EDQM Webinar On Elemental Impurities 16 May 2017 Presentation
EDQM Webinar On Elemental Impurities 16 May 2017 Presentation
EDQM Webinar On Elemental Impurities 16 May 2017 Presentation
EDQM Webinar
Elemental Impurities:
Implementation of ICH Q3D
16 May 2017
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2017© EDQM, Council of Europe 16/05/2017
Elemental impurities
in the Ph. Eur.
A (r)evolution
EMA guideline on
specification limits for ICH Q3D development
No guideline for safety limits 2008 residues of metal catalysts or 2013 and implementation 2018
metal reagents
Flexibility
Method
2.4.20
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EMA timelines
Source: http://www.ema.europa.eu/docs/en_GB/document_library/Other/2015/03/WC500184920.pdf
Ph. Eur aligned to the extent possible with these implementation dates
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Implementation
in general text 5.20 (1/2)
• Current text refers to the EMA guideline on metal catalysts and metal
reagents
• Replacement of the EMA guideline by the principles of the ICH Q3D
guideline
• No verbatim reproduction to avoid introducing a “Ph. Eur. Copy” of the
guideline. The enforceable text is the version as published by the ICH.
• Modules for implementation available from ICH website
• Publication: Ph. Eur. Suppl. 9.3 [impl. date 01/2018]
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Implementation
in general text 5.20 (2/2)
• Only parts of the introduction and the scope of ICH Q3D are
reproduced together with information specific to Q3D in the Ph. Eur.
• Extracts of the new version of chapter 5.20:
[…] The European Pharmacopoeia (Ph. Eur.) applies this guideline to medicinal products except
products for veterinary use, unlicensed preparations and products excluded from the scope of the
guideline […]
[…] The PDEs established in the guideline are considered to be protective of public health for all
patient populations. In some cases, lower levels of elemental impurities may be warranted when
levels below toxicity thresholds have been shown to have an impact on other quality attributes of
the medicinal product or one of its ingredients (e.g., element catalysed degradation of a
substance for pharmaceutical use).[…]
Implementation in general
method
General method 2.4.20 Determination of elemental impurities:
1. Editorial revision to align the wording with the ICH Q3D guideline
Publication foreseen in Ph. Eur. Suppl. 9.3 (no public consultation)
“metal catalyst and metal reagent residues” to “elemental impurities”
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Implementation in general
monographs 1/2
• Substances for pharmaceutical use (2034) :
• Elements intentionally added are controlled during production.
The identity of the elemental impurities derived from intentionally added catalysts and reagents is
known and strategies for controlling them should be established by using the principles of risk
management.
Implementation in general
monographs 2/2
• Pharmaceutical Preparations (2619) :
• Addition of a cross reference to general text 5.20 (principles of ICH Q3D) to render
the text legally binding for medicinal products in scope of Q3D.
• Clarification for medicinal products outside of the scope of ICH Q3D guideline
EIs at least considered in risk management strategy
Elemental impurities. General chapter 5.20 Elemental impurities applies to medicinal products
except products for veterinary use, unlicensed preparations and other products excluded from the
scope of general chapter 5.20.
For pharmaceutical preparations outside the scope of general chapter 5.20, manufacturers of these
products remain responsible for controlling the levels of elemental impurities using the principles of
risk management.
If appropriate, testing is performed using suitable analytical procedures according to general chapter
2.4.20 Determination of elemental impurities.
To be published in Ph Eur suppl. 9.3 [impl. date 01/2018]
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HOWEVER:
No extension of the scope of ICH Q3D GL
Q3D sets human toxicological limits (PDE)
Control = comprehensive approach using risk management
EIs are an important quality attribute of substances and products; just as
any other type of impurity
In the absence of specifications for EIs Should be covered by a risk
management strategy in line also with good manufacturing practices
Implementation in individual
monographs – HM tests
• Suppression of heavy metals tests (2.4.8) from individual monographs (except those for
vet. use only). Published in the 9th Edition.
• Total number of texts: 754 monographs (43%) combined with a new edition for
practical reasons
• No anticipated entry into force expected for already marketed products: from a
regulatory point of view manufacturers are expected to comply with ICH Q3D by
december 2017 at latest.
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Other monographs
• Individual monographs on finished products: no
additional requirement for EI (covered by general
monograph on pharmaceutical preparations 2619)
• Water, purified (0008) : public consultation ended;
comments under consideration by the relevant group
Elemental impurities. If purified water in bulk does not meet the requirement for conductivity
prescribed for Water for injections (0169) in bulk, a risk assessment according to general chapter
5.20. […] is carried out, taking into consideration the role of water in the manufacturing process, in
particular when water is used in a process but is no longer present in the final product.
Implementation in individual
monographs - specific metal tests
• In Ph. Eur. approx. 300 monographs describe more than 450 specific metal
tests
• Discussions started in 2015 in groups of experts (ICH Q3D classes 1, 2a, 2b and 3)
• Concerns :
• Historical reason for the presence of the test in the monograph
• No change control for updating production pathways (intentionally added
metals)
• Substances of natural origin (e.g. mined excipients) => EI potentially present
but not intentionally added
See example
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Example monograph
Example monograph
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Second phase
• Obtain batch data and revise these tests / or add new ones, if necessary,
based on batch data
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Acknowledgments
Ms B. Jacquel
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PA/PH/CEP (16) 23
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Summary
- Policy document
- Scenario 1: Risk Management Summary provided
- Scenario 2: no RMS provided
- Specification
- Analytical methods
- Limits
- Assessment
- Revision/Renewal
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Policy document
PA/PH/CEP (16) 23
published 04/08/2016
in force for all CEPs granted from 01/09/2016
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Concept
Applicant has the choice between two possible
approaches:
1. Provide a Risk Management Summary (RMS)
performed at the level of the drug substance
(component approach as per ICH Q3D). This is
the preferred scenario.
2. No Risk Management is done on elemental
impurities (EI).
The approach taken is independent of the use or
non-use of EI in the manufacturing process.
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Process aids 4 Pb, Cu Activated charcoal used in last step. Pot. impurities No further action
limited in raw material specification. required.
Reagents 1-4 Cd, Pb, As, Hg, HCl, NaOH, H2SO4. Based on data on raw materials and Verify risk assessment
Ni, Se, Sb, Cu, the used quantities limited carry-over is expected. for class 1 EI by
Cr screening.
Solvents 1-4 Ni Cyclohexane used in last step. Purified by distillation. No further action
For other solvents no catalyst is used. required.
Water 4 Cd, Pb, As, Hg, Purified water is used. No further action
Ni, Sb, Cu required.
Equipment 1-4 Ni, Mo, Cr Glass-lined steel and steel 1.4435 is used. Harsh Perform screening for
conditions (pH < 5.0) and high mechanical forces during these EI to check carry-
particle size reduction. over.
Container closure - Sb Used as catalyst in PET synthesis. Low concentration of No further action
system EI in packaging material. Solid substance and thus required.
limited interaction.
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In final specification
Detailed method description + full validation
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if applicable
− Test for elemental impurities by ICP-MS (Annex 3)
Palladium not more than 10 ppm
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0.2 ppm / 0.1 ppm / 0.4 ppm < 0.5 ppm or < 1 ppm or < 5 ppm
1.5 ppm / 0.9 ppm / 1.8 ppm < 2 ppm or < 5 ppm or < 10 ppm
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or
No elemental impurity classified in ICH Q3D is intentionally introduced in the
manufacture of the substance.
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Specification
For both scenarios:
EI intentionally introduced prior to the last step
Specification in the active substance as
proposed by applicant to be mentioned on CEP
(absent or not)
No specification proposed by applicant:
no question
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Specification
For both scenarios:
EI intentionally introduced in last synthetic step
specification for final substance is normally
expected unless levels below 30% of option 1
limit
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Specification
Li
V Cr Co Ni Cu As Se
Mo Ru Rh Pd Ag Cd Sn Sb
Ba Os Ir Pt Au Hg Tl Pb
ICH
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Analytical methods
Ph. Eur. General Method 2.4.8. Heavy metals
Ti V Cr Mn Fe Co Ni Cu Zn As Se
Mo Ru Rh Pd Ag Cd Sn Sb
W Pt Au Hg Tl Pb Bi
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Limits
Limits will be accepted as proposed.
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Limits
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Limits
Limit unrealistic?
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Assessment
Catalyst in SM
considered as contaminant and not intentionally
introduced use of cat. not mentioned on CEP
starting material
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Assessment
Process alternatives
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Assessment
Applicant does not apply option 1 limits but absence can be
concluded.
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Assessment
Use of a CEP to describe a material used in an application
for another CEP.
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Assessment
Ophthalmic (or dermal,...) use only
No PDE in ICH Q3D (oral PDE can provide the basis of a route-specific safety
assessment). No safety assessment at the stage of component possible.
Applicant can propose oral route or parenteral route (higher safety factor, more
EI covered). Suitability has to be assessed at the stage of DP.
Assessment
maximum daily dose > 10 g
Colestyramine 36 g/d
Sodium phenylbutyrate 20 g/d (lifetime)
Contrast agents
Iohexol, gadobutrol monohydrate,… >> 10 g (single administration)
Lactulose 120 g
RMS:
No conclusion on absence (based on option 1) possible.
Applicants should report levels as described on slide 12 for all
EI.
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Revision/Renewal
What to do for existing CEP’s?
- Renewal: Dossiers are systematically reviewed
against the principles of the Gdl.
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Revision/Renewal
Deletion of reference to General Method 2.4.8
- CEP holders/applicants have not been contacted.
- Update of specification under responsibility of
holder’s QA system.
- If no analytical control is necessary, deletion of
heavy metals test should be included in next
submission for revision (for filing; no assessment).
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Revision/Renewal
Deletion of reference to General Method 2.4.8
- Addition of alternative tests should be done
according to EDQM “Guideline on Requirements
for Revision/renewal” (PA/PH/CEP (04) 2)
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Revision/Renewal
No plan to revise all existing CEPs.
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Conclusion:
Several applications
with RMS received
and
CEPs granted with
RMS as annex.
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Conclusion:
This is still a new policy for everybody.
Sufficient experience has to be gained on how to
handle ALL scenarios.
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Questions?
EDQM Helpdesk
or
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2017© EDQM, Council of Europe
EDQM Webinar
Elemental Impurities:
Implementation of ICH Q3D
16 May 2017