technical_guide_for_the_elaboration_of_monographs_7th_editio

ELABORATION OF MONOGRAPHSTechnical guide for the European PharmacopoeiaEDQM7th Edition2015 ELABORATION OF MONOGRAPHS

Technical guide for the

European Pharmacopoeia7th Edition

2015

European Directorate for the Quality of Medicines & HealthCare

English version

2015

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European Directorate for the Quality of Medicines & HealthCare (EDQM)

Council of Europe 7, allée Kastner

CS 30026

F-67081 STRASBOURG

FRANCE Cover image: ? EDQM - Council of Europe Director of the Publication: Dr S. Keitel

Page layout: EDQM

www.edqm.eu

? Council of Europe, 2015

TECHNICAL GUIDE FOR THE ELABORATION OF MONOGRAPHS

7th Edition – 2015

TABLE OF CONTENTS

I. I.1. I.2. I.3. I.4. I.5. I.6. I.7. II.

INTRODUCTION ............................................................................................................................................... 1 PURPOSE OF THE GUIDE .............................................................................................................................. 1 TEST PROCEDURES ...................................................................................................................................... 1 EQUIPMENT .................................................................................................................................................... 2 QUANTITIES ................................................................................................................................................... 2 REAGENTS ...................................................................................................................................................... 4 COMMERCIAL NAMES ................................................................................................................................. 4 REFERENCE STANDARDS ........................................................................................................................... 4 MONOGRAPH ON A SUBSTANCE FOR PHARMACEUTICAL USE ........................................................ 5

II.1. TITLE ................................................................................................................................................................ 5 II.2. DEFINITION .................................................................................................................................................... 6 II.2.1. Combinations ............................................................................................................................................ 7 II.2.2. Content ..................................................................................................................................................... 7 II.3. CHARACTERS ................................................................................................................................................ 8 II.3.1. Appearance ............................................................................................................................................... 8 II.3.2. Taste ......................................................................................................................................................... 9 II.3.3. Odour ....................................................................................................................................................... 9 II.3.4. Solubility ................................................................................................................................................... 9 II.3.5. Stability factors ....................................................................................................................................... 10 II.3.6. Hygroscopicity ........................................................................................................................................ 10 II.3.7. Solid-state properties .............................................................................................................................. 10 II.3.8. Other characteristics .............................................................................................................................. 10 II.3.9. Behaviour in solution .............................................................................................................................. 11 II.4. IDENTIFICATION ......................................................................................................................................... 11 II.4.1. General ................................................................................................................................................... 11 II.4.2. Second Identification series .................................................................................................................... 12 II.4.3. Infrared absorption spectrophotometry .................................................................................................. 13 II.4.4. Ultraviolet and visible absorption spectrophotometry ............................................................................ 13 II.4.5. Melting point, freezing point and boiling point ....................................................................................... 14 II.4.6. Specific optical rotation .......................................................................................................................... 15 II.4.7. Thin-layer chromatography .................................................................................................................... 15 II.4.8. Gas chromatography and liquid chromatography .................................................................................. 16 II.4.9. Chemical reactions ................................................................................................................................. 16 II.5. TESTS ............................................................................................................................................................. 16 II.5.1. General ................................................................................................................................................... 16 II.5.2. Title of tests ............................................................................................................................................ 17 II.5.3. Solution S ................................................................................................................................................ 18 II.5.4. Appearance of solution ........................................................................................................................... 19

II.5.4.1. Clarity and degree of opalescence (2.2.1.) ................................................................................................................. 19 II.5.4.2. Degree of coloration (2.2.2.) ...................................................................................................................................... 19

II.5.5. II.5.6. pH and Acidity or alkalinity .................................................................................................................... 20 Optical rotation (2.2.7.) .......................................................................................................................... 21

II.5.7. II.5.8.

II.5.8.1. Thin-layer chromatography (TLC) (2.2.27.) .............................................................................................................. 27 II.5.8.2. Liquid chromatography (LC) (2.2.29.) ...................................................................................................................... 28 II.5.8.3. Gas-liquid chromatography (GC) (2.2.28.) ................................................................................................................ 33 II.5.8.4. Capillary electrophoresis (CE) (2.2.31.) .................................................................................................................... 33

Absorption spectrophotometry (ultraviolet and visible) (2.2.25.) ........................................................... 22 Related substances .................................................................................................................................. 23

II.5.9. Readily carbonisable substances ............................................................................................................ 34 II.5.10. Foreign anions and/or cations ................................................................................................................ 35 II.5.11. Heavy metals – Elemental Impurities ..................................................................................................... 35 II.5.12. Loss on drying (2.2.32.) .......................................................................................................................... 36 II.5.13. Thermogravimetry (2.2.34.) .................................................................................................................... 36 II.5.14. Semi-micro determination of water (2.5.12.) – (volumetric Karl Fischer) .............................................. 37 II.5.15. Micro determination of water (2.5.32.) – (coulometric Karl Fischer) .................................................... 37 II.5.16. Gas chromatographic determination of water ........................................................................................ 37 II.5.17. Determination of water by distillation (2.2.13.) ...................................................................................... 38 II.5.18. Sulfated ash (2.4.14.) .............................................................................................................................. 38 II.5.19. Residue on evaporation .......................................................................................................................... 38 II.5.20. Residual solvents (2.4.24.) ...................................................................................................................... 38 II.5.21. Bacterial endotoxins ............................................................................................................................... 38 II.6. ASSAY ............................................................................................................................................................ 39 II.6.1. Ultraviolet and visible spectrophotometry (2.2.25.) ............................................................................... 40

II.6.1.1. Direct measurement ................................................................................................................................................... 40 II.6.1.2. Measurement after a colour reaction.......................................................................................................................... 40

II.6.2. Volumetric analysis................................................................................................................................. 40 II.6.3. Chromatography ..................................................................................................................................... 41 II.6.4. Determination of nitrogen by sulfuric acid digestion (2.5.9.) ................................................................. 41 II.7. STORAGE ...................................................................................................................................................... 41 II.8. LABELLING .................................................................................................................................................. 42 II.9. IMPURITIES .................................................................................................................................................. 42 II.10. FUNCTIONALITY-RELATED CHARACTERISTICS ................................................................................ 43 III.

ANALYTICAL VALIDATION ........................................................................................................................ 44

III.1. DEFINITIONS AND TERMINOLOGY ......................................................................................................... 44 III.1.1. Introduction ............................................................................................................................................ 44 III.1.2. Types of analytical procedures to be validated ....................................................................................... 44 III.1.3. Validation characteristics and requirements .......................................................................................... 45 III.1.4. Glossary .................................................................................................................................................. 46 III.2. METHODOLOGY .......................................................................................................................................... 47 III.2.1. Introduction ............................................................................................................................................ 47 III.2.2. Specificity ............................................................................................................................................... 48

III.2.2.1. Identification ............................................................................................................................................................ 48 III.2.2.2. Assays and impurity tests ......................................................................................................................................... 49

III.2.3. III.2.4. III.2.5.

III.2.5.1. Assay ........................................................................................................................................................................ 51 III.2.5.2. Impurities (quantification) ........................................................................................................................................ 51 III.2.5.3. Recommended data .................................................................................................................................................. 51 III.2.6.1. Repeatability ............................................................................................................................................................ 52 III.2.6.2. Intermediate precision .............................................................................................................................................. 52 III.2.6.3. Reproducibility ......................................................................................................................................................... 52 III.2.6.4. Recommended data .................................................................................................................................................. 52 III.2.7.1. Based on visual evaluation ....................................................................................................................................... 52 III.2.7.2. Based on signal-to-noise ratio .................................................................................................................................. 52 III.2.7.3. Based on the standard deviation of the response and the slope ................................................................................ 53 III.2.7.4. Recommended data .................................................................................................................................................. 53 III.2.8.1. Based on visual evaluation ....................................................................................................................................... 53 III.2.8.2. Based on signal-to-noise ratio .................................................................................................................................. 53 III.2.8.3. Based on the standard deviation of the response and the slope ................................................................................ 54

Linearity ................................................................................................................................................. 49 Range ...................................................................................................................................................... 50 Accuracy ................................................................................................................................................. 51

III.2.6. Precision ................................................................................................................................................. 51

III.2.7. Detection limit ........................................................................................................................................ 52

III.2.8. Quantitation limit.................................................................................................................................... 53

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