Evaluation of substances i Certification H. Bruguera ©2014 EDQM, Council of Europe, All rights reserved Vrsac, 14-15 N Mrs Hélène Head of the Certifica the quality of in the EDQM n procedure November 2014 e BRUGUERA ation Division, EDQM
Evaluation of the quality of substances in the EDQMCertification procedureCertification procedure
H. Bruguera ©2014 EDQM, Council of Europe, All rights reserved
Vrsac, 14-15 November 2014
Mrs Hélène BRUGUERA
Head of the Certification Division, EDQM
Evaluation of the quality of substances in the EDQMCertification procedureCertification procedure
15 November 2014
Mrs Hélène BRUGUERA
Head of the Certification Division, EDQM
HAPPY BIRTHDAY ALIMS !
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ALIMS !HAPPY BIRTHDAY
ALIMS !ALIMS !
The EDQM
• European Directorate for the Quality of Medicines & HealthCare
• A directorate from the Council of Europe, international organisation promoting democracy, rules of laws and human rightshuman rights
• Located in Strasbourg, France
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The EDQM
European Directorate for the Quality of Medicines &
A directorate from the Council of Europe, international organisation promoting democracy, rules of laws and
Located in Strasbourg, France
The Ph. Eur
• A common Pharmacopoeia for 37 countries (+EU) + 25 observers (+WHO)
• Contains general texts, general chapters, general monographs and individual monographs
• Mandatory standards with the same implementation • Mandatory standards with the same implementation date in all countries
• 50 years in 2014
• 8th edition in force since January
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The Ph. Eur
A common Pharmacopoeia for 37 countries (+EU) +
Contains general texts, general chapters, general monographs and individual monographs
Mandatory standards with the same implementation Mandatory standards with the same implementation
edition in force since January
The Certification procedure
• Created in 1994, linked to the European Pharmacopoeia
• Assessment of the quality of pharmaceutical substances with regards to the criteria of the Ph. Eur. monograph(s) (“chemical”
� Ensures that all possible impurities � Ensures that all possible impurities can be suitably controlled (or not)
� Demonstrates compliance of European regulatory requirements
• Guarantee compliance with the general monograph on Products with TSE risk
� « TSE CEP »
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The Certification procedure
Created in 1994, linked to the European Pharmacopoeia
Assessment of the quality of pharmaceutical substances with regards to the criteria of the Ph. Eur.
(“chemical” or “herbal” CEP)
Ensures that all possible impurities of a source of substance Ensures that all possible impurities of a source of substance suitably controlled (or not) by the monograph(s)
compliance of a source of a substance withrequirements
Guarantee compliance with the general monograph on
The CEP procedure (2)• Contributes to updating Ph.
• Includes the EDQM Inspection manufacturers
• Procedure is optional – in the EU, • Procedure is optional – in the EU, between 3 different proceduresactive substances in the quality
� CEP
� ASMF
� Full details in Module 3 of the marketing applications
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The CEP procedure (2)Contributes to updating Ph. Eur monographs
Includes the EDQM Inspection programme for API
in the EU, applicant has the choicein the EU, applicant has the choiceprocedures (« Summary of requirements for
dossier »):
in Module 3 of the marketing applications
The Certification procedure (3)
Benefits:
• Centralised assessment
• Easier management of marketing authorisation applications – CEP replaces main part of 3.2.S of CTDCTD
• CEPs accepted in Ph. Eur. countries + others (eg. Canada, Australia, Singapore, etc.)
=> saving of time & money for applicants and National Authorities
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The Certification procedure (3)
marketing authorisation CEP replaces main part of 3.2.S of
CEPs accepted in Ph. Eur. countries + others (eg. Canada, Australia, Singapore, etc.)
=> saving of time & money for applicants and National
Scope
• Substances described in monographs in the Ph. Eur.
�Active substances, excipients, herbal drugs / herbal preparations
• Products with risk of TSE (APIs, raw materials, intermediates, reagents,..)intermediates, reagents,..)
Open to any manufacturer regardless of geographical origin
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Scope
Substances described in monographs in the Ph. Eur.
, excipients, herbal drugs /
Products with risk of TSE (APIs, raw materials, intermediates, reagents,..)intermediates, reagents,..)
Open to any manufacturer regardless of
How to obtain a CEP• Intended holder to send an application to EDQM
– Guidelines, application form, available on the EDQM website
– Dossier describes manufacture & quality control of the substance
• Application assessed by 2 assessors• Application assessed by 2 assessorsco-rapporteur), 1 from EDQM and 1 authority, who both sign the report
• EDQM is in charge of consistencyreview, communication with
• Generally a new CEP is obtained
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How to obtain a CEPIntended holder to send an application to EDQM
Guidelines, application form, available on the EDQM
Dossier describes manufacture & quality control of the
assessors (rapporteur and assessors (rapporteur and EDQM and 1 from a national
the report
consistency with policies, peer-with applicants
obtained within 18 months
Policies for assessment of an application
• Based on ICH and EU requirements & quality guidelines for pharmaceutical substances (mainly APIs)
• Specific EDQM policies prepared for more detailed guidance and harmonisation purposesguidance and harmonisation purposes
� Adopted by the Certification Steering Committee (SC)
� Circulated to assessors for implementation
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Policies for assessment of an application
Based on ICH and EU requirements & quality guidelines for pharmaceutical substances (mainly APIs)
Specific EDQM policies prepared for more detailed guidance and harmonisation purposesguidance and harmonisation purposes
Adopted by the Certification Steering Committee (SC)
Circulated to assessors for implementation
Hot topics for assessment
• Regularly EDQM publishes a document called “Top 10 deficiencies in CEP applications” (EDQM website)
• Useful for applicants to identify “hot topics” and to prepare better applications
• Current hot topics include:• Current hot topics include:
� Definition and quality of the API starting materials
� Genotoxic impurities
� Metal residues
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Hot topics for assessment
Regularly EDQM publishes a document called “Top 10 deficiencies in CEP applications” (EDQM website)
Useful for applicants to identify “hot topics” and to prepare better applications
Current hot topics include:Current hot topics include:
Definition and quality of the API starting materials
API Starting materials
Background:
• More and more manufacturers of APIs propose short steps (1 or 2) synthesis
• Proposed Starting Materials to the final APIto the final API
• API Starting Materials are often
• Poor level of information on impurities and their control from Starting Materials
� The proposed SM(s) are not accepted in a large number of cases and redefinition of the SMsdeficiency)
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API Starting materials
More and more manufacturers of APIs propose short
Materials have a structure very close
API Starting Materials are often outsourced/purchased
Poor level of information on impurities and their control
proposed SM(s) are not accepted in a large number of is then requested (Top 2
Regulatory guidance
• EU NfG on the chemistry of new active substance CPMP/QWP/130/96, Rev 1 (February 2004)
• ICH Q7: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (November 2000)
• ICH Q11: Development and manufacture of drug substances • ICH Q11: Development and manufacture of drug substances (May 2012)
• EU reflection paper on API Starting Materials (October 2014)
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Regulatory guidance
EU NfG on the chemistry of new active substance CPMP/QWP/130/96, Rev 1 (February 2004)
Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (November 2000)
ICH Q11: Development and manufacture of drug substances ICH Q11: Development and manufacture of drug substances
EU reflection paper on API Starting Materials (October 2014)
API Starting material / what to do• The approved starting materials
and variations and must be representativesynthetic process
• The synthetic steps critical for the API should be included in the description of the process (S.2.2)
• Purification, salt formation, saltconsidered synthetic step
• A one step synthesis is not acceptablecircumstances:
� If API SM described in Ph. Eur. and covered by a CEP
� If API SM is an active substance authorised in a EU
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API Starting material / what to domaterials are the starting point for GMP
representative of the overall
he synthetic steps critical for the safety and the efficacy of the API should be included in the description of the process (S.2.2)
transformation or milling are not
not acceptable unless in certain specified
If API SM described in Ph. Eur. and covered by a CEP
API SM is an active substance authorised in a medicine in
API Starting material / what to do (2)
• Name and address of manufacturers of Starting Materials (SM) should be given
• Discussion on impurities present in the API SM + possibility of their carry over (or as derivatives) into the final API (deficiency)
• Information about the synthesis of the SM (flowassessors to judge of the suitability of the proposed specifications
• Information about the synthesis of the SM (flowassessors to judge of the suitability of the proposed specifications
• Complete specifications of the SM should be described including suitable limits for impurities (know, unknown, total), and also solvents, catalysts, etc. Analytical methods should be described (Top 5 deficiency)
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API Starting material / what to do (2)
Name and address of manufacturers of Starting Materials (SM)
Discussion on impurities present in the API SM + possibility of their carry over (or as derivatives) into the final API (Top 1
Information about the synthesis of the SM (flow-chart) to enable assessors to judge of the suitability of the proposed specificationsInformation about the synthesis of the SM (flow-chart) to enable assessors to judge of the suitability of the proposed specifications
Complete specifications of the SM should be described including suitable limits for impurities (know, unknown, total), and also solvents, catalysts, etc. Analytical methods should be described
« Quinolone »
« Piperazine »
Example: synthesis of Aripiprazole
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Example: synthesis of Aripiprazole
Redefinition always requested by EDQM
• Suitability (or unsuitability) of the method(s) of the monograph to control all the related substances of the source of API should be demonstrated
� Compare the impurity profile with the transparency list of the monograph
� For impurities present in the substance and not listed (“in
How to set specificationsRelated substances
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� For impurities present in the substance and not listed (“inimpurities”, verify if Ph. Eur method is able or not to control
• If the Ph. Eur method is not suitable to control inimpurities then an additional (proposed
• For in-house related substances, establish a suitable limit (qualification, identification)
of the method(s) of the monograph to control all the related substances of the source of API should be demonstrated
Compare the impurity profile with the transparency list of the
For impurities present in the substance and not listed (“in-house
specifications for impurities? Related substances
For impurities present in the substance and not listed (“in-house method is able or not to control
method is not suitable to control in-house impurities then an additional (validated) method has to be
house related substances, establish a suitable limit
How to set specificationsGenotoxic impurities
Reference documents:� “Guideline on the limits of genotoxicEMEA/CHMP/QWP/251344/2006 (in force since 01/2007)� “Q&As on the Guideline on the limits of
EMA/CHMP/SWP/431994/2007 Rev.3 (adopted 09/2010)
• Applies to substances not marketed
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• Applies to substances not marketedof synthesis which may lead to a
• Not applied retrospectively to authorisedspecific concerns for genotoxicity are shown by recent data
• N.B. A specific discussion on potential expected in the dossier (section 3.2.S.3.2)
specifications for impurities? Genotoxic impurities
genotoxic impurities”EMEA/CHMP/QWP/251344/2006 (in force since 01/2007)
Q&As on the Guideline on the limits of genotoxic impurities”EMA/CHMP/SWP/431994/2007 Rev.3 (adopted 09/2010)
marketed in Europe or for new routesmarketed in Europe or for new routesa change in the impurity profile
authorised products unless specific concerns for genotoxicity are shown by recent data
N.B. A specific discussion on potential genotoxic impurities is expected in the dossier (section 3.2.S.3.2)
« Quinolone »
« Piperazine »
Example: synthesis of Aripiprazole
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»
Example: synthesis of Aripiprazole
Synthesis of «
Several reagents and intermediates have structural alerts
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Several reagents and intermediates have structural alerts
Bis(2-chloroethyl)amine and 2,3-dichloroaniline can be limited in [B] or in [D] ”if it is unambiguously demonstrated by analysis results that their presence of this impurity does not exceed 30% of the limit, derived either from TTC or otherwise defined acceptable limit etc, in the drug substance”[question 9, example 2 of Q&A document]
- thionyl chloride: complete hydrolysis ensured
of « piperazine »
Several reagents and intermediates have structural alerts
(Ph. Eur. impurity B)
Several reagents and intermediates have structural alerts
dichloroaniline can be limited in [B] or in [D] ”if it is unambiguously demonstrated by analysis results that their presence of this impurity does not exceed 30% of the limit, derived either from TTC or otherwise defined acceptable limit etc, in the drug substance”[question 9, example 2 of Q&A document]
thionyl chloride: complete hydrolysis ensured ?
Genotoxic impurities
Aripriprazole TTC-based limit for an
If pGTI found in the final drug substance at
• > 50 ppm : toxicological study necessary
• 15 – 50 ppm (> 30% of TTC limit): introduce
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• < 15 ppm and limited in an intermediate
• < 15 ppm and NOT limited in an intermediatespecification of API
• Any pGTI likely to be formed in last of API
Alternatively tox data may be provided to show absence of
Genotoxic impurities
for an alerting structure= 50 ppm
substance at levels:
necessary
introduce in the specification of API
intermediate: not in the specification
intermediate: introduce in the
in last step is introduced in the specification
data may be provided to show absence of genotoxicity
How to set specificationsMetal catalysts
Reference documents:
� EMA Guideline on the Limits of (EMEA/CHMP/SWP/4446/2000
� EMA Q & A “Harmonisation of policies on setting specifications for potentially genotoxic impurities, heavyfor potentially genotoxic impurities, heavyresidues and class-1 solvent residues”
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specifications for impurities? Metal catalysts
Guideline on the Limits of Metal Residues EMEA/CHMP/SWP/4446/2000)
of policies on setting specifications for potentially genotoxic impurities, heavy-metal-catalyst for potentially genotoxic impurities, heavy-metal-catalyst
residues”
Voriconazole – route of
acc. to “The Art of Drug Synthesis”, John Wiley & Sons, 26.02.2013
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No specific test in monograph.Deliberately introduced metals: Zn, Pd, Pb
route of synthesis
acc. to “The Art of Drug Synthesis”, John Wiley & Sons, 26.02.2013
No specific test in monograph.Deliberately introduced metals: Zn, Pd, Pb
EMA Guideline on the specification for residues of metal catalysts or metal reagents:
Voriconazole
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EMA Guideline on the specification for residues of metal catalysts or metal
Voriconazole
Voriconazole
• Zinc: class 3 metal
� “For class 3 metals, the test may be deleted from the relevant specification if adequate removal of the metal residue from the API is guaranteed.” (<30% of the limit in 3 industrial batches)
� � Demonstrate absence� � Demonstrate absence
• Pd: class 1 metal
� Pd is introduced in last synthetic step. No formation or breaking of a covalent bond afterwards.
� Class-1 metal introduced in the final synthesis step, to be included in the specifications
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Voriconazole
“For class 3 metals, the test may be deleted from the relevant specification if adequate removal of the metal residue from the API is guaranteed.” (<30% of the limit in 3 industrial
Pd is introduced in last synthetic step. No formation or breaking of a covalent bond afterwards.
1 metal introduced in the final synthesis step, to be included in the specifications
Voriconazole
• Pb: not listed in EMA guideline
� Of higher toxicity than EMA class 1 metals
� PDE proposed in ICH Q3D is 5 µg/day
� Treat similar to EMA metals. Propose and justify a limit and control strategy
� Control in intermediate is possible together with demonstration of absence (< 30% of limit) in the API
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Voriconazole
not listed in EMA guideline
Of higher toxicity than EMA class 1 metals
PDE proposed in ICH Q3D is 5 µg/day
Treat similar to EMA metals. Propose and justify a limit and
Control in intermediate is possible together with demonstration of absence (< 30% of limit) in the API
How to set specificationsClass 1 and Class 2 solvents
Reference documents
� ICH Q3C / Ph.Eur. General Chapter
� CPMP/QWP/450/03 “Annex 1: specifications for class 1 and class 2 residual solvents in active substances”
• The use of Class 1 solvents should be avoided unless strongly
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• The use of Class 1 solvents should be avoided unless strongly justified
• Many solvents are known to be contaminated by For example, benzene is potentially present in acetone, toluene, ethanol, methanol, isopropanol, xylene, hexane and petroleum ether. This is acceptable provided a demonstration is given that benzene residues are not present in the API (
specifications for impurities? Class 2 solvents
. General Chapter 5.4
“Annex 1: specifications for class 1 and class 2 residual solvents in active substances”
The use of Class 1 solvents should be avoided unless strongly The use of Class 1 solvents should be avoided unless strongly
Many solvents are known to be contaminated by class 1 solvents. For example, benzene is potentially present in acetone, toluene, ethanol, methanol, isopropanol, xylene, hexane and petroleum
. This is acceptable provided a demonstration is given that benzene residues are not present in the API (Top 6 deficiency).
Class 1 solvents as contaminant of another solvent
Where a class 1 solvent mightroutine test for this class 1 solventoptions listed is met:
• Option 1. Limit applied to originator1 solvent will be present in theICH limit, taking into account
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1 solvent will be present in theICH limit, taking into accountcontamination of the Class 1 solvent
Toluene in API: NMT 200 ppm
Benzene in toluene: NMT 500 ppm
Class 1 solvents as contaminant of another solvent
be present in another solvent, asolvent is not required if one of the 3
originator solvent is such that the classthe API at levels below 30% of the
account the maximum likely level ofthe API at levels below 30% of the
account the maximum likely level ofsolvent.
ppm Max level of benzene in the API: 0.1 ppm
•Option 2. Demonstration (validatedsolvent is NMT 30% of its ICHfinal API. Supporting data on 6 consecutiveconsecutive industrial scale batches
Class 1 solvents as contaminant of another solvent
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•Option 3. The specificationincludes a routinely performed test
� Benzene limited to NMT 20 ppm
(validated method) that the class 1limit in a suitable intermediate or
consecutive pilot scale batches or 3batches.
Class 1 solvents as contaminant of another solvent
for the originator solvent usedtest and limit for the class 1 solvent.
ppm in toluene and tested routinely
• All Class 2 solvents used in the purification steps of the synthesis should be included in the specification and routinely controlled in API (even if demonstrated absent)
• For a class 2 solvent used prior to of a limit in the specification of the API
How to set specificationsClass 2 solvents
of a limit in the specification of the API its content has been demonstrated to be the corresponding ICH limitfinal substance.
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All Class 2 solvents used in the purification steps of the synthesis should be included in the specification and routinely controlled in API (even if demonstrated
used prior to purification, inclusion of a limit in the specification of the API is not required if
specifications for impurities? Class 2 solvents
of a limit in the specification of the API is not required if demonstrated to be NMT 10% of
limit, in an intermediate or in the
Certification- Key figures
• More than 5800 CEP applications received for >850 different substances
• Currently more than 3800 valid CEPs public database www.edqm.eu
• More than 1000 manufacturers from 50 different • More than 1000 manufacturers from 50 different countries
• >275 sites inspected, in 26 countries (mainly in Asia)
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Key figures
More than 5800 CEP applications received for >850
Currently more than 3800 valid CEPs (list available in the www.edqm.eu)
More than 1000 manufacturers from 50 different More than 1000 manufacturers from 50 different
countries (mainly in Asia)
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www.edqm.euwww.edqm.eu