how to prepare a new cep application top ten deficiencies during

How to prepare a new CEP applicationTop ten deficiencies during assessment

of CEP dossiers

P.Poukens-Renwart, PhDEuropean Directorate for the Quality of

Medicines & HealthCare (EDQM) Hyderabad, 27 September 2012

P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved

Summary

• How to apply for a new CEP • How to avoid deficiencies?• Some data


Reminder of the Scope of the CEP procedure

• Substances described in monographs in the Ph. Eur. (Active substances, excipients, herbal drugs / herbal preparations) if you apply for a “Chemical” or “Herbal” CEP.

• Products with risk of TSE (SM, intermediates, reagents,..) if you apply for a “TSE” CEP


Out of Scope of the CEP procedure

• Substances not included in Ph. Eur• Human tissues derivatives, blood derivatives,

vaccines• Finished products• Products extracted from animal tissues (still

acceptable for TSE risk): – Ex. heparins, aprotinin,….


Requirements for a complete application:

• Application form (for new application) available from www.edqm.eu (updated version to be used from 01 September 2012– Contains tables to be filled in, statements and declarations to

be signed

• Quality Overall Summary using the template available on the EDQM website

• Dossier


Requirements for a complete application:• Dossier in English preferably (or French); single copy;

• Content in compliance with:- Content of the Dossier for Chemical CEP :

comparable to ASMF or 3.2.S of CTD- For TSE risk CEP: requirements from Ph Eur general

text, 5.2.8 (=EU nfg)- Content of the dossier for herbal drugs/herbal drug

preparations


Requirements for a complete application:

• Fee: 3000 Euros - to be paid after receipt and invoicing

• Electronic submissions encouraged (eCTD, NeeS, pdf). Guidance available on our website PA/PH/CEP (09) 108, 1R(www.edqm.eu)


Electronic submission requirements:

• Content of submission:Module 1 containing :

• application form (including declarations)• cover letter• Expert (information about expert, CV etc.)• other supporting information (e.g. Toxicological

report, signed copy of referenced CEP etc.)Module 2 containing

• Quality Overall Summary, in pdf format using template available from the EDQM website



Module 3 containing:• Dossier containing technical documentation in

CTD format.

Notes: eCTD welcome.The draft guidance document from EMA “Practical guidelines on the use of the eCTD format for ASMFs for Active Substance Master File Holders and Marketing Authorisation Holders” may be used as a basis and this may be found at:

http://esubmission.ema.europa.eu/doc/index.htmlIt is not encouraged to submit Applicant’s and Restricted parts but it can be accommodated.



• Choice of formats:

PDFNeeSeCTD (only for chemical CEP applications not for TSE applications)



• PDF:• The documents in module 1 should typically be

submitted as individual pdf files within the module structure.

• The eQos should be submitted in module 2 as a single pdf

• The technical dossier should be submitted in module 3 as a single pdf structured and bookmarked according to CTD format.


Electronic submission requirements:• NeeS:

The guidance documents for a NeeS submission are available at the following internet locations:

• The NeeS structure and specification should be in accordance with the following guidance:http://esubmission.emea.europa.eu/doc/eGuidance_Document_1.4.pdf

• The validation criteria for NeeS may be found at:• http://esubmission.emea.europa.eu/doc/EU%20NeeS%20validati

on%20Criteria%20v1.0.pdf• The CTD file/directory structure shall be implemented with the

addition of a Table of Content(s) as appropriate.


Electronic submission requirements:• eCTD:

• Submission of an eCTD is recommended for chemical submissions. The eCTD structure should be in accordance with the current ICH M2 EWG eCTD specification which can be found at:

• - ICH eCTD specification: • http://estri.ich.org/eCTD/index.htm• - EU M1 eCTD specification:

http://esubmission.ema.europa.eu/eumodule1/index.htm

• The eCTD CEP dossier remains, from a technical perspective, a stand alone dossier and is distinct from any marketing authorisation eCTD dossier and lifecycle.


CEP Process Overview:


Administrative validation at receipt

* Dossier not in CTD format* QOS is missing or not signed* Dossier is not written in official language* Electronic submission not in accordance

with the requirements


Administrative validation at receipt

Dossier is also blocked when: • Information from application form is missing:

– Names and addresses of the parties involved– Agreement letters

o Representative agent or when holder ≠ manufacturer– Declaration of Manufacture according to the dossier and GMP

(ICH Q7/EU GMP if sterile)– Declaration of Willingness to be inspected

o Manufacturer, and holder if different – Use of animal (TSE risk or other origin) / human material– Holder’s commitments


Technical validation at reception

• Summarise the commercial history - make clear if, and in what product THIS source of API is on the EUROPEAN market. Information on ASMF submitted for the same substance

• Give as much information as possible (companies, products names, countries, registration dates, marketing dates). --> Impact on Qualification (limits) of impurities


Technical validation at reception (cont)

• Clarify whether a retest period is requested (recommended) and if yes, specify the proposed retest period:

• Justified by stability data based on ICH conditions studies• Recommended storage conditions

• Specify the packaging material (primary & secondary packaging will be mentioned on the CEP)


Technical validation at reception (cont) Applications are blocked when:

• Reference is made to an old version of the Ph. Eur monograph• Description of route of synthesis and/or impurity profile of the

starting material is missing• Use of Class I solvents without justification and control• Unsuitable information on impurities, solvents,…• Absence of validation data for analytical methods• Absence of quantitative method to replace a non-specific TLC test

of the monograph• Sterile substances: absence of validation data on the sterilisation


Technical validation at reception (cont)

Application blocked (20% in 2011)

information not suitable to start the evaluation processthe clock does not start until suitable information is

given

An incomplete application delays the CEP!!!

⇒Read PA/PH/Exp CEP/T (08) 37 Note for applicants: « Procedure for validation of new applications »


Evaluation 1

•• After validation is satisfactorily completed, the dossier After validation is satisfactorily completed, the dossier is then evaluated is then evaluated –– EDQM has 5 months to complete EDQM has 5 months to complete the evaluation and inform the applicant of the the evaluation and inform the applicant of the outcome.outcome.

•• →→ Currently the deadlines are being respected.Currently the deadlines are being respected.

•• See monthly report published on See monthly report published on www.edqm.euwww.edqm.eu


Streamlined evaluation procedure

•• 1 deficiency letter only 1 deficiency letter only

•• if responses unsuitable if responses unsuitable →→ dossier closeddossier closed

•• →→ Important to avoid deficiencies.Important to avoid deficiencies.


Deficiencies: How to avoid them ?• Read :

PA/PH/ CEP (04) 1 4R issued, February 2007,entitled “Content of the dossier for chemical purity and microbiological quality”

It is FREE,It is available on our website.It describes what we expect to see in the dossier.


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.


Deficiencies: How to avoid them ?

• The top ten deficiencies observed in applications treated in 2011 is listed in this presentation

• The corresponding summary is published on the EDQM website.


Top 10 deficiencies (beginning of 2011)1. Route of synthesis from the declared starting

material(s), carry-over of impurities / solvents

2. Redefinition of starting material(s)2. Genotoxic impurities

4. Demonstration that quality of the substance is equivalent whatever the supplier of starting material(s)

5. Specification of starting material(s)


Top 10 deficiencies (beginning 2011)6. Class I solvents as contaminants of other solvents6. Specification of reagent(s) / solvents(s)

8. Limits for impurities in key intermediate(s)

9. Cross validation PhEur / In-house methods for related substances

10. Maximum batch size10. Suitability of the monograph


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

EXAMPLE:• 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• Substance obtained from a 3-step synthesis


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

What do we expect as information?• 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)


(2) Redefinition of starting material• The approved starting material is the starting point for GMP and

variations and must be representative of the overall synthetic process, and not just a late intermediate resulting in a shortened synthesis. There should be a sufficient number of steps.

• 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/willingness to be inspected declarations becomenecessary

NB Information submitted from third parties is not acceptable. The applicant must be aware of the information supplied.


(2) Redefinition of starting material (cont.)


• Synthesis of ofloxacin (one step described in the file)

Q-Acid is a complex compound. It cannot be accepted as a starting material but will be considered as an intermediate

(2) Genotoxic impuritiesGuideline 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 in showing compliance to NfG (short term use see EMA Q&A document)

NB: not applied retrospectively to authorised products unless there is recent data demonstrating the genotoxicity of a specific compound relevant to the application


(2) 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 …



• structural alert compound:



Carvedilol– Treatment of hypertension– MDD: 100 mg/day

– Epoxy moiety is alerting structure => TTC approach:– TTC limit: TTC value = 1.5 μg = 15 ppm

MDD 0.1 g


(2) Genotoxic impurities (cont.)Carvedilol– TTC limit: TTC value = 1.5 μg = 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 and limited in an intermediate:

• Impurity not mentioned on the CEP– If level < 4.5 ppm and NOT limited in an intermediate :

• Impurity is mentioned on the CEP– Any GTI likely to be formed in last step

• Impurity is mentioned on the CEP



Please read the Q&A on the guideline on the limits of genotoxic impurities (EMA/CHMP/SWP/431994/2007 Rev. 3 ) which is available on the EMA website, In particular for:– the staged TTC concept, – the addition of impurities which are structurally related

such that total does not exceed the TTC,– the requirement to introduce limits in specifications (even

where absence has been demonstrated).


(4) 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


(4) Quality of API is equivalent whatever the supplier of SM (cont.)

• Demonstration should be given that the quality of API is equivalent if manufactured using SM from source A or B.

• Batch results from the substance manufactured from the suppliers should be given to confirm that the impurity profile is identical (same impurities/solvents/ catalysts).


(4) Quality of API is equivalent whatever the supplier of SM (cont.)

• If profile of API is not the same then 2 CEPs would be necessary to cover the substance obtained from each source of starting material:

In this example, any carry-over of impurity B, impurity C, methanol or ethanol would result in a substance with different specifications depending on the starting material used.


(5) Incomplete specification for the declared Starting Materials

• Specifications of the SM are often not sufficient and do not include limits for impurities/solvents/catalysts.

• Specification for SM should include limits for critical compounds used in its synthesis and also likely impurities


paracetamolp-nitrophenol p-aminophenol

(5) Incomplete specification for the declared Starting Materials (cont.)

• Suitable specifications for assay and purity with consideration for mass balance should be provided. 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% Unspecified n.d.

Total impurities <0.5%

Specifications not sufficiently detailed and not justified based on batch data.


(6) Class I solvents as contaminants of other solvents

Many solvents are known to be contaminated by class I solvents.

For example, benzene is potentially present in Acetone, Toluene, Ethanol, Methanol, Isopropanol, Xylene, Hexane and Petroleum ether


(6) Class I solvents as contaminants … (cont.)

Potential residues of the contaminant in an intermediate or inthe final substance should be addressed.

ICH guideline Q3C/Ph. Eur. General chapter 5.4Annex to Specifications for class 1 and class 2 residual solvents in active substances (CPMP/QWP/450/03)

Compliance with this guideline should be demonstrated in the justification of the quality of raw materials used or in the Impurities section.


(6) Class I solvents as contaminants… (cont.)

Where Class 1 solvent might be present in another solvent, a routine test for this solvent, on a suitable intermediate oron the final active substance, is not required when one of the 3options listed is met and demonstrated as such in the application :



• Limit applied to originator solvent is such that the Class 1 solvent will be present in the API at levels below the acceptable limits, taking into account the maximum likely level of contamination of the Class 1 solvent.

Toluene in API: NMT 200 ppmBenzene likely to be up to 0.05% in toluene⇒Max level of benzene : 0.1 ppm



OR

• Demonstration (validated method) that the Class 1 solvent is NMT 30% of its ICH limit, in a suitable intermediate / API. Supporting data on 6 consecutive pilot scale batches or 3 consecutive industrial scale batches. Absence is defined as less than 30% of the ICH limit therefore for benzene, should be less than 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


(6) Specification of reagent(s) / solvents(s)

• 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.


(8) Limits for impurities in a key intermediate• The specifications for the intermediates are not

detailed or not adapted to batch results.

A discussion on the potential impurities likely to arise from the process and their limits is expected and whether the monograph is capable of controlling the quality of the substance.


(9) Cross validation PhEur / In-house methods for related substances

• All in-house methods should be validated (incl. non-routine methods)

ICH Q2B for methodologyTypical chromatograms

• Where alternative methods are employed, cross-validation against Ph. Eur. methods to be supplied:

comparative results obtained from the same samples


(10) Maximum batch size

• The maximum batch size for which the manufacturer has acquired experience with the defined process and which should correspond to batches referred to in the dossier, should be stated.

• = production batch size


(10) 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 Ph. Eur impurities A & B and impurity X which is limited to 0.15%. Total impurities are limited to NMT 1.0%


(10) Suitability of the monograph (cont.)Need to address:• Suitability (or unsuitability) of the method(s) of the

monograph must be demonstrated for the detection of all additional impurities actually present in the material

If the method of the monograph is not suitable then needto supplement it with an additional (validated) method.

• Set appropriate limits


(10) Suitability of the monograph (cont.)

• Ph Eur and in-house methods need to be cross-validated• Methods are equivalent→ impurity X is limited on the CEP by the Ph Eur method

• Methods are not equivalent (Ph Eur method does not control impurity X)→ impurity X is limited on the CEP by the in-house method (appended to the CEP)


Other deficiencies observed

• Manufacturing Process• Control of Materials• Control of Critical steps and Intermediates• Impurities• Stability


3.2.S.2.2 Manufacturing Process and Process Controls

Different sites, different manufacturing methods(including alternatives) and reprocessing can beincluded in one dossier if:

• the impurity profile of final substance is the SAME,i.e.solvents, impurities, reagents etc.

NB: re-working is not allowed as typically implies the use ofalternate reagents and /or solvents and consequently leads toa different impurity profile


3.2.S.2.2 Manufacturing Process and Process Controls

For semi-synthetic products:Fermentation steps involved in synthesis of starting material, must address:• Information on the fermentation process, strain etc• Characterisation of fermented starting material, incl.

detailed impurity profile• Carry-over of fermentation impurities, proteins,

DNA,…• Use of TSE risk substances in manufacture?


3.2.S.2.3 Control of Materials

If material of animal origin is used:

• If a TSE risk substance is involved: CEP will not be granted for a chemical until the TSE risk has been assessed →“Double” CEP (chemical + TSE)

• The use of animal or human origin material will be mentioned on the CEP and the viral safety risk has to be assessed in the relevant marketing application.


3.2.S.2.4 Control of Critical steps and Intermediates

Provide sufficient information on the intermediatecontrol and the in-process controls.

Especially important if you use this control to avoid acontrol later in the process!!


3.2.S.7 StabilityCPMP guideline “Stability testing of existing activesubstances” (CPMP/QWP/ 122/02 Rev. 1)• A retest period is recommended• ICH conditions, incl. accelerated conditions• Study description - relevant parameters• Detailed results• Validation of in-house methods (stability indicating) • Majority of monograph methods are stability indicating

but some older methods may need to be supplemented by (validated!) in-house methods


Conclusions: how to avoid deficiencies?• Data given in the dossier should be:

– Clear– Concise– Readable– Obtained from recent analysis

• Use CTD format – Address the requirements of « Content of the Dossier »– Address the deficiencies detailed in this presentation– Implement recent developments if appropriate

• Provide complete administrative information• Visit our website (news and general information)


After evaluation 1• Less than 5% of CEPs are granted after the first round of

evaluation, a request for additional information is sent for the other 95% of dossiers (beginning of 2012: 2.2% were granted after first round).

• The applicant has 6 months to respond to this request

Deficient application delays the CEP!!!


Administrative validation at receipt of additional information response

* Updated sections of dossier impacted by responses not provided* Responses to all questions not provided


Technical validation at receipt of additional information response

• The technical validation at the reception of the response involves checking that not only are there answers to each of the questions but that they seem complete and coherent BUT the responses are not assessed.

• Evaluation of additional information takes 4 months

Deficient response may lead to dossier rejection!!


Closing of sleeping dossiers

Dossiers lying dormant for months without reply:

• Applicants are given 6 months to provide additional information following a deficiency letter

• If no response : dossier is closed


Some figures• In 2011:• 332 new CEPs (chemical and double) were granted

after evaluation of the dossier submitted• 2% were granted without a request for additional

information• 61% were granted between 0-18 months after

submission rising to 97% by 24 months after submission

• By the end of May 2012, 25% of these new CEPS had been revised


THANK YOU !


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