1 helene bruguera [compatibility mode]

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 !


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


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


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 »


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


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


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


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


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


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


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)


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)


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


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)


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



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


� 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


• 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 »



»


Synthesis of «

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 »


(Ph. Eur. impurity B)


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


• < 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”


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


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


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


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


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


• 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


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


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



•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.


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.


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)


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)


www.edqm.euwww.edqm.eu

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