Q3D Implementation Working Group Training Plans
John Kauffman
Rapporteur and Regulatory Chair, ICH Q3D IWG
Lab Chief, Branch II
FDA, CDER Division of Pharmaceutical Analysis
Disclaimer: This presentation reflects the views of the author and
should not be construed to represent FDA’s views or policies.
1
Background
• June 2010, ICH convened Q3D Expert Working
Group (EWG) to develop harmonized limits for
elemental impurities in pharmaceuticals
• June 2013, ICH Q3D reached step 2
– Public comments were addressesd at June 2014 Meeting of
the ICH EWG in Minneapolis, MN USA
• November 2014, ICH Q3D reached step 4
– Published on the ICH Website on 16 December, 2014
2
Background
• Why do we need a Q3D IWG?
– Discussions of Q3D in public forums reflect a divergence
of expectations for implementation.
– The use of Risk Assessment is still a relatively new and
potentially complex approach to pharmaceutical quality.
"The potential for variability of interpretation is high."
• Training material can reduce the differences in interpretation for
both industry and regulatory authorities.
3
Background
• October 2014, ICH approved the formation of a Q3D
Implementation Working Group (IWG)
• Nine (9) training modules will be prepared
• Expected to be completed in Summer, 2015
• Objectives
– Facilitate an aligned interpretation and harmonized
implementation of Q3D
– Provide detailed examples of the application of Q3D to
situations that are described, but not illustrated, in the
Guideline.
• Training material must not expand the scope of the final guideline
4
The ICH Q3D IWG was formed in
December, 2014
• Toxicologists and Chemists
– High degree of homology between EWG and IWG
• Six ICH Parties
– EMA, EFPIA, MHLW, JPMA, FDA, PhRMA
• Observers
–
–
–
–
Health Canada, Swissmedic
Pharmacopeias: Ph.Eur., JP, USP
IPEC, WSMI, IGPA, BIO, API Industry
Brazil, Chinese Taipei, Singapore
5
Overview of the Guideline
• Main body, references and glossary (pages 1-17)
• Appendix 1: Method for Establishing Exposure
Limits (pages 18-20)
• Appendix 2: Established Permitted daily exposures
(PDEs) for Elemental Impurities by oral, parenteral
and inhalation routes of administration
• Appendix 3: Individual Safety Assessments for 24
elements (pages 23-67)
• Appendix 4: Illustrative Examples (pages 68-73)
6
Workplan
1. Introduction
2. Scope
3. Safety Assessment of Potential Elemental Impurities
3.1 Principles of the Safety Assessment …
Module 1
3.2 Other Routes of Administration
3.3 Justification for Elemental Impurity Levels Higher than
Module 2
an Established PDE
3.4 Parenteral Products Module 4: Large Volume Parenterals
4. Element Classification
7
Workplan
5. Risk Assessment and Control of Elemental Module 5
Impurities
6. Control of Elemental Impurities Module 6
7. Converting between PDEs and Concentration Limits
Module 7
8. Speciation and other Considerations
9. Analytical Procedures
10. Lifecycle Management
Appendix 1: Method for Establishing Exposure Limits
Module 3: Acceptable exposures for elements without a PDE
Module 8: Case Studies
Module 9: Frequently Asked Questions
8
Summary of Training Modules
1. How to Apply Q3D Concepts to Routes of Administration, not
addressed in Q3D
2. Justification for Elemental Impurity Levels Higher than an
Established PDE
3. Application of Q3D concepts to determining safe levels of
elements not included in Q3D
4. Large Volume Parenterals
5. Risk Assessment
6. Control of Elemental Impurities
7. Converting between PDEs and Concentrations
8. Case Studies
9. FAQs
Toxicology
Chemistry
9
Consolidated Workflow
Product Risk
Assessment
Lifecycle Change
Management
(e.g. new supplier, change
in process, etc.)
Drug product
assessment
approach
Component
assessment
approach
Gather information on
drug product, analyze
representative lots of
drug product if necessary
Gather information on
components of the drug
product, analyze
representative lots of
components if necessary
Summarize available
information, tabulate
elemental impurity
concentrations in the
drug product
Compute permissible EI
concentrations using
Options 3, compare with
tabulated concentrations
Elements that are not likely to
be present (e.g., class 2B that
have not been intentionally
added; class 3 for solid oral;
elements not identified as
likely to be present in Risk
Assessment)
Product independent
information (e.g. equipment
information, container
closure information)
Summarize available
information, tabulate
elemental impurity
concentrations in
components of the drug
product
Compute permissible
EI concentrations using
Options 1, 2a or 2b,
compare with
tabulated
concentrations
Output of the risk
assessment
Elements <30% PDE (below
control threshold)
Elements 30-100% PDE
Elements > PDE
Evaluate safety assessment
and rationale to support
levels higher than the PDE
for specific element(s)
Document elements of
minimal concern. No further
action required
Higher level justified?
No
Existing controls adequate
Upstream
Control
Define Additional controls
Add upstream control and
evaluate impact on EI levels
Specification
Yes
Establish specification on drug
product or appropriate component of
drug product
Document Risk Assessment
and Control Strategy
10
Consolidated Workflow
11
Consolidated Workflow
12
Consolidated Workflow
Product Risk
Assessment
Module 5
Drug product
assessment
approach
Component
assessment
approach
Gather information on
drug product, analyze
representative lots of
drug product if necessary
Gather information on
components of the drug
product, analyze
representative lots of
components if necessary
Summarize available
information, tabulate
elemental impurity
concentrations in the
drug product
Module 7
Compute permissible EI
concentrations using
Options 3, compare with
tabulated concentrations
Elements that are not likely to
be present (e.g., class 2B that
have not been intentionally
added; class 3 for solid oral;
elements not identified as
likely to be present in Risk
Assessment)
Product independent
information (e.g. equipment
information, container
closure information)
Summarize available
information, tabulate
elemental impurity
concentrations in
components of the drug
product
Compute permissible
EI concentrations using
Options 1, 2a or 2b,
compare with
tabulated
concentrations
Output of the risk
assessment
Elements <30% PDE (below
control threshold)
Lifecycle:
Module 6
Lifecycle Change
Management
(e.g. new supplier, change
in process, etc.)
Elements 30-100% PDE
Module 2
Elements > PDE
Evaluate safety assessment
and rationale to support
levels higher than the PDE
for specific element(s)
Module 6
Document elements of
minimal concern. No further
action required
Higher level justified?
No
Existing controls adequate
Upstream
Control
Define Additional controls
Add upstream control and
evaluate impact on EI levels
Specification
Yes
Establish specification on drug
product or appropriate component of
drug product
Document Risk Assessment
and Control Strategy
13
Frequently Asked Questions
• Sources of FAQs
– Public comments on Step 2b document
– Constituents, referred to Q3D EWG through industry representatives
– Other industry groups
• FAQs include
– Common questions that could not be addressed in the Guideline
– Questions related to how decisions were made during development of Q3D
– Examples
• Why are herbal products out of scope?
• How did the EWG select the 24 elements? USP and EMA have fewer
elements in their documents.
• Why is aluminum not included?
14
Thank you!
Questions?
15