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1
ICH Guidelines Elemental Impurities:
Strategies for Implementation for APIs
Frankfurt, October 2017
Dr. Landry Le Chevanton
2
ICH Guidelines Elemental Impurities:
Strategies for Implementation for APIs
• Introduction
• ICH Q3D: short history
• What has changed
• Increased complexity
• Practical implications
• Conclusions
3
Introduction
What / who is APIC?
• A Technical European Industry Association, based in Brussels
• Focused on APIs from a quality and regulatory
perspective
4
Introduction
APIC‘s Mission
• To promote the use of compliant APIs in medicinal
products to ensure patient safety
• To represent the interests of pharmaceutical and
chemical companies producing APIs and
intermediates in Europe by being recognized
experts who advance and influence the global
GMP and Regulatory environment
5
Introduction
What / who is Landry Le Chevanton
• Working for DSM Nutritional Products Ltd. in Switzerland as
Head of Global Regulatory Affairs and Quality Management
Operations
• Over 10 years of experience in the regulatory field
• Excom member of APIC, Chair of APIC TaskForce on ICH Q3D.
6
Short History of ICH Q3D (1/2)
• The story started in 1995 with USP publishing a stimuli article
identifying issues with the ‘Heavy Metals Limit Test’
• 1998 EMA drafted a guideline on Specification Limits for
Residues of Metal Catalysts
• 2008 EMA issued the Guideline on Residual Catalysts and
Reagents
• 2010, ICH convened Q3D to develop harmonized limits for
elemental impurities in pharmaceuticals
7
Short History of ICH Q3D (2/2)
• June 2013 ICH Q3D reached step 2
• 16 December 2014, ICH Q3D (at step 4) was published on the
ICH Website
8
What are the changes introduced by ICH
Q3D
Before (EMA Guideline) ICH Q3D
Apply to Drug Products Apply to Drug Products
14 elements considered 24 elements considered
PDE defined Certain PDE revised
Focused on metals intentionally
added during syntheses
Takes into account all possible
sources of EI
Control strategy defined in
guideline
Risk Assessment is basis for
control strategy
9
Consequences of the Change: Complexity
Increased
10
Where to start ?
ICH Q3DGuidelines
ICH Q3DModules 1-9
EMA
Implementation strategy of ICH Q3D guideline (Mar
2017)
EDQM
Implementation of ICH Q3D in the Certification Procedure (Aug 2016)
The essentials
11
And also…
Trade Associations(ask APIC!)
Webinars
Conferences Scientific Literature
FurtherSupport
12
API
MetalCatalysts
Manufact. Equip.
Processingaids
Inorganicreagents
Organicmaterials
Water
Solvents
Packaging
Primary sources of elemental impurities in API
13
Frequently encountered issues
Issue APIC position
Request for confirmation that API
complies with ICH Q3D.
ICH Q3D does not apply to APIs.
This confirmation cannot be
provided.
Request for providing batch data on
API for all 24 elements listed in ICH
Q3D.
Availability of such data is not
required by ICH Q3D.
ICH Q3D is not a testing guideline
14
Not all API are the same
Contribution of the API to the total mass of the drug products varies
a lot.
Some APIs works at a really low dose.
Levothyroxine 25 – 300 µg/tablets
Vitamin D3 20 µg/tablets
In those case the contribution to potential contamination of
elemental impurities are really negligible
15
The reality. (1/2)
The reality is that to date there is simply no evidence of a substantive risk
to patients regarding elemental impurities in pharmaceuticals.
Assessments of both development compounds and marketed products
across the industry have shown there to be virtually no risk, and
specifically for established products, there has proven to be virtually no
incidence where it has been necessary to replace the outdated heavy
metals limit test with specific testing.(Teasdale A., Org. Process Res. Dev. 2016, 20, 1850−1854)
16
The reality. (2/2)
This is confirmed also at the API level, where EDQM communicated in
June 2017 that approximatively 150 Risk Management Summary were
submitted during CEP revisions to the agency, none of them indicated
higher level of risks than before, on the contrary, in several cases, the
control strategy could be ‘relaxed’.