SPECIFIC MONOGRAPHS - The Indian …ipapharma.org/events/IPA - EDQM pdf/Claude Coune... · 2010-02-05 · Use of excipients • Definition indicates where applicable that additives

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.)


Specific monographsSpecific monographs• Requirement for a substance consists

of:

– Specific monograph + general monograph(s)

• Whole set of requirements define quality



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)


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


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!


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)


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.)


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


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


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


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)


16

TESTSTESTS

• To detect: organic impurities, inorganic impurities, volatiles

• Methods: – Physical and physico-chemical– Chemical– Chromatographic


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


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


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


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


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


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)


Rs

CF CF

Specified impurities: A, B, C, D.

Example : Torasemide for system suitability CRS


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.


Knowledge databaseKnowledge database


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


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.”


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.”


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:


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


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


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


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


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


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


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)


Documents

SPECIFIC MONOGRAPHS - The Indian …ipapharma.org/events/IPA - EDQM pdf/Claude Coune... · 2010-02-05 · Use of excipients • Definition indicates where applicable that additives