1. Certification of Substances Division,
EDQM Certification scheme: Common deficiencies observed in new chemical applications
Dr P.Poukens-Renwart
Certification of Substances Division,
EDQM & HealthCare
P.Poukens-Renwart Beijing, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved
Pascale Poukens-Renwart, 06/06/08 ©2008 EDQM, Council of Europe, All rights reserved

2. Regulatory background
Active substances in marketing authorisation applications :
Directive 2003/63/EC and the various quality
guidelines give options on how to fulfil the same basic requirements.
The information required is the same regardless of the route selected (CEP or ASMF or Marketing Authorisation Application)
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3. NfG CHMP/QWP/297/97 rev. 1 corr «Summary of requirements for active substances in the quality part of the dossier»
This document describes how to communicate the information on the active substance (API) to authorities in Europe.
It gives three choices:
2.1 Certificate of suitability
2.2 Active Substance Master File (ASMF)
2.3 Full details of manufacture
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4. Useful background (cont)
Resolution AP-CSP(07) 1 of the CoE:
Describes the process for the Certification procedure
Content of the (CEP) dossier: PA/PH/CEP (04) 1, 4R
Describes by section information to be included in the dossier
 Both available on EDQM website
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5. Useful background (cont)
Notes for guidance (ICH + CHMP/CVMP) apply, in particular:
Impurities testing (ICH Q3A + Ph. Eur. General Monograph 2034, Substances for Pharmaceutical Use)
Solvents (ICH Q3C = Ph. Eur. general text 5.4 )
Specifications limits for residues of metal catalysts or metal reagents (CHMP/SWP)
Limits of genotoxic impurities (CHMP-SWP)
(Stability testing (ICH Q1 + CHMP guidelines for existing substances.)
GMP (ICH Q7, Annex 1 to EU GMP)
TSE (CPMP/CVMP guideline = PhEur general text 5.2.8)
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6. Deficiencies
May be observed during validation of the application upon receipt (dossier pre-check)
May be observed during the assessment of the application
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Pascale Poukens-Renwart, 06/06/08 ©2008 EDQM, Council of Europe, All rights reserved

7. After evaluation (the clock has started)
Most applications require one request for additional information (only few applications accepted at the time of first evaluation)
Evaluation of additional information takes 4 months
! A deficient application delays the CEP
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8. Deficiencies: How to avoid them ?
Keep in mind
The scheme is Certification of suitability to the monographs of the EUROPEAN Pharmacopoeia.
References, terminology, etc. should be to the Ph. Eur or at least traceable to it
There is a requirement to show that the monograph is suitable to control the actual quality of your substance.
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9. Top 10 deficiencies (end 2009)
Redefinition of starting material
Carry-over of impurities/solvents from the declared Starting Material(s)
Class I solvents as contaminants of other solvents
Genotoxic impurities
Demonstration that quality of API is equivalent whatever the supplier of SM
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10. Top 10 deficiencies (end 2009)
6. Specification of the Starting Materials
7. Suitability of the monograph
8. Container closure system
9.Compliance with requirements of GM 2034 /limit for
unspecified impurities
10.Solvent recovery
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11. (1) Redefinition of starting material
Synthesis of ofloxacin (one step)
This compound is not accepted as starting material but will be considered as intermediate
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12. (1) Redefinition of starting material (cont)
The approved starting material is the starting point for GMP and must be representative of the overall synthetic process and not just a late intermediate resulting in a shortened synthesis
Applicant must justify the proposed starting material which may or may not be accepted by the assessor and could lead to a redefinition of the starting material
External suppliers may thus become suppliers of intermediates and consequently GMP declarations would be necessary
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13. (2) Carry-over of impurities/solvents from the Starting Materials
Starting material specifications:
Assay (HPLC) NLT 97.0%, water content NMT 1.0%,
impurity X NMT 0.5%, impurity Y NMT 0.8%, any impurity 0.2%, total impurity NMT 2.5%
Impurity X = impurity A of the monograph
Methanol is used in the last step of the synthesis of SM.
API obtained from a 3-step synthesis
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14. (2) Carry-over of impurities/solvents from the Starting Materials (cont)
Starting material specifications should include suitable specifications for methanol and/or its carry-over in the API should be discussed.
Impurity X (PhEur impurity A) should be found in the API < limit of the monograph.
Carry-over of Impurity Y in API should be discussed (justification of its absence/limit to be defined)
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15. (3) Class I solvents as contaminants of other solvents
The following solvents are known to be
contaminated by class I solvents e.g. Benzene:
Acetone
Toluene
Ethanol
Methanol
Isopropanol
Xylene
Hexane
Petroleum ether
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16. (3) Class I solvents as contaminants of other solvents (cont)
ICH guideline Q3C/Ph. Eur. General chapter 5.4
Annexes to Specifications for class 1 and class 2 residual solvents in active substances (CPMP/QWP/450/03)
Where Class 1 solvent might be present in another
solvent, a routine test for this solvent, on a suitable
intermediate or on the final active substance, is not
required when:
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17. (3) Class I solvents as contaminants of other solvents (cont)
Limit applied to originator solvent is such that the Class 1 solvent will be present in the AS at levels below the limits set out in the guideline, taking into account the maximum likely level of contamination of the Class 1 solvent.
Toluene in AS: NMT 200 ppm
Benzene limited to 0.05% in toluene
=> Max level of benzene : 0.1 ppm
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18. (3) Class I solvents as contaminants of other solvents (cont)OR
Demonstration (validated method) that the Class 1 solvent is NMT 30% of its ICH limit, in a suitable intermediate / AS. Supporting data on 6 consecutive pilot scale batches or 3 consecutive industrial scale batches.
Benzene in suitable intermediate / AS:
Data on 6 pilot batches OR data on 3 production batches should be < 0.6 ppm
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19. (3) Class I solvents as contaminants of other solvents (cont)OR
The specification for the originator solvent used includes a routinely performed test and limit for the Class 1 solvent.
Benzene is limited to 20 ppm in toluene and is tested routinely
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20. (4) Genotoxic impurities
Guideline on the Limits of Genotoxic Impurities
(EMEA/CHMP/QWP/251344/2006), in force since 01/2007
Compliance with the NfG to be demonstrated for substance not yet marketed in Europe, or for new routes of synthesis which may lead to a change in the impurity profile
A specific discussion should be provided with regard to impurities with potential genotoxicity (e.g. Structural alert)
The use of the substance may be taken into consideration
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21. (4) Genotoxic impurities (cont)
If no structural alert:
Provide a short illustrative discussion which includes reagents, solvents etc. Synthesis of starting materials should also be considered.
Examples of structural alerts:
N-hydroxyaryls, N-acetylated aminoaryls, aza-aryl N-oxides, alkylated aminoaryls, N Nitrosamines, nitrocompounds, epoxides, aziridines, hydrazines, alkyl esters of phosphonates, mesylates, primary halides …
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22. (4) Genotoxic impurities (cont)
structural alert compound:
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23. (4) Genotoxic impurities (cont)
Carvedilol
Treatment of hypertension
MDD: 100 mg/day
Epoxy moiety is alerting structure
=> TTC approach:
TTC limit: TTC value = 1.5 g = 15 ppm
MDD 0.1 g
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24. (4) Genotoxic impurities (cont)
Carvedilol
TTC limit: TTC value = 1.5 g = 15 ppm
MDD g
If level > 15 ppm : toxicological study necessary
If level is 4.5 ppm – 15 ppm (i.e. > 30% of TTC limit)
Impurity is mentioned on the CEP
If level < 4.5 ppm
Impurity not mentioned on the CEP
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25. (5) Quality of API is equivalent whatever the supplier of SM
Starting material source X:
Impurity A NMT 0.2%
Impurity B NMT 0.3%
Any impurity NMT 0.1%
Total impurity NMT 1.5%
Methanol NMT 3000 ppm
Toluene NMT 890 ppm
Starting material from source Y:
Impurity A NMT 0.3%
Impurity C NMT 0.2%
Any impurity NMT 0.10%
Total impurity NMT 1.0%
Ethanol NMT 4000 ppm
Toluene NMT 890 ppm
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26. (5) Quality of API is equivalent whatever the supplier of SM
Demonstration should be given that the quality of API is equivalent if manufactured using SM from source A or B.
This means that any carry-over of impurity B, impurity C, methanol or ethanol into the API would result in an API with different specifications depending on the starting material used.
In that case 2 CEPs would be necessary to cover the API obtained from each source of starting material.
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27. (6) Specification of the Starting Materials
Specification for SM (e.g p-aminophenol) should include limits for critical compounds used in its synthesis ‘e.g. p-nitrophenol and also likely impurities e.g. ortho isomer
paracetamol
p-nitrophenol
p-aminophenol
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28. (6) Specification of the Starting Materials (cont)
Suitable specifications for assay and purity with consideration for mass balance. Limits for impurities should be justified by batch data and should include a limit for unspecified impurities
Specification Batch data
Assay NLT 90% Assay >98%
Impurity X nmt 3% Impurity X < 0.5%
Total impurities nmt 5% Unspecifieds n.d.
Total impurities <0.5%
Specifications not sufficiently detailed and not justified based on batch data
Mass balance only 95%!
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29. (7)Suitability of the monograph
Acitretin monograph:
Impurities A & B are specified (each NMT 0.3%)
Total impurities NMT 1.0%
Applicant has developed an in-house method which allows the control of PhEur impurities A & B and impurity X which is limited to 0.15%. Total impurities are limited to NMT 1.0%
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30. (7) Suitability of the monograph
Need to address:
Suitability of the method(s) of the monograph must be demonstrated for the detection of all impurities present in the material
->If the method of the monograph is not suitable then need to supplement it with an additional (validated!) method.
Set appropriate limits
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31. (7) Suitability of the monograph
PhEur and in-house methods need to be cross-validated .
Methods are equivalent
 impurity X is limited on the CEP by the PhEur method
Methods are not equivalent (Pheur method does not control impurity X)
 impurity X is limited on the CEP by the in house method (appended to the CEP)
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32. (8) Container closure system
Provide a description of the packaging used (both primary and secondary) e.g. Double LDPE bags in a fiber drum
Provide specifications for the materials used
Refer to compliance with appropriate guidelines (i.e. EMEA CHMP Plastic Primary Packaging Materials (CPMP/QWP/ 4359/03))
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33. (9) Compliance with requirements of GM 2034
In addition to the requirements of the individual monograph, the requirements of the General Monograph 2034 ‘Substances for Pharmaceutical Use’ must be met.
If the individual monograph is not in compliance with GM 2034, the applicant should include an appropriate test and limits (i.e., supplement the monograph).
Daily dose <2g >2g
Reporting threshold 0.05% 0.03%
Identification threshold % 0.05%
Qualification threshold 0.15% 0.05%
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34. (9) Compliance with requirements of GM 2034 (cont)
Metronidazole benzoate monograph states:
Impurities A, B & C NMT 0.1%
Any other impurity NMT 0.1%
Total : NMT 0.2%
Specified impurities: A, B & C
 The above specifications must be completed by a
limit for any unspecified impurity set at NMT 0.10%.
This additional limit will be mentioned on the CEP.
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35. (10) Solvent recovery If recovered solvents are used:
Specifications of recovered solvents should be given and compared to those of pure solvents
Steps where recovered solvents are used should be highlighted
Any potential impact on the impurity profile should be considered
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36. Other deficiencies on impurities (3.2.S.3.2)
In addition to the requirements of the individual monograph, the requirements of the General Monograph 2034, Substances for Pharmaceutical Use, must be met.
In particular, monographs not yet revised which still include a non-specific & non-quantitative TLC method :
->Suitably validated QUANTITATIVE test method for related substances & suitable limits for these impurities must be proposed in the application
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37. Limits for impurities
Impurities of the monograph: apply the limits of the monograph
Additional impurities:
Propose individual limits for specified impurities
Propose individual limits for identified non-qualified impurities
Propose limit for unspecified impurities
Include limit for total related substances
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38. Qualification of impurities
Qualification by use
History of the product
Consistency with manufacturing capability
Shown to be present in other products already approved
Qualification by toxicological data
Or limited to qualification/identification threshold
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39. Impurities: special cases
For products out of the scope of the general monograph 2034 (e.g. antibiotics):
Characterise the impurity profile
Apply the principles of the general monograph (limits for specified, unspecified, total impurities)
Propose justified limits (not necessarily ICH Q3A)  on the CEP
For peptides, revised GM 2034:
Identification threshold: 0.5%
Qualification threshold: 1.0%
Policy applied for new applications and renewals
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40. Thank you !
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