EDQM Webinar On Elemental Impurities 16 May 2017 Presentation

2017 © EDQM, Council of Europe
EDQM Webinar
Elemental Impurities:
Implementation of ICH Q3D
16 May 2017
©2017 EDQM, Council of Europe. All rights reserved.
Webinar on Elemental Impurities
Welcome to all participants.
To ensure the best experience for you we will

now give you some technical information related
to the webinar.
1
2017© EDQM, Council of Europe 16/05/2017
Implementation of the ICH

Q3D guideline in the Ph. Eur.
Webinar on Elemental Impurities

16 May 2017
Bruno Spieldenner, Ph. Eur. Department, EDQM
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
Non specific « heavy metals » test

Limit at 10 or 20 ppm Lead
Flexibility
Method
2.4.20
Bruno Spieldenner ©2017 EDQM, Council of Europe. All rights reserved.

2
1
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

3
Press releases on Ph. Eur.

strategy
• 18th July 2014 : Ph. Eur. strategy regarding
elemental impurities and implementation of ICH
Q3D.
• 28th April 2015: Ph.Eur. policy on elemental
impurities and timelines for revision of general and
individual texts.
• 7th August 2015: clarification for products outside
of the scope of ICH Q3D.
• 11th January 2017: update on the Ph. Eur.
implementation strategy
4
2
Content and structure of the

Ph. Eur.
Provide basic and very general information that
are valid for all texts. Help to understand S
aspects of wording, structure and requirements P
of the Ph. Eur. E
C
• General methods: general
recommendations for analytical procedures.
I
• General texts: informative texts, guidelines F
(e.g. microbiology, chemometrics) I
Become mandatory when cited in monograph C
I
• Dosage forms: applied during licensing T
• Group of products: defined by production Y
method, risk factors or intended use.
Summarises mandatory quality aspects
common to a given group.

5
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]

6
3
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).[…]
To be published in Ph Eur suppl. 9.3 [impl. date 01/2018]

7
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”
2. International harmonisation (coordinating pharmacopoeia: USP)

Work ongoing with high priority within the PDG.
Other general methods : e.g. Heavy metals (2.4.8), Arsenic (2.4.2)

Not foreseen to delete yet (e.g. needed for products for veterinary use)

8
4
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.
• Clarification for the deletion of specifications for substances

Elemental impurities. Permitted daily exposures for elemental impurities (e.g. as included in the
ICH Q3D guideline, the principles of which are reproduced in general chapter 5.20 Elemental
impurities) apply to the medicinal product. Individual monographs on substances for pharmaceutical
use therefore do not contain specifications for elemental impurities unless otherwise prescribed.

9
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.

10
5
Outcome of public consultation

Public consultation ended on 31st August 2016
For products out of scope of ICH Q3D GL: Some concern

expressed that additional requirements might be introduced
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

11
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.
• See press release from April 2015:

”The absence of the heavy metals test from an individual monograph does not preclude substance manufacturers from
controlling the levels of elemental impurities in their products. Control of heavy metals according to method 2.4.8 is still
acceptable until ICH Q3D comes into force for a given finished product.”

12
6
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.
• Materials/containers : discussion ongoing in group of

experts

13
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

14
7
Example monograph
In the test section :

9 tests

15
Example monograph

16
8
Specific metal tests

 EIs without a PDE (“other elements”, e. g. Fe, Ca, Al): Tests remain
 EIs having a PDE in ICH Q3D: No systematic deletion of individual
tests from monographs
 RISK ANALYSIS FOR EI CONTAMINATION
 Residues from elements intentionally added Covered by general monograph*
 Not intentionally added but potentially present Keep test in monograph
 Potentially introduced from manufacturing equipment  GMP*
 Potentially leached from container closure system  CCS compatibility studies*
*: Not covered in individual monographs

17
Specific metal tests – next steps

First phase
• Each group of experts involved to assess case by case whether the specific
tests can be suppressed (case ,  and ) or maintained (case )
• Focus: Substances of natural origin (mainly mined excipients)
Second phase
• Obtain batch data and revise these tests / or add new ones, if necessary,
based on batch data
Need for more expertise and support (especially from manufacturers)

to revise/maintain these tests

18
9
Acknowledgments
EDQM Special thanks

Dr S. Keitel Dr M. Tuerck, chair of the
Group 9 (inorganics)
Ms C. Vielle
Dr JL Robert, former chair of
Dr U. Rose the EPC
Ms I. Mercier Dr T Gosdschan present chair
Dr E. Pel of the EPC
Ms B. Jacquel

19
Thank you for your attention!

20
10
2017 © EDQM, Council of Europe 16/05/2017
Implementation of ICH Q3D in

the Certification Procedure
PA/PH/CEP (16) 23
Webinar for industry

16 May 2017
Dégardin, Feeney, Seidler, Thouvenel ©2017 EDQM, Council of Europe. All rights reserved.
1
Summary
- Policy document
- Scenario 1: Risk Management Summary provided
- Scenario 2: no RMS provided
- Specification
- Analytical methods
- Limits
- Assessment
- Revision/Renewal
2
1
EU policy for component approach
3
Policy document
PA/PH/CEP (16) 23
published 04/08/2016
in force for all CEPs granted from 01/09/2016
only applicable to substances used in products

within the scope of Q3D
(e.g. not implemented for vet. only, herbals, etc.)
4
2
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.
5
Scenario 1: RMS provided

It should be apparent that the component approach is
followed.
The route of administration should be indicated.
oral, parenteral or inhalation
ICH Q3D option 1 (10 g drug product/d) should be used.
A RMS should be provided:
+ Why are impurities considered?
+ Justification of control strategy
- Screening alone is not a RMS
6
3

Possible way to present RMS:
Source used in known/likely EI Risk assessment Risk of Action
step X of 4 carry-over
Catalyst 4 Pd Homogeneous catalyst (Ph3P)4Pd used in last step. Specification in final

substance.
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.
(does not replace the summary table for the CEP)
7

Which EI should be included in the screening?
Impurities which might reach the control threshold. This could be
for example EI:
- introduced close to the final substance,
- originated from multiple sources,
- with low PDE and/or
- introduced as contaminants of raw materials at highly variable
levels,
- present in packaging material for non-solid APIs/excipients
(leaching study).
8
4

Analytical methods:
For screening
Analytical methodology (ICP-MS/AES / AAS; no
method description) + specificity and sensitivity
In final specification
Detailed method description + full validation
9

CEP:
A risk management summary for elemental impurities has been provided. (Annex 2)
if applicable
− Test for elemental impurities by ICP-MS (Annex 3)
Palladium not more than 10 ppm
10
5

Outcome:
 will be annexed to the CEP Does not restrict the
use of the CEP!
“Yes” for all which have been discussed
< 30% option

1 limit
11

How should EI residues be reported in the table
when they are not considered as absent?
An upper level should be indicated.
Example:
Batch results for an EI To be reported in the table as
conclusion
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
12
6
Scenario 2: no RMS provided

All intentionally introduced EI should be declared
(catalysts, reagents).
Carry-over data should be provided.
13

Analytical methods (in final specification):
Detailed method description + full validation
14
7

CEP:
The following elemental impurity classified in ICH Q3D is intentionally introduced in the
manufacture of the substance: Palladium
or
No elemental impurity classified in ICH Q3D is intentionally introduced in the
manufacture of the substance.
No information about absence of EI on CEP.
15
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
16
8
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
EI intentionally introduced (absent or not)

 Specification as proposed by applicant on CEP
17
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
Routine screening by e.g. ICP-MS: only relevant EI to be mentioned on CEP (not

24 EI on each CEP)
RMS  ≥ 30% or intentionally added
No RMS  no test for contaminants
18
9
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
Pharmeuropa Sep.-Dec. 1989 Vol. I

(rare metals not verified in this study)
not detectable
colour not comparable to lead
 Specific methods should be used.
19
Limits
Limits will be accepted as proposed.
“short term” use.
reproduced from Arzneibuch-Kommentar
20
10
Limits
Unless other quality attributes affected (sulfated

ash, element catalysed degradation).
21
Limits
Limit unrealistic?
mdd 75 mg; API probably only Pd source in DP  1333 ppm toxicologically

acceptable
22
11
Assessment
Catalyst in SM
considered as contaminant and not intentionally
introduced  use of cat. not mentioned on CEP
starting material
modified from Arzneibuch-Kommentar
23
Assessment
Process alternatives
24
12
Assessment
Applicant does not apply option 1 limits but absence can be
concluded.
mdd 200 µg; inhalation  excipients likewise << 10 g
25
Assessment
Use of a CEP to describe a material used in an application
for another CEP.
Se to be mentioned on both CEPs
modified from Arzneibuch-Kommentar
26
13
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.

27
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.
28
14
Revision/Renewal
What to do for existing CEP’s?
- Renewal: Dossiers are systematically reviewed
against the principles of the Gdl.
- Revisions: The Gdl is only considered when

the changes relate to controls for EI, changes
in the mfg process involving addition/removal
of EI, or when an RMS has been provided.
29
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).
30
15
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)
31
Revision/Renewal
No plan to revise all existing CEPs.
Only a small number of CEPs which refer to

“option 2a of Chapter 5.20 of Ph. Eur.” (EMA
guideline) to be revised.
32
16
Conclusion:
Several applications
with RMS received
and
CEPs granted with
RMS as annex.
33
Conclusion:
This is still a new policy for everybody.
Sufficient experience has to be gained on how to
handle ALL scenarios.
The policy will be reviewed in 2017 when more

applications have been received and adopted if
necessary.
34
17
Questions?
EDQM Helpdesk
or
cep@edqm.eu
35
18
2017© EDQM, Council of Europe
EDQM Webinar on Elemental Impurities:

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Elemental Impurities:
16 May 2017

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2017 © EDQM, Council of Europe

©2017 EDQM, Council of Europe. All rights reserved.

Webinar on Elemental Impurities

Welcome to all participants.

To ensure the best experience for you we will

©2017 EDQM, Council of Europe. All rights reserved.

Implementation of the ICH

Webinar on Elemental Impurities

Bruno Spieldenner, Ph. Eur. Department, EDQM

Non specific « heavy metals » test

Bruno Spieldenner ©2017 EDQM, Council of Europe. All rights reserved.

Bruno Spieldenner ©2017 EDQM, Council of Europe. All rights reserved.

Press releases on Ph. Eur.

Content and structure of the

Bruno Spieldenner ©2017 EDQM, Council of Europe. All rights reserved.

Bruno Spieldenner ©2017 EDQM, Council of Europe. All rights reserved.

To be published in Ph Eur suppl. 9.3 [impl. date 01/2018]

Bruno Spieldenner ©2017 EDQM, Council of Europe. All rights reserved.

2. International harmonisation (coordinating pharmacopoeia: USP)

Other general methods : e.g. Heavy metals (2.4.8), Arsenic (2.4.2)

Bruno Spieldenner ©2017 EDQM, Council of Europe. All rights reserved.

• Clarification for the deletion of specifications for substances

To be published in Ph Eur suppl. 9.3 [impl. date 01/2018]

Bruno Spieldenner ©2017 EDQM, Council of Europe. All rights reserved.

Bruno Spieldenner ©2017 EDQM, Council of Europe. All rights reserved.

Outcome of public consultation

For products out of scope of ICH Q3D GL: Some concern

Bruno Spieldenner ©2017 EDQM, Council of Europe. All rights reserved.

• See press release from April 2015:

Bruno Spieldenner ©2017 EDQM, Council of Europe. All rights reserved.

• Materials/containers : discussion ongoing in group of

Bruno Spieldenner ©2017 EDQM, Council of Europe. All rights reserved.

Bruno Spieldenner ©2017 EDQM, Council of Europe. All rights reserved.

In the test section :

Bruno Spieldenner ©2017 EDQM, Council of Europe. All rights reserved.

Bruno Spieldenner ©2017 EDQM, Council of Europe. All rights reserved.

Specific metal tests

 Residues from elements intentionally added Covered by general monograph*

 Not intentionally added but potentially present Keep test in monograph

 Potentially introduced from manufacturing equipment  GMP*

 Potentially leached from container closure system  CCS compatibility studies*

*: Not covered in individual monographs

Specific metal tests – next steps

Need for more expertise and support (especially from manufacturers)

Bruno Spieldenner ©2017 EDQM, Council of Europe. All rights reserved.

EDQM Special thanks

Bruno Spieldenner ©2017 EDQM, Council of Europe. All rights reserved.

Thank you for your attention!

Bruno Spieldenner ©2017 EDQM, Council of Europe. All rights reserved.

Implementation of ICH Q3D in

Webinar for industry

EU policy for component approach

only applicable to substances used in products

Scenario 1: RMS provided

Scenario 1: RMS provided

Catalyst 4 Pd Homogeneous catalyst (Ph3P)4Pd used in last step. Specification in final

(does not replace the summary table for the CEP)

Scenario 1: RMS provided

Scenario 1: RMS provided

Scenario 1: RMS provided

Scenario 1: RMS provided

“Yes” for all which have been discussed

< 30% option