Transcript Diapositive 1

Common deficiencies observed
in new chemical applications
Dr P.Poukens-Renwart
Certification of Substances Division,
EDQM & HealthCare
P.Poukens-Renwart 07/09/09 ©2009 EDQM, Council of Europe, All rights reserved
Regulatory background
Active substances in marketing 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
Application)
P.Poukens-Renwart 07/09/09 ©2009 EDQM, Council of Europe, All rights reserved
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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Useful background
• 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
 Both available on EDQM website
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Useful background
• 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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Deficiencies
• Observed during the validation process of the
application (see presentation 5th September)
• Observed during assessment process of the
application
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After evaluation (the clock has started)
• Most applications require one or several requests
for additional information (3% only of 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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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.
P.Poukens-Renwart 07/09/09 ©2009 EDQM, Council of Europe, All rights reserved
Top 10 deficiencies (end 2008)
1.
2.
3.
4.
5.
6.
Carry-over of impurities/solvents from the
declared Starting Materials
Class I solvents as contaminants of other
solvents
Genotoxic impurities
Container closure system
Specification of the Starting Materials
Compliance with requirements of GM 2034 /
limit for unspecified impurity
P.Poukens-Renwart 07/09/09 ©2009 EDQM, Council of Europe, All rights reserved
Top 10 deficiencies (end 2008)
6. Compliance with requirements of GM 2034 /limit for
unspecified impurity.
7. Purity test for solvents/reagents
8. Residual catalyst
9. Suitability of the monograph
9. Solvent recovery
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(1) 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 2-step synthesis
P.Poukens-Renwart 07/09/09 ©2009 EDQM, Council of Europe, All rights reserved
(1) Carry-over of impurities/solvents from
the Starting Materials (cont)
• Starting material specifications should include
suitable specifications for methanol and/or its carryover 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)
P.Poukens-Renwart 07/09/09 ©2009 EDQM, Council of Europe, All rights reserved
(2) 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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(2) 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:
P.Poukens-Renwart 07/09/09 ©2009 EDQM, Council of Europe, All rights reserved
(2) 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
P.Poukens-Renwart 07/09/09 ©2009 EDQM, Council of Europe, All rights reserved
(2) 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
P.Poukens-Renwart 07/09/09 ©2009 EDQM, Council of Europe, All rights reserved
(2) 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
P.Poukens-Renwart 07/09/09 ©2009 EDQM, Council of Europe, All rights reserved
(3) 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 in the application
with regard to impurities with potential genotoxicity
The use of the substance may be taken into consideration
Look for structural alert.
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(3) Genotoxic impurities (cont)
If no structural alert => Provide a short illustrative discussion
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(3) Genotoxic impurities (cont)
• Structural alert compound:
N-hydroxyaryls, N-acetylated aminoaryls,
aza-aryl N-oxides, alkylated aminoaryls, N
Nitrosamines, nitrocompounds, epoxides,
aziridines, hydrazines, alkyl esters of
phosphonates, mesylates, primary halides,
…
P.Poukens-Renwart 07/09/09 ©2009 EDQM, Council of Europe, All rights reserved
(3) Genotoxic impurities (cont)
• structural alert compound:
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(3) 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
P.Poukens-Renwart 07/09/09 ©2009 EDQM, Council of Europe, All rights reserved
(3) Genotoxic impurities (cont)
• Carvedilol
– TTC limit: TTC value = 1.5 g = 15 ppm
MDD
0.1 g
– If level > 15 ppm : toxicological study
– If 4.5 ppm (30% of TTC limit) < level < TTC limit
• Mention on CEP
– If level < 4.5 ppm
• No mention on CEP
P.Poukens-Renwart 07/09/09 ©2009 EDQM, Council of Europe, All rights reserved
(4) Container closure system
The applicant states:
• « A re-test period of 3 year is requested for the
substance stored in HDPE double bag ».
• The container is a transparent plastic bag (10 x 20 cm)
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(4) Container closure system (cont)
• Provide a description of the packaging used (1ary
and 2ary)
• Provide specification of materials used
• Refer to compliance with appropriate guidelines (i.e.
EMEA CHMP Plastic Primary Packaging Materials
(CPMP/QWP/4359/03))
P.Poukens-Renwart 07/09/09 ©2009 EDQM, Council of Europe, All rights reserved
(5) Specification of the Starting Materials
• Specification for SM (e.g p-aminophenol). should include
limit for critical compounds used in its synthesis ‘e.g. pnitrophenol)
P.Poukens-Renwart 07/09/09 ©2009 EDQM, Council of Europe, All rights reserved
(5) Specification of the Starting Materials (cont)
Applicant to propose and justify which
substance(s) is the starting material(s) e.g.
incorporated as a significant structural fragment into
the structure of the final substance.
P.Poukens-Renwart 07/09/09 ©2009 EDQM, Council of Europe, All rights reserved
(6) Compliance with requirements of GM 2034
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
P.Poukens-Renwart 07/09/09 ©2009 EDQM, Council of Europe, All rights reserved
(6) Compliance with requirements of GM 2034 (cont)
• 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 supply an
appropriate test and limits (i.e., supplement the
monograph).
P.Poukens-Renwart 07/09/09 ©2009 EDQM, Council of Europe, All rights reserved
(6) Compliance with requirements of GM 2034 (cont)
Specifications for metronidazole benzoate should
be completed by a limit for any unspecified impurity
set at NMT 0.10%.
 This additional limit will be mentioned on the CEP
P.Poukens-Renwart 07/09/09 ©2009 EDQM, Council of Europe, All rights reserved
(7)Purity test for solvents/reagents
• Acetone: water NMT 0.6%, residue on evaporation NMT
0.001%.
• Dimethylbutyryl chloride (used as reagent in the last
step):assay NLT 98.0%.
Purity should be defined.
Suitable mass balance should be observed between
purity and related substances limits.
P.Poukens-Renwart 07/09/09 ©2009 EDQM, Council of Europe, All rights reserved
(8) Catalysts
• In the manufacture of substance Z, Pd/C is used in
the 2d step (out of 3).
• The substance complies with the heavy metal test
• Pd content found on 5 batches is up to 4 ppm
• Substance Z is for oral use only
P.Poukens-Renwart 07/09/09 ©2009 EDQM, Council of Europe, All rights reserved
(8) Catalysts (cont)
 Limit or absence to be demonstrated
 CHMP guideline on the specification limits for
residues of metal catalysts or metal reagents
(CPMP/SWP/4446/00; effective from 1st
September 2008) is a useful base.
P.Poukens-Renwart 07/09/09 ©2009 EDQM, Council of Europe, All rights reserved
(8) Catalysts (cont)
• Test for heavy metals is not suitable to control Pd.
 Results from AAS need to be taken into account
• According to CPMP/SWP/4446/00, the limit for Pd
(oral use) is 10 ppm
• Pd needs to be limited on the CEP since found at
significant level (> 30% of 10 ppm)
P.Poukens-Renwart 07/09/09 ©2009 EDQM, Council of Europe, All rights reserved
(9) 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%
P.Poukens-Renwart 07/09/09 ©2009 EDQM, Council of Europe, All rights reserved
(9) 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
P.Poukens-Renwart 07/09/09 ©2009 EDQM, Council of Europe, All rights reserved
(9) Suitability of the monograph
• PhEur and in-house methods need to be crossvalidated .
• 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)
P.Poukens-Renwart 07/09/09 ©2009 EDQM, Council of Europe, All rights reserved
(9) Solvent recovery
• Recovered solvents used?
– If yes
 Specifications of recovered solvents should be
given and compared to those of pure solvents
 Steps where recovered solvents are used
should be highlighted.
P.Poukens-Renwart 07/09/09 ©2009 EDQM, Council of Europe, All rights reserved
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
P.Poukens-Renwart 07/09/09 ©2009 EDQM, Council of Europe, All rights reserved
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 nonqualified impurities
– Propose limit for unspecified impurities
– Include limit for total related substances
P.Poukens-Renwart 07/09/09 ©2009 EDQM, Council of Europe, All rights reserved
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
P.Poukens-Renwart 07/09/09 ©2009 EDQM, Council of Europe, All rights reserved
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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 Thank you !
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