusion of new Permitted Daily Exposure (PDE) levels as new toxicological data for solvents become available.

As part of the Maintenance Process, the Q3C(R8) Guideline incorporated the PDE levels for 2-methyl tetrahydrofuran, cyclopentyl methyl ether and tert-butanol.

Date of Step 4: 22 April 2021

Status of Step 5: Implementation

Q3C (R9): Maintenence of the Guideline for Residual Solvents:

The Q3C ICH Guidelines for impurities was finalized under Step 4 in July 1997, providing recommendations on the use of less toxic solvents in the manufacture of drug substances and dosage forms, and setting pharmaceutical limits for residual solvents (organic volatile impurities) in drug products.

Maintenance Process

A Maintenance process for the Q3C Guidelines for impurities was setup to enable the revision and inclusion of new Permitted Daily Exposure (PDE) levels as new toxicological data for solvents become available. 

Q3D (R2): Guideline for Elemental Impurities:

ICH Q3D(R2) Guideline for Elemental Impurities is a quality guideline for the control of elemental impurities in new drug products (medicinal products), and it establishes Permitted Daily Exposures (PDEs) for 24 Elemental Impurities (EIs) for drug products administered by the oral, parenteral and inhalation routes of administration. In addition, guidance is provided in Q3D(R2) on how to develop an acceptable level for EIs for drug products administered by other routes of administration.

The current Q3D(R2) Guideline reached Step 4 in April 2022 and included a correction of PDEs for Gold, Silver and Nickel; Gold and Silver monographs; and the addition of limits for elemental impurities by the cutaneous and transcutaneous route. The Q3D(R2) Guideline replaces the previous Q3D(R1) Guideline, which reached Step 4 of the ICH process in 2019,  further to the initial Q3D Guideline which reached Step 4 in 2014.

Date of Step 4: 26 April 2022

Status of Step 5: Implementation

Q3E: Impurity: Assessment and control of extractable and Leachables for pharmaceuticals and biologics:

This topic was endorsed by the ICH Assembly in June 2019.

Further to the MC’s endorsement of the Q3E Concept Paper and Business Plan in July 2020, the Q3E EWG was established to work on the development of the Q3E Guideline on the assessment and control of extractable and leachable (E&L), and is expected would assist both
applicants and regulators by providing a focus on critical aspects, and improving transparency in requirements for medicinal products including drug delivery device components.

Further information can be found in the Q3E Concept Paper and Business Plan.

Status: Step 1

Q3 ICH Guidelines for Impurities

Q3 ICH Guidelines for Impurities

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