SPECIFIC MONOGRAPHS. A Guide Through The Different Sections. Claude Coune

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) 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 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

Version date English or French title Latin subtitle Objective : to test impurities, residual solvents and / or related substances Molecular and graphic formulae Relative atomic or molecular mass CAS number Official definition Section for information e.g. appearance, solubility Further information provided on knowledge database (internet) Confirmation of the chemical structure / composition of the product Reference standard available from EDQM Claude Coune, EDQM, Council of Europe, All rights reserved, 2010 7

Reagent described in the EP Recommandations Reference to general chapters List of known and potential impurities When applicable, line in the margin indicating where part of the text has been modified Claude Coune, EDQM, Council of Europe, All rights reserved, 2010 8

TITLE 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

DEFINITION 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) 10 Claude Coune, EDQM, Council of Europe, All rights reserved, 2010

SCOPE 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 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 SECTION Instructions to manufacturers May relate to source materials, manufacturing process, its validation and control or to inprocess testing Cannot necessarily be verified by independent analyst Compliance established by competent authorities -> e.g. by examination of data or inspection Claude Coune, EDQM, Council of Europe, All rights reserved, 2010 13

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 physicochemical method only) Vaccines: often extensive production section Claude Coune, EDQM, Council of Europe, All rights reserved, 2010 14

CHARACTERS 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

IDENTIFICATION 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

IMPURITIES 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 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 19 Claude Coune, EDQM, Council of Europe, All rights reserved, 2010

Basis 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 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 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 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

Related substances: Example: Amiodarone HCl reversed phase LC elution, UV detection Column: _ size: l =0.15 m, Ø = 4.6 mm _ stationary phase: octadecylsilyl silica gel for chrom. (5µm) _ temperature: 30 C What you will find in the monograph: dimensions, type of stationary phase, particle size. Claude Coune, EDQM, Council of Europe, All rights reserved, 2010 25

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/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 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 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: 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

ASSAY 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, 2010 32

STORAGE 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

LABELLING 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 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) 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) 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