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SPECIFIC MONOGRAPHSA Guide Through The Different
Sections
SPECIFIC MONOGRAPHSSPECIFIC MONOGRAPHSA Guide Through The Different A Guide Through The Different
SectionsSections
Claude Coune
1Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010
Contents of the European Pharmacopoeia:nearly 2100 monographs
Contents of the European Pharmacopoeia:nearly 2100 monographs
Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010
Drug products: specific monographs
Drug products: specific monographs
• No monographs on specific preparations, except – Vaccines and sera– Blood products– Radiopharmaceuticals– Insulin preparations
Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010 3
Drug products (2)Drug products (2)
In the European regulatory situation:• Drug product specifications are largely
individually tailored • Monograph alone often insufficient to
ensure quality• Exemptions would often be needed
(interference from excipients, etc.)
Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010 4
Specific monographsSpecific monographs• Requirement for a substance consists
of:
– Specific monograph + general monograph(s)
• Whole set of requirements define quality
Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010 5
English or French title
Latin subtitle
Molecular and graphic formulae
Relative atomic or molecular mass
CAS number
Official definition
Section for information e.g. appearance, solubility
Confirmation of the chemical structure / composition
of the product
Objective : to test impurities, residual solvents and / or related substances
Version date
Reference standard available from EDQM
Further information provided on knowledge database (internet)
7Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010
Reference to general chapters
Reagent described in the EP
When applicable, line in the margin indicatingwhere part of the text has been
modified
Recommandations
List of known and potential impurities
8Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010
TITLETITLE• INNs used almost universally (modified
to indicate salt)
• Titles now include degree of hydration
• Use in labelling required
• Molecular formula and mass: do not have to be checked!
Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010 9
DEFINITIONDEFINITION• Chemical nomenclature
• Assay limits– LC assay: reflect assay variability and purity (eg:, 96.0-102.0%
means 2% assay variability and 3.0% total impurities)
– Microbiological assay: minimum activity (IU/mg, as is)
– Biological assay: specific activity (eg: IU/mg)
• Solvent-free substance is implied even where not stated (see Substances for Pharmaceutical Use, residual
solvents)
Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010
10
SCOPESCOPE• May include statements on scope (eg
route of synthesis)
• Monograph applies to all grades, unless otherwise stated
• Special grades may be mentioned in body of monograph (parenteral etc.)
Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010 11
Use of excipientsUse of excipients• Definition indicates where applicable that additives
can be used (diluents, antioxidants, etc).
• An active substance is presented with an excipient (antioxidant etc.): does the monograph apply?
• See Substances for Pharmaceutical Use: “Processing with addition of excipients is permitted only where this is specifically stated in the Definition of the individual monograph.”
• Indication on the label
Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010 12
PRODUCTION SECTIONPRODUCTION SECTION• Instructions to manufacturers• May relate to source materials, manufacturing
process, its validation and control or to in-process testing
• Cannot necessarily be verified by independent analyst
• Compliance established by competent authorities
-> e.g. by examination of data or inspectionClaude Coune, © EDQM, Council of Europe, All rights reserved, 2010 13
PRODUCTION SECTION (2)PRODUCTION SECTION (2)
• Development and validation tests (e.g. preservative efficacy, abnormal toxicity)
• Biologicals: specific activity, if this cannot be checked on the finished product (when the assay of the substance uses a physico-chemical method only)
• Vaccines: often extensive production section
Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010 14
CHARACTERSCHARACTERS• Not analytical requirements, do not have to be checked
• Useful information for the analyst (solubility, hygroscopicity)
• Polymorphism, where known, is mentioned (see also 5.9 Polymorphism)
• Physical properties may be mentioned (melting point, refractive index, density)
• 5.11 Characters section in monographs: methods used for checking by EDQM
Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010 15
IDENTIFICATIONIDENTIFICATION• First and Second identifications: defined in General
Notices
• First identification alone is always sufficient, Second is never mandatory
• Use of Second identification depends on competent authority
• First identification always has to be carried out at some point (upstream)
Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010
16
TESTSTESTS
• To detect: organic impurities, inorganic impurities, volatiles
• Methods: – Physical and physico-chemical– Chemical– Chromatographic
Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010 17
IMPURITIES CONTROLIMPURITIES CONTROL
• Adapt to global trade
• Define practice for future monographs
• Reflect regulatory practice in monographs
• Harmonise the approach for different monograph authors
• Define revision needs
Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010 18
Basis for monographsBasis for monographs
• SAFETY FIRST!
• Products of proven safety
• Products evaluated and approved by competent authorities of Member States
• Impurity profiles for existing, approved synthetic routes
• Robust, validated analytical methods based on collaborative laboratory testing
Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010
19
Basis for impurities controlBasis for impurities control
• Specifications for approved products and batch analysis data for approved products
• Specified impurities are those in specifications for approved products
• Specified impurities are qualified at or above the level indicated in the monograph
Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010 20
Template for requirementsTemplate for requirements• Limits for:
• Specified impurities
• Unspecified impurities
• Total impurities
• Impurities section• Specified impurities
• Other detectable impurities
• If the Impurities section is not divided, all the impurities listed are specified
Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010 21
List of impurities and CRSList of impurities and CRS
Specified impurities identified by means of CRS in case of:
- specific limit- correction factor to be applied
Impurity mix CRS supplied with chromatogram
Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010 22
Other Detectable ImpuritiesOther Detectable Impurities• Specific EP category
• Impurities sections in monographs may have a list of ODIs
• Analytical information only: the impurity is detected by the monograph method
• ODIs are limited in the monograph by the limit for “unspecified impurities” (or Substances for Pharmaceutical Use)
Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010 23
Rs
CF CF
Specified impurities: A, B, C, D.
Example : Torasemide for system suitability CRS
Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010 24
Related substances:Related substances:
Example: Example: Amiodarone HClAmiodarone HClreversed phase LC elution, UV detectionreversed phase LC elution, UV detection
Column:Column:_ size: l =0.15 m, _ size: l =0.15 m, ØØ = 4.6 mm= 4.6 mm_ stationary phase: _ stationary phase: octadecylsilyl silica gel for chrom. (5octadecylsilyl silica gel for chrom. (5µµm)m)_ temperature: 30 _ temperature: 30 °°CC
What you will find in the monograph:What you will find in the monograph:dimensions, type of stationary phase, particle size.dimensions, type of stationary phase, particle size.
Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010 25
Knowledge databaseKnowledge database
Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010
Information on Information on -- Reference standardsReference standards-- ColumnColumn or reagent or reagent brand namesbrand names
26
IMPURITIES SECTION IMPURITIES SECTION
• Gives impurities that are known to be detected by monograph tests
• Usually controlled by related substances test, but may be other tests
• Not necessarily exhaustive
• Based on information obtained and verified during elaboration
Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010 27
Directive 2003/63/ECDirective 2003/63/EC“ However, where a starting material in the
European Pharmacopoeia … has been prepared by a method liable to leave impurities not controlled in the pharmacopoeia monograph, these impurities and their maximum tolerance limits must be declared and a suitable test procedure must be described.”
Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010 28
Monograph revisionMonograph revision• Impurities control has to be updated for newly
authorised products/sources:• “[Where] a monograph … [may] be insufficient … the
competent authorities shall inform the European Pharmacopoeia. The marketing authorisation holder shall provide the European Pharmacopoeia with the details of the alleged insufficiency and the additional specifications applied.”
Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010 29
Residual solventsResidual solvents
• Dealt with in Substances for Pharmaceutical Use and general chapter 5.4 Residual solvents
• Specific monographs do not include a test for residual solvents, except:
Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010 30
Residual solvents: Residual solvents: • Class 1 solvents are always named and
limited in monographs• Class 3 solvents are only named and
limited in monographs when they exceed 0.5% (impact on assay results)
• Class 2 solvents are NOT named and limited in monographs: chapter 5.4 applies
Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010 31
ASSAYASSAY• Well-defined salts: normally only the
pharmacologically active part is determined by titration
• Ph.Eur. policy prefers unspecific but precise assay (titration) provided related substances test is sufficiently characteristic and searching
• For chromatographic assays chapter 2.2.46 defines repeatability requirements
Claude Coune, © EDQM, Council of Europe, All rights reserved, 201032
STORAGESTORAGE• Section is not mandatory
• Competent authority decides on storage -may decide to make Ph Eur mandatory
• Product has to be stored so as to ensure compliance with monograph
• Conventional expressions defined in General Notices
Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010 33
LABELLINGLABELLING• Covered by national and international
regulations
• Ph Eur indicates labelling items needed for application of monographs
• For example, nominal values (especially excipients)
• Informational items sometimes included
Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010 34
LABELLING (2)LABELLING (2)
• “Labelling” is interpreted in broad sense• Not just what is read on container
• Information provided with the product is also included in “labelling”: package, leaflet, certificate of analysis
• What appears where is for labelling regulations and regulatory authority
Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010 35
FUNCTIONALITY-RELATED CHARACTERISTICS (1)FUNCTIONALITY-RELATED CHARACTERISTICS (1)
• New feature of monographs on excipients
• Section is not mandatory
• Tests are linked to use (lubricant, tablet compression, etc.)
• Section provides information on important parameters
Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010 36
FUNCTIONALITY-RELATED CHARACTERISTICS (2)FUNCTIONALITY-RELATED CHARACTERISTICS (2)
• May include test methods, limits, tolerance on label claim
• Useful common language for suppliers and users
• Should lead to better standardisation
• Information chapter on FRCs (5.15)
Claude Coune, © EDQM, Council of Europe, All rights reserved, 2010 37