EDQM Certification scheme: Common deficiencies observed in new chemical applications Dr P.Poukens-Renwart Certification of Substances Division, EDQM &

EDQM Certification scheme:Common deficiencies observed in new

chemical applications

EDQM Certification scheme:Common deficiencies observed in new

chemical applicationsDr P.Poukens-Renwart

Certification of Substances Division,

EDQM & HealthCare P.Poukens-Renwart Beijing, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved

Regulatory backgroundRegulatory background

Active substances in marketing authorisation applications :

• Directive 2003/63/EC and the various qualityguidelines 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)

P.Poukens-Renwart Beijing, 30/03/10 ©2010 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»

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 suitability2.2 Active Substance Master File (ASMF)2.3 Full details of manufacture


Useful background (cont)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, 4RDescribes by section information to be included in the dossier

Both available on EDQM websiteP.Poukens-Renwart Beijing, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved

Useful background (cont)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)


DeficienciesDeficiencies

• May be observed during validation of the application upon receipt (dossier pre-check)

• May be observed during the assessment of the application


After evaluation (the clock has started)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


Deficiencies: How to avoid them ?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.


Top 10 deficiencies (end 2009)Top 10 deficiencies (end 2009)

1. Redefinition of starting material2. Carry-over of impurities/solvents from the

declared Starting Material(s)3. Class I solvents as contaminants of other

solvents4. Genotoxic impurities5. Demonstration that quality of API is equivalent

whatever the supplier of SM


Top 10 deficiencies (end 2009)Top 10 deficiencies (end 2009)

6. Specification of the Starting Materials

7. Suitability of the monograph

8. Container closure system9.Compliance with requirements of GM 2034 /limit forunspecified impurities10.Solvent recovery


(1) Redefinition of starting material(1) Redefinition of starting material


• Synthesis of ofloxacin (one step)

This compound is not accepted as starting material

but will be considered as intermediate

(1) Redefinition of starting material (cont)(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


(2) Carry-over of impurities/solvents from the Starting Materials(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


(2) Carry-over of impurities/solvents from the Starting Materials (cont)(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)


(3) Class I solvents as contaminants of other solvents(3) Class I solvents as contaminants of other solvents

The following solvents are known to becontaminated by class I solvents e.g. Benzene:

• Acetone• Toluene• Ethanol• Methanol• Isopropanol• Xylene• Hexane• Petroleum ether


(3) Class I solvents as contaminants of other solvents (cont)(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 anothersolvent, a routine test for this solvent, on a suitableintermediate or on the final active substance, is notrequired when:



• 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 ppmBenzene limited to 0.05% in toluene=> Max level of benzene : 0.1 ppm


(3) Class I solvents as contaminants of other solvents (cont)(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



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


(4) Genotoxic impurities(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


(4) Genotoxic impurities (cont)(4) Genotoxic impurities (cont)

• If no structural alert:If no structural alert:Provide a short illustrative discussion which includes Provide a short illustrative discussion which includes

reagents, solvents etc. Synthesis of starting materials reagents, solvents etc. Synthesis of starting materials should also be considered.should also be considered.

• Examples of structural alerts:Examples of structural alerts:N-hydroxyaryls, N-acetylated aminoaryls, aza-aryl N-oxides, N-hydroxyaryls, N-acetylated aminoaryls, aza-aryl N-oxides, alkylated aminoaryls, N Nitrosamines, nitrocompounds, epoxides, alkylated aminoaryls, N Nitrosamines, nitrocompounds, epoxides, aziridines, hydrazines, alkyl esters of phosphonates, mesylates, aziridines, hydrazines, alkyl esters of phosphonates, mesylates, primary halides …primary halides …



• structural alert compound:



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



Carvedilol – TTC limit: TTC value = 1.5 g = 15 ppm

MDD 0.1 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


(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




• 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.


(6) Specification of the Starting Materials(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


paracetamolp-nitrophenol p-aminophenol

(6) Specification of the Starting Materials (cont)(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 dataAssay 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 dataMass balance only 95%!


(7)Suitability of the monograph(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%


(7) Suitability of the monograph(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


(7) Suitability of the monograph(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)


(8) Container closure system(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))


(9) Compliance with requirements of GM 2034 (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 >2gReporting threshold 0.05% 0.03%Identification threshold 0.10% 0.05%Qualification threshold 0.15% 0.05%


(9) Compliance with requirements of GM 2034 (cont)(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.


(10) Solvent recovery(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


Other deficiencies on impurities (3.2.S.3.2)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


Limits for impuritiesLimits 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


Qualification of impuritiesQualification 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


Impurities: special casesImpurities: 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


Thank you ! Thank you !


Documents

EDQM Certification scheme: Common deficiencies observed in new chemical applications Dr P.Poukens-Renwart Certification of Substances Division, EDQM &