1903_1615_RefStandards_VEsecured

1 VE ©2008 EDQM, Council of Europe, All rights reserved REFERENCE STANDARDS OF THE EUROPEAN PHARMACOPOEIA Vincent EGLOFF Head of Division - Reference Standards & Samples - EDQM, Council of Europe VE ©2008 EDQM, Council of Europe, All rights reserved Content of the presentation • Need and Role • Uses • Definition • How presented • How established • CRS Database • How to order • Dispatch and storage • Conclusion 2 VE ©2008 EDQM, Council of Europe, All rights reserved Need In chemistry, the history of (measurement) standards is closely linked with the development of analytical techniques. In the 19th Century all chemicals were, in comparison of those of today, of poor purity. Thus, for volumetric analysis suitable purified materials as primary standards had to be specified. One of the first examples was the recommendation of As(III) oxide by Gay Lussac (1824). VE ©2008 EDQM, Council of Europe, All rights reserved Role • Intended to define a quantity to serve as a reference (International vocabulary of basic and general terms of metrology -ISO) • To achieve adequate quality control of a substance for Pharmaceutical use • 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 dispute. 3 VE ©2008 EDQM, Council of Europe, All rights reserved USES • Identification • Purity testing • Assay VE ©2008 EDQM, Council of Europe, All rights reserved European Pharmacopoeia nearly 2,000 monographs; > 2,000 reference standards 4 VE ©2008 EDQM, Council of Europe, All rights reserved Classification of reference standards TYPE ♦ Chemical Reference Substances ♦ Biological Reference Preparations ESTABLISHMENT  Primary standards (without comparison to an existing standard)  Secondary standards (by comparison with a primary standard) PURPOSE  QUALITATIVE (Identification, system suitability)  QUANTITATIVE (Assay, external standard) VE ©2008 EDQM, Council of Europe, All rights reserved 5 VE ©2008 EDQM, Council of Europe, All rights reserved European Pharmacopoeia reference standards Chemical reference substance (CRS) A chemical compound or mixture of compounds which has been established for use as a standard in an identity test, a purity test and/or an assay as prescribed in a monograph. The standard is valid only for the specific test(s) for which it has been established VE ©2008 EDQM, Council of Europe, All rights reserved European Pharmacopoeia Reference Standard 6 VE ©2008 EDQM, Council of Europe, All rights reserved VE ©2008 EDQM, Council of Europe, All rights reserved 7 VE ©2008 EDQM, Council of Europe, All rights reserved European Pharmacopoeia Reference Standards VE ©2008 EDQM, Council of Europe, All rights reserved Establishment of Reference Standards  candidate examined at the EDQM Lab.  inter-laboratory study for assay CRS  approved by the Group of Experts  adopted by the Ph. Eur. Commission 8 VE ©2008 EDQM, Council of Europe, All rights reserved Extent of analytical testing: according to the CRS use Identification => structure elucidation + compliance Peak ID, system suitability => structure elucidation + fitness for purpose External standard => structure elucidation + purity Assay: assignment based on interlaboratory study involving five laboratories: EDQM Laboratory + Official Laboratories and Experts; the manufacturer is normally invited to participate. VE ©2008 EDQM, Council of Europe, All rights reserved Requirements for a candidate CRS Pharmaceutical Substance subject of a monograph: The CRS must comply with the requirements of the monograph, no special purity required Impurity CRS (i.e. not subject of a monograph) Minimum content : qualitative use : 90%; quantitative use : 95%, otherwise value assigned 9 VE ©2008 EDQM, Council of Europe, All rights reserved CRS for identification Compliance / structure elucidation : The EDQM laboratory carries out all tests of the monograph. The structure of the substance is elucidated by means of NMR, MS and FT-IR data as well as by comparison to literature data. VE ©2008 EDQM, Council of Europe, All rights reserved CRS used in the test for related substances Qualitative use - System suitability - Peak identification Quantitative use - Limit test - Quantitative test 10 VE ©2008 EDQM, Council of Europe, All rights reserved In general an impurity is to be identified, i.e. located in the chromatogram or electropherogram: - when it has an individual limit and/or - when a correction factor must be applied CRS used in the test for related substances VE ©2008 EDQM, Council of Europe, All rights reserved Types of impurity CRS : qualitative use  Individual “impurity” : preferred option but sometimes difficult to obtain  Mixtures of impurities  Batches containing one or more impurities  Spiked samples 11 VE ©2008 EDQM, Council of Europe, All rights reserved Impurity CRS : qualitative use A representative chromatogram is supplied together with the CRS when indicated in the monograph VE ©2008 EDQM, Council of Europe, All rights reserved Impurity CRS : Quantitative use  Individual impurities with an assigned value if necessary  Batch containing the impurity with an assigned value 12 VE ©2008 EDQM, Council of Europe, All rights reserved CRS used for assay Assay methods :  LC  GC  UV spectrophotometry  Microbiological assay  Bio- or immunoassay VE ©2008 EDQM, Council of Europe, All rights reserved Establishment of assay CRS (1) Internal preliminary work • Elucidation of the structure of the candidate CRS • Verification of compliance with the monograph requirements • Additional tests, such as residual solvents, DSC purity, non- aqueous titration. 13 VE ©2008 EDQM, Council of Europe, All rights reserved 1. Protocol (method-specific approach) developed and checked in the EDQM laboratory 2. Production of the batch 3. Dispatch of samples to the participants 4. Analysis of analytical results 5. Report with proposed assigned value 6. Approval from the group of experts 7. Adoption by the Commission 8. Labelling 9. QA release of the batch Establishment of assay CRS (2) Internal preliminary work VE ©2008 EDQM, Council of Europe, All rights reserved Example protocol: CRS for LC- assay Collaborative study: Loss on drying or det. of water (by KF / coulometry) Quantitative determination of the impurities by LC Residual solvents by head-space GC 14 VE ©2008 EDQM, Council of Europe, All rights reserved pre-defined acceptance criteria:  Repeatability (water determination/ LOD)  Selectivity test (LC-GC)  Symmetry factor (LC-GC)  Repeatability (LC-GC) CRS for LC-assay Acceptance of results VE ©2008 EDQM, Council of Europe, All rights reserved Estimation of the uncertainty of the assigned content Ph. Eur. Commission policy : the uncertainty of the value assigned as a result of an interlaboratory trial should be within a predetermined limit which is calculated in relation with the intended use. 15 VE ©2008 EDQM, Council of Europe, All rights reserved Dealing with uncertainty VE ©2008 EDQM, Council of Europe, All rights reserved Content If the CRS is supplied as a powder to be weighed, the value assigned is the % (m/m) content on an «as is» basis. NO NEED TO DRY. Example: Benzathine benzylpenicillin CRS 2 16 VE ©2008 EDQM, Council of Europe, All rights reserved CRS with assigned content VE ©2008 EDQM, Council of Europe, All rights reserved Non-assay CRS 17 VE ©2008 EDQM, Council of Europe, All rights reserved Content If the CRS is supplied in a pre-dispensed form such as a freeze-dried substance to be reconstituted, the value assigned is the quantity per vial. Example: Calcitonin (salmon) CRS 5 VE ©2008 EDQM, Council of Europe, All rights reserved 18 VE ©2008 EDQM, Council of Europe, All rights reserved Order code Batch number Quantity per vial Unique identifier per label 2 D barcodeRS nameSentences for customs New over label (peel off) VE ©2008 EDQM, Council of Europe, All rights reserved Use of Ph. Eur. CRS • Ph. Eur. CRS are to be used in conjunction with the corresponding monograph(s). • Ph. Eur. CRS are to be used for the purpose for which they are intended. • Any different use is in the responsibility of the user. • Storage of opened containers is discouraged and is in any case the responsibility of the user. 19 VE ©2008 EDQM, Council of Europe, All rights reserved Monitoring programme Once established and adopted, the CRS undergoes periodic testing in order to ensure its continuous fitness for use. The periodicity of testing depends on the use of the CRS and the stability information available. The extent of testing also depends on the use of the CRS. In general the focus is on the properties that may change during the life cycle of a CRS, i.e.: appearance, purity by HPLC, GC or TLC, DSC, water and solvent content. No expiry dates: see batch validity statement VE ©2008 EDQM, Council of Europe, All rights reserved REFERENCE STANDARDS CATALOG ON LINE Paper or PDF 3 issues a year 20 VE ©2008 EDQM, Council of Europe, All rights reserved VE ©2008 EDQM, Council of Europe, All rights reserved Non-official information intended to facilitate the use of the CRS can be found in the knowledge database and CRS database (website). 21 VE ©2008 EDQM, Council of Europe, All rights reserved Reference standards database Knowledge database Availability Origin Assigned Value Presentation Batch Validity Statement Safety Data Sheets Info on reagents and columns Chromatograms VE ©2008 EDQM, Council of Europe, All rights reserved 22 VE ©2008 EDQM, Council of Europe, All rights reserved VE ©2008 EDQM, Council of Europe, All rights reserved 23 VE ©2008 EDQM, Council of Europe, All rights reserved VE ©2008 EDQM, Council of Europe, All rights reserved 24 VE ©2008 EDQM, Council of Europe, All rights reserved VE ©2008 EDQM, Council of Europe, All rights reserved 25 VE ©2008 EDQM, Council of Europe, All rights reserved How to order - CRS order form (catalog or web site) Or - Official purchase order on company letterhead To be sent: - by E-mail: orders@edqm.eu - by Fax: +33 (0)3 88 41 27 71 - by Letter: Council of Europe, European Directorate for the Quality of Medicines & HealthCare, Sales Section, 7 allée Kastner, CS 30026, F-67081 Strasbourg, France VE ©2008 EDQM, Council of Europe, All rights reserved 26 VE ©2008 EDQM, Council of Europe, All rights reserved Between: The European Directorate for the Quality of Medicines & HealthCare of the Council of Europe, F- 67081 Strasbourg, represented by Dr Agnès Artiges, Director (hereafter referred to as “Council of Europe – EDQM”) On the one part And: Shanghai Oriental Pharmaceutical Science and Technology Co., Ltd., 1500 Zhangheng Road, Shanghai, represented by Mrs. Chen Longdi, General Manager (affiliate of Shanghai Institute for Food and Drug Control (SIFDC) (hereafter referred to as “SOPST”) (June 2007) Memorandum of Agreement VE ©2008 EDQM, Council of Europe, All rights reserved 1. The Council of Europe - EDQM grants SOPST non-exclusive distributions rights for its EPRS (European Pharmacopoeia Reference Standards) on the territories of People’s Republic of China (hereafter referred to as “the territory”) for the duration of the present contract. (Extract) 27 VE ©2008 EDQM, Council of Europe, All rights reserved SOPST Shanghai Oriental Pharmaceutical Science and Technology Co. Ltd. Address: No.1500 Zhangheng road,Shanghai Postcode: 201203 Tel: +86-21-50798017, Fax: +86-21-50798137 Contact: Chen Longdi, General Manager Email: for EPRS orders: edqmcrs@sh163.net Website: www.shdfgs.com VE ©2008 EDQM, Council of Europe, All rights reserved Dispatch and storage at reception • Dispatching conditions: Ambient temperature Under ice Under dry ice • Recommended storage conditions  +5°C or -20°C  +5°C or -20°c  -20°C or -80°C 28 New Chapter of the European Pharmacopoeia 5.12 Pharmaceutical Reference Standards Effective Jan 1st, 2007 ESTABLISHMENT USE PRESENTATION of pharmaceutical reference standards in general & European Pharmacopoeia reference standards in particular. VE ©2008 EDQM, Council of Europe, All rights reserved Ph. Eur. CRS take home messages • They are official, primary standards • They constitute an essential part of the monograph • They are guaranteed only for the intended purpose • The assay value is assigned “as is” • Their continuous fitness for purpose is assured by a regular monitoring programme • User interface => website - Consult before use - • The Ph. Eur. policy on reference standard is reflected in general chapter 5.12 29 VE ©2008 EDQM, Council of Europe, All rights reserved Thank you for your attention. If you have questions after this symposium please make use of our Helpdesk.