Q3A - Q3E Impurities Guidelines
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 clarifying some inconsistencies, to revise the decision tree, to harmonise with Q3B and to address some editorial issues.
The Attachment 2 of this Guideline has been revised under Step 4 without further public consultation on 25 October 2006 (Q3A(R2)).
Date of Step 4: 25 October 2006
Status: Step 5
Guidelines (Click the links below for complete guidelines)
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 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.
The 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: Step 5
Guidelines (Click the links below for complete guidelines)
Endorsed Documents (Click the links below for complete guidelines)
Q3C (R8) Guideline for Residual Solvents
The Q3C ICH Guideline was finalised 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 setup 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-methyltetrahydrofuran, cyclopentylmethylether and tert-butanol.
Date of Step 4: 22 April 2021
Status: Step 5
Guidelines (Click the links below for complete guidelines)
Endorsed Documents (Click the links below for complete guidelines)
WG Presentations / Trainings (Click the links below for complete guidelines)
Q3C (R9) Maintenance EWG - Maintenance of the Guideline for Residual Solvents
The Q3C ICH Guideline was finalised 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 Guideline was setup to enable the revision and inclusion of new Permitted Daily Exposure (PDE) levels as new toxicological data for solvents become available.
Status: Step 1
Endorsed Documents (Click the links below for complete guidelines)
Q3D (R1) Guideline for Elemental Impurities
ICH Q3D 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 on how to develop an acceptable level for EIs for drug products administered by other routes of administration.
In March 2019, the Q3D(R1) Guideline, which was the result of a revision of the PDE level for Cadmium by inhalation in the Q3D Guideline, reached Step 4 of the ICH process.
Date of Step 4: 22 March 2019
Status: Step 5
Guidelines (Click the links below for complete guidelines)
Endorsed Documents (Click the links below for complete guidelines)
Q3D (R2) Maintenance EWG Revision of Q3D(R1) for Cutaneous and Transdermal Products
ICH Q3D(R1) 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(R1) on how to develop an acceptable level for EIs for drug products administered by other routes of administration.
Maintenance Process
A Maintenance Procedure applies to revision of the Q3D(R1) Guideline for Elemental Impurities. These changes includes the incorporation of Permitted Daily Exposure (PDE) for new elemental impurities(EI)/routes of administration and revising the PDE for EI already listed in Q3D(R1) as new toxicological data for EI becomes available.
Products administered on skin and its appendages (e.g., hair, nails) remain the largest area where PDEs for EIs have not been established. In September 2016, the ICH Management Committee approved the revision of the ICH Q3D Concept Paper to include PDEs for the cutaneous and transdermal Route of Administration to continue the process of harmonisation, where necessary. This leads to the establishment of an Expert Working Group (EWG) to develop PDEs levels for all 24 EI included in the Q3D(R1) Guideline for products administered by the cutaneous and transdermal routes of administration.
In April 2022, the Q3D(R2) Guideline, which was the result of a correction of PDEs for Gold, Silver and Nickel; Gold and Silver monographs; and an addition of limits for elemental impurities by the cutaneous and transcutaneous route in the Q3D(R1) Guideline, reached Step 4 of the ICH Process.
Date of Step 4: 26 April 2022
Status: Step 5
Guidelines (Click the links below for complete guidelines)
Endorsed Documents (Click the links below for complete guidelines)
Q3D (R2) Maintenance Concept Paper
Q3D (R2) Maintenance Work Plan
WG Presentations / Trainings (Click the links below for complete guidelines)
Q3D Training Implementation Guideline for Elemental Impurities
The Q3D Implementation Working Group (IWG) was endorsed by the ICH Steering Committee in October 2014. Throughout the development of the Q3D Guideline, external audiences, constituents and interested parties have clearly communicated the complexity of the implementation approaches for this Guideline. The ICH Steering Committee considered that the development of a comprehensive training programme and supporting documentation sponsored by ICH was necessary to ensure the proper interpretation and effective utilisation by industry and regulators alike to enable a Harmonised and smooth implementation of Q3D on a global basis. The first training package (Modules 0-7) was endorsed by the ICH Assembly in December 2015. The final Modules 8-9 of the Q3D training package were endorsed by the ICH Assembly in June 2016.
Endorsed Documents (Click the links below for complete guidelines)
Q3E EWG Impurity: Assessment and Control of Extractables 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 extractables and leachables (E&L), and is expected would assist both applicants and regulators by providing 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.
Endorsed Documents (Click the links below for complete guidelines)
Q3A - Q3E Impurities Guidelines
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