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Österreichische Agentur für Gesundheit und Ernährungssicherheit GmbHwww.basg.at
Dr. Wolfgang HerzogAGES PharmMed, Institut Zulassung & Lifecycle Management
AGES-Gespräch „Am Pulsschlag des Arzneimittelwesens – Das Institut LCM“25.11.2010
Wirkstoffdokumentation & CEP- Verfahren
www.basg.at 2Wolfgang Herzog, 25.11.2010
Documentation of Drug Substance
• Guideline of requirements for active substances in the quality part of the dossier (CHMP/QWP/297/97 Rev. 1):
-Classification of active substances
- Feasible ways to submit the required information
www.basg.at 3Wolfgang Herzog, 25.11.2010
• New active substances
• Existing active substances not described in Ph. Eur./pharmacopoeia of EU member state
• Existing active substances described in Ph. Eur./ pharmacopoeia of EU member state
Documentation of Drug Substance
www.basg.at 4Wolfgang Herzog, 25.11.2010
Documentation of Drug Substance
• Inorganic substances
• Herbal drugs and herbal drug preparations
• Organic substances (isolated from material of animal/human origin)
• Organic substances (synthetic or semi-synthetic or isolated from herbal sources or microorganism)
www.basg.at 5Wolfgang Herzog, 25.11.2010
Documentation of Drug Substance
• Certificate of Suitability (CoS/CEP)
• Active Substance Master File (ASMF):
• Full Documentation as part of the MA application
www.basg.at 6Wolfgang Herzog, 25.11.2010
Documentation of Drug Substance
• Chemistry of Active Substances (3AQ5A)
• Chemistry of New Active Substances (CPMP/QWP/130/96 Rev. 1)
www.basg.at 7Wolfgang Herzog, 25.11.2010
3.2.S Drug Substance• 3.2.S.1 General Information• 3.2.S.2 Manufacture• 3.2.S.3 Characterisation• 3.2.S.4 Control of Drug Substance• 3.2.S.5 Reference Standards or Materials• 3.2.S.6 Container Closure System• 3.2.S.7 Stability
Documentation of Drug Substance
www.basg.at 8Wolfgang Herzog, 25.11.2010
Active Substance Master File (ASMF):
- Nfg on ACTIVE SUBSTANCE MASTER FILE CPMP/QWP/227/02 Rev. 1Date for coming into operation: 31.08.2004
- "Applicants Part " (AP) and "Restricted Part " (RP)
- Structure of the ASMFo human: in CTD format (since 1st January 2005) o veterinary: according to NtA veterinary format or CTD
www.basg.at 9Wolfgang Herzog, 25.11.2010
Scope:
- New active substances
- Existing active substances not included in the Ph. Eur. or pharmacopoeia of an EU Member State
- Pharmacopoeial active substances
Not in the Scope:Biological Substances!!!!!
Active Substance Master File (ASMF):
www.basg.at 10Wolfgang Herzog, 25.11.2010
The EDMF holder should submit to the Applicant:
- A copy of the latest version of the AP
- A copy of the QOS/ER on the latest version of the AP
- Letter of access where this letter has not been sumitted earlier for the product concerned
Active Substance Master File (ASMF):
www.basg.at 11Wolfgang Herzog, 25.11.2010
The EDMF holder should submit to the Competent Authorities:
- The EDMF accompanied by a covering letter
- Letter of access where this letter has not been sumitted earlier for the product concerned
Active Substance Master File (ASMF):
www.basg.at 12Wolfgang Herzog, 25.11.2010
3.2.S Drug Substance- 3.2.S.1 General Information
o 3.2.S.1.1 Nomenclature
rINN, compendial (Ph. Eur.) name, national approved names (Company or laboratory code)…
Reference CPMP Guideline: “Chemistry of the Active Substance”
o 3.2.S.1.2 Structure
Structural formula, rel. molecular mass
o 3.2.S.1.3 General Properties
Physicochemical properties (solubility, isomerism,…)
Common Technical Document (CTD):
www.basg.at 13Wolfgang Herzog, 25.11.2010
3.2.S Drug Substance- 3.2.S.2 Manufacture
o 3.2.S.2.1 Manufacturer(s)
Name, Address
o 3.2.S.2.2 Description of the Manufacturing Process
Flow diagram
Sequential procedural narrative
Alternative processes, reprocessing
Operating conditions
Yield
Common Technical Document (CTD):
www.basg.at 14Wolfgang Herzog, 25.11.2010
3.2.S Drug Substance- 3.2.S.2 Manufacture
o 3.2.S.2.3 Control of Materials
Starting material, solvents, reagents, catalysts, etc.
Specifications should be submitted
o 3.2.S.2.4 Control of critical steps and intermediates
Tests und Acceptance criteria
Common Technical Document (CTD):
www.basg.at 15Wolfgang Herzog, 25.11.2010
3.2.S Drug Substance- 3.2.S.2 Manufacture
o 3.2.S.2.5 Process validation and/or Evaluation
aseptic processing
sterilisation
o 3.2.S.2.6 Manufacturing Process Development
Description of any significant changes
Common Technical Document (CTD):
www.basg.at 16Wolfgang Herzog, 25.11.2010
3.2.S Drug Substance- 3.2.S.3 Characterisation
o 3.2.S.3.1 Elucidation of Structure and other Characteristica
Unequivocal proof of structure (Elemental analysis, UV/VIS Maxima, IR, 1H/13C NMR, MS,…)
Information regarding Isomerism, Polymorphism (melting point, X-Ray powder diffraction,…see EP 5.9), etc.
Common Technical Document (CTD):
www.basg.at 17Wolfgang Herzog, 25.11.2010
3.2.S Drug Substance- 3.2.S.3 Characterisation
o 3.2.S.3.2 Impurities
Impurity profile:
Starting material
By-products
Degradation products
Reagents, ligands and catalysts
Residual solvents
Inorganic impurities
Common Technical Document (CTD):
www.basg.at 18Wolfgang Herzog, 25.11.2010
3.2.S Drug Substance- 3.2.S.4 Control of the Active Substance(see EP-Monograph „Substances for Pharmaceutical Use“
01/2008:2034)
o 3.2.S.4.1 Specification
o 3.2.S.4.2 Analytical Procedures
o 3.2.S.4.3 Validation of Analytical Procedures
Common Technical Document (CTD):
www.basg.at 19Wolfgang Herzog, 25.11.2010
3.2.S Drug Substance- 3.2.S.4.1 Specification: minimum requirements
o Descriptiono Identificationo Assay and/or potencyo Impuritieso - identified Impuritieso - unidentified Impuritieso - total Impurities
Common Technical Document (CTD):
www.basg.at 20Wolfgang Herzog, 25.11.2010
3.2.S Drug Substance- 3.2.S.4.1 Specification – additional Parameters- (see ICH Q6A-“decision trees“)
o Physicochemical propertieso Particle sizeo Polymorphic forms (CPMP/ICH/2738/99 does not
apply)o Tests for chiral substance (CPMP/ICH/2738/99 does
not apply)o Water contento Inorganic impuritieso Microbial limits (TAMC/TYMC see EP 5.1.4)
Common Technical Document (CTD):
www.basg.at 21Wolfgang Herzog, 25.11.2010
3.2.S Drug Substance- 3.2.S.4 Control of the Active Substance
o 3.2.S.4.4 Batch Analysis
Recent consecutive batches (at least 3 pilot batches)
Date of manufacture
Batch size and number
Place of manufacture
Results of analytical determination
o 3.2.S.4.5 Justification of Specification
Common Technical Document (CTD):
www.basg.at 22Wolfgang Herzog, 25.11.2010
3.2.S Drug Substance- 3.2.S.5 Reference standards
o Information on the reference standards used for testing of the active substance
o Establishing of the reference standards (Primary and Secondary)
o Specification
Common Technical Document (CTD):
www.basg.at 23Wolfgang Herzog, 25.11.2010
Common Technical Document (CTD):
3.2.S Drug Substance- 3.2.S.5 Reference standards
o A European Pharmacopoeia reference standard is an integral and essential part of the monograph and as such is an official standard that is alone authoritative in case of doubt or disbute (see also chapter 5.12)
www.basg.at 24Wolfgang Herzog, 25.11.2010
Common Technical Document (CTD):
3.2.S Drug Substance- 3.2.S.6 Container Closure System
o Primary packaging material (see CPMP/QWP/4359/03)
Details of the materials of construction
Chemical name of the material
Specification (EP-conformity if applicable)
o Secondary packaging material
www.basg.at 25Wolfgang Herzog, 25.11.2010
Common Technical Document (CTD):
3.2.S Drug Substance- 3.2.S.7 Stability
o 3.2.S.7.1 Stability Summary and Conclusiono CPMP/QWP/122/02 Rev. 1 corro CPMP/ICH/2736/99 (ICH Q1A (R2)) o CPMP/ICH/279/95 (ICH Q1B)
www.basg.at 26Wolfgang Herzog, 25.11.2010
Common Technical Document (CTD):
3.2.S Drug Substance- 3.2.S.7 Stability
o 3.2.S.7.2 Post-approval Stability Protocol and Stability Commitment
o 3.2.S.7.3 Stability Data
www.basg.at 27Wolfgang Herzog, 25.11.2010
Council of Europe
www.basg.at 28Wolfgang Herzog, 25.11.2010
Certificate of Suitability (CoS/CEP)*
Purpose of the procedure
• Facilitating and simplifying exchanges between the partners to ensure that the quality of substances is guaranteed
• These substances comply with the European Pharmacopoeia
• Promote free movement of medicines
www.basg.at 29Wolfgang Herzog, 25.11.2010
Certificate of Suitability (CoS/CEP)*
Excluded from the Application:
• Direct gene products (proteins)
• Products obtained from human tissues, vaccines and blood products and preparations
• „other biological substances“ (see list of CMD(h))
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Application types
- Simple certificate (chemical or TSE or herbal product)
- Certificate for chemical purity and sterility
- Double certificate (chemical and TSE)
- Double certificate (chemical and TSE) covering also sterility
www.basg.at 31Wolfgang Herzog, 25.11.2010
Overview of the procedure
- Submission of the dossier
- Acknowledgement of receipt
- Designation of a rapporteur
- Assessment
- Notification of the decision
- Follow up the Certification of Suitability
www.basg.at 32Wolfgang Herzog, 25.11.2010
Assessment
- Preparation of a report in three parts:
- Report A or „Confidential report“
- Report B or „Request for revision of the monograph“
- Report C or „Comments for the inspectors“
www.basg.at 33Wolfgang Herzog, 25.11.2010
Certificate of Suitability (CoS/CEP)*
Documentation in the MA application:
- Copy of the CoS has to be enclosed
- Declaration of Access (not mandatory!)
- GMP Declaration from the Qualified Person of the Batch Releaser and Manufacturer
- Specification of the Applicant (with additional Parameters e.g. physical-chemical characteristics such as particle size)
www.basg.at 34Wolfgang Herzog, 25.11.2010
Certificate of Suitability (CoS/CEP)*
Ländervergleich 2009
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5 5 5 4 2 48
2 2 2 41 1 1 1
4
62
37 35 33
2623 21 21 21 19
1410 9 8 8 6
4
0
10
20
30
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60
70
DE AT ES UK NL BE
*CH* FR IT DK FI SE IS CZ HU IE
*Can
ada*
Gutachter Gutachtertage Quelle: EDQM
Österreichische Agentur für Gesundheit und Ernährungssicherheit GmbHwww.basg.at
Thank You!
