information on the certification procedure dr p. poukens-renwart certification of substances...

Information on the Certification Procedure

Information on the Certification Procedure

Dr P. Poukens-RenwartCertification of Substances Division,

EDQM

P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

SummarySummary

• Some deficiencies

• How to read and use a CEP?

• Finding information on the procedure

• Key figures

• Recent developments

• Benefits of the procedure


DeficienciesDeficiencies

• Observed during the validation process of the application

• Observed during assessment process of the application and other then those listed in top 10.


A complete application requires:A complete application requires:• Application form (for new application)• Single copy of the dossier in English preferably (or

French) under CTD format;• Quality Overall Summary: use the EDQM template

and submit electronic version as Word file• Samples: ! new policy: commitment to provide

samples upon request from EDQM• Electronic submission welcome:NEES (instructions

on EDQM website)Send the package to EDQM. Fee to be paid after receipt and invoicing


Validation at receiptapplications are blocked when:Validation at receiptapplications are blocked when:

1. Administrative information is not complete

2. Technical information is not sufficient


Administrative validation at receipt Administrative validation at receipt

Dossier is blocked when: • Dossier not in CTD format• QOS is missing or not signed• Information from application form is missing:

– Names and addresses of the parties involved– Agreement letters

• 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

• Manufacturer, and holder if different – Use of animal (TSE risk or other origin) / human material


Validation at receipt (cont)Validation at receipt (cont)

• 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


Validation at receipt (cont) Validation at receipt (cont)

• Retest period– Is an Option– Specify the proposed retest period:

• Justified by stability data • Studies according to ICH conditions

– Recommended storage conditions – Specify the packaging material


Technical validation at receiptTechnical validation at receiptApplications 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• Quantitative method to replace a non-specific TLC test

of the monograph• Sterile substances: validation of the sterilisation


Validation at receiptValidation at receipt

23% blocked at this step in June 2009 (up to 38% in 2007= not suitable to start the evaluation)

Application blocked --> the clock does not startuntil 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 »


After evaluation (the clock has started)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 CEPP.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

Deficiencies: How to avoid them ?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 and is the Revision of

Annex I, Resolution AP-CSP (93) 5 as amended.

It describes what we expect to see in the dossier.


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.


Deficiencies: How to avoid them ?Deficiencies: How to avoid them ?

• Presentation on top ten deficiencies 2008 (9th September 2009)

• Read summary of the main deficiencies found in the dossiers for Certificates:

PA/PH/CEP (08) 11


Other deficiencies observedOther deficiencies observed

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


3.2.S.2.2 Manufacturing Process and Process controls3.2.S.2.2 Manufacturing Process and Process controlsYou should provide:• Brief outline and flow chart for your process• Detailed process description :

– typical/maximum batch size – narrative description of the synthesis (incl

temperatures, quantities, times etc.)– structure of isolated intermediates


3.2.S.2.2 Manufacturing Process and Process Controls3.2.S.2.2 Manufacturing Process and Process ControlsDifferent sites, different manufacturing methods(including alternatives) and reprocessing can beincluded in one dossier if:

the impurity profile of final substance is the SAME-> detailed information to be provided

re-working is not allowed (->introduction of newsolvents)-> normally this results in a change in the impurityprofile


3.2.S.2.2 Manufacturing Process and Process Controls3.2.S.2.2 Manufacturing Process and Process ControlsFor semi-synthetic products:

Fermentation steps involved in synthesis of starting material, must address:

• Characterisation of fermented starting material, incl. detailed impurity profile, compliance with the GM 1468

• Carry-over of fermentation impurities, proteins, DNA,…• Use of TSE risk substances in manufacture?


3.2.S.2.3 Control of Materials3.2.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

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


3.2.S.2.4 Control of Critical steps and Intermediates3.2.S.2.4 Control of Critical steps and IntermediatesProvide sufficient information on the intermediatecontrol and the in-process controls.

Especially important if you use this control toavoid a control later in the process!!


3.2.S.7 Stability3.2.S.7 StabilityCPMP guideline “Stability testing of existing activesubstances” (CPMP/QWP/ 122/02 Rev. 1)• A retest period is optional (does not block the granting of

the CEP)• ICH conditions, incl. accelerated conditions• Study description - relevant parameters• Detailed results• Validation of in-house methods (stability indicating) +

cross validation with Ph.Eur method• 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?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)


How to read a CEP chemical?How to read a CEP chemical?

• Certifies that the quality of a given substance can be suitably controlled by the Ph.Eur. monograph - with additional tests if necessary (stated on the CEP).

• It DOES NOT certify that a batch or batches of the substance complies with the Pharmacopoeia monograph.

• It IS NOT a GMP certificate


How to read a CEP TSE ?How to read a CEP TSE ?

• Certifies that the substance complies with the EMEA NfG on minimising the TSE risk

• It DOES NOT certify that the quality of the substance can be suitably controlled by the Ph.Eur. monograph

• It DOES NOT certify that a batch of the substance complies with the monograph

• It IS NOT a GMP certificate


All CEPs specify:All CEPs specify:• Unique Reference number

(e.g. R0-CEP 2000-001-Rev01)• Title: clear definition of the substance

+ grade when requested (eg. micronised, sterile,…)• Holder + manufacturing site(s)• Monograph(s) concerned• Starting validity date • Line numbering and annex details if appropriate


And as necessary, chemical CEPs:And as necessary, chemical CEPs:

• Additional impurities/Solvents/Catalysts– With limits and methods

• Re-test period– With storage conditions + container

• Specs (limit + test) for a specific grade• Tests of the monograph which can be omitted• Use or non-use of materials of animal origin


And if for a sterile material:And if for a sterile material:

• Description of sterilisation method and container/closure

• Statement that the validation of the sterilisation has been evaluated

NB: the information on the sterilisation process and itsvalidation needs to be submitted separately in themarketing authorisation dossier


And for a TSE certificate:And for a TSE certificate:

• Country(ies) of origin of animals• Animal and nature of tissue(s) used• Manufacturing process applied (when relevant, e.g.

gelatins)• Quality assurance system applied


The CEP looks like:The CEP looks like:


How to use a CEP ?How to use a CEP ?


• Certification pages• Certification on-line database• Useful links• Contacting us


Finding information on the Certification ProcedureFinding information on the Certification Procedure

http://www.edqm.euhttp://www.edqm.eu

Homepage - Finding your wayHomepage - Finding your waySix main groups to help visitors find information directed at them. They are:

•EDQM: Latest news & general Information about the EDQM•HealthCare: Blood Transfusion & Organ Transplantation activities•European Pharmacopoeia: Commission & Work Programme, Reference Standards & Biological Standardisation Programme (BSP).


Homepage - Finding your way (cont)Homepage - Finding your way (cont)

• Certification of Pharmaceutical Substances: Procedure of Certification (CEP)

• Control of Medicines: OMCL Network, PTS Studies, etc• Products & Services: Publications, Reference Standards

(Ph. Eur. & WHO ISA) & Certification


Certification pagesCertification pages


Click on the links within

the main areas

Place mouse on

the top menu to open the

submenus

Certification / News and General Information (1)Certification / News and General Information (1)


Click on the links within the

submenus


Certification/News and General Information (2)Certification/News and General Information (2)

Certification/New ApplicationsCertification/New Applications


Certification/Revisions and RenewalsCertification/Revisions and Renewals


Certification On-Line Database (1)Certification On-Line Database (1)



• Here is an example of the information provided

• Our databases are linked, clicking on the monograph number takes you into our Knowledge Database




From our Knowledge Database, you can also see other information

How to contact us ?How to contact us ?• For general queries for which the answer is not in

the FAQs, you can contact us via the helpdesk.

• For application specific queries you can contact us via the email address which we include in our communications about your application: [email protected]


Key figuresKey figures


Certificates of suitabilityCertificates of suitability

• > 3700 applications since procedure launched• ~ 2250 valid certificates• > 760 substance monographs involved • …


Certificates of SuitabilityCertificates of Suitability

… > 560 manufacturers from 43 countries

Repartition of manufacturing sites covered by CEPs (2008)

Europe41%

Asia38%

America15%

Pacific zone4%

Middle East1% Africa

1%


Recent developmentsRecent developments

1.1. Validation of new applications at receipt (= Validation of new applications at receipt (= completeness check)completeness check)

• Implemented in 2007 Implemented in 2007

• Both administrative & technical informationBoth administrative & technical information

• Performed within 8 days of application receiptPerformed within 8 days of application receipt

• If dossier complete: AR --> evaluation clock startsIf dossier complete: AR --> evaluation clock starts



2.2. Closing of sleeping dossiers (dossiers lying Closing of sleeping dossiers (dossiers lying dormant for months without reply)dormant for months without reply)

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

• If no response : dossier closedIf no response : dossier closed



3.3. Streamlined evaluation procedure (From Streamlined evaluation procedure (From September 2008)September 2008)

• 1 deficiency letter only 1 deficiency letter only

• if responses unsuitable if responses unsuitable dossier closed dossier closed



4.4. Electronic submission (from September 2009):Electronic submission (from September 2009):

• EncouragedEncouraged

• For all types of submissionsFor all types of submissions

• e-CTD, or NEES suitably bookmarkede-CTD, or NEES suitably bookmarked

• Check regularly EDQM website forinstructionsCheck regularly EDQM website forinstructions

• Paper Paper OROR electronic (no longer both) electronic (no longer both)



5.5. Manufacturing sites mentioned on CEPsManufacturing sites mentioned on CEPs• When manufacturer of API purchases crude or late When manufacturer of API purchases crude or late

intermediate and performs only a final purification or intermediate and performs only a final purification or salification, the site(s) of manufacture of the purchased salification, the site(s) of manufacture of the purchased material(s) will be mentioned on the CEP;material(s) will be mentioned on the CEP;

• GMP apply to manufacturer(s) of crude or late intermediate;GMP apply to manufacturer(s) of crude or late intermediate;

• Declarations to be submitted;Declarations to be submitted;

• Also applicable to post-production operations (micronisation Also applicable to post-production operations (micronisation or sterilisation), when these are claimed and approvedor sterilisation), when these are claimed and approved


Certification: benefitsCertification: benefits

• Single & harmonised assessment• Replaces Active Substance Master File• Savings of time and resources• Updating of monographs (impurities)• Revision of monographs (new or replacement test

methods)• CEPs are recognised in Europe and abroad


Thank you !


information on the certification procedure dr p. poukens-renwart certification of substances...

Documents

council of europe

rights reservedp

edqm template

edqm websitesend

rights reservedvalidation

receipt dossier

application form

completetechnical information