European Pharmacopoeia Reference Standards

1 1 European Pharmacopoeia Reference StandardsA Lodi, Head of the Laboratory Department, EDQM, Council of EuropeAL 2016 EDQM, Council of Europe. All rights Eur. Reference Standards General notices, terms and definitions Key attributes Establishment Distribution and storage Secondary StandardsAL 2016 EDQM, Council of Europe. All rights Eur. General NoticesCertainmonographsrequiretheuseofr eferencestandards. The European PharmacopoeiaCommissionestablishes the official Reference Standards , which arealone authoritative in case of Reference Standards are available from the EuropeanDirectorate for the Quality of Medicines & HealthCare(EDQM).

2 AL 2016 EDQM, Council of Europe. All rights Eur. General NoticesThe limits prescribed in a monograph are based on data obtained innormal analytical practice; they take account of normal analyticalerrors, of acceptable variations in manufacture and compounding andof deterioration to an extent considered further tolerances are to be applied to the limitsprescribedto determine whether the article being examined complies with therequirement of the 2016 EDQM, Council of Europe. All rights PHARMACOPOEIALINK BETWEEN TEXTS AND Reference STANDARDSM ethodsSpecificationsReference StandardsAL 2016 EDQM, Council of Europe.

3 All rights Chapter for informationContent: Terminology Use of Reference Standards Establishment of Reference Standards Processing, Labelling, Storage and Distribution Re-Test ProgrammeAL 2016 EDQM, Council of Europe. All rights EUR. Reference STANDARDSAL 2016 EDQM, Council of Europe. All rights Eur. Chapter 4/2015 The term Reference standard is used as a general term coveringreference substances, preparations and spectra. Reference Standards are used to achieve adequate quality EUR. Reference STANDARDSAL 2016 EDQM, Council of Europe.

4 All rights Eur. Chapter 4 RS: Reference standard established under the aegis of and adopted by the European Pharmacopoeia Eur. chemical Reference substance (CRS) & biological Reference preparation (BRP): substance or mixture of substances intended for use as stated in a monograph or general chapter of the European Eur. herbal Reference substance (HRS): herbal drug preparation or herbal drug intended for use as stated in a monograph or general chapter of the European AND DEFINITIONSISO GUIDE 30:2015-Ph. Eur. Chapter 4/2015 Reference MaterialMaterial, sufficiently homogeneous and stable with respect toone or more specified properties1, which has been established tobe fit for its intended use2in a measurement can be quantitative or qualitative2 Uses may include calibration/assessment of a measurement system/procedure , assigning values to other materials and quality controlAL 2016 EDQM, Council of Europe.

5 All rights GUIDE 30:2015-Ph. Eur. Chapter 4/2015 Certified Reference Material (CRM) Reference material characterized by a metrologically validprocedure for one or more specified properties, accompanied bya certificate that provides the value of the specified property, itsassociated uncertainty, and astatement of 2016 EDQM, Council of Europe. All rights OF PH. EUR. Reference STANDARDSTYPES OF PH. EUR. Reference STANDARDSI dentification45%Assay 17%Impurities quantitative11%Impurities (qualitative11%Mixtures for SST/peak 2016 EDQM, Council of Europe.)

6 All rights LIFECYCLEAL 2016 EDQM, Council of Europe. All rights DistributionCharacterizationEstablishmen tProcessingPackagingQCValidity statementMonitoringAdoptionProcurementSD SI nformationleafletHelp DeskPh. Eur. needReplacementBatch needed7AL 2016 EDQM, Council of Europe. All rights : RS FOR IDENTIFICATIONEXAMPLE:RS FOR PEAK ID / SSTAL 2016 EDQM, Council of Europe. All rights HRS (quantitative use)LC assay Valerian dry extract HRS with assigned content for valerenic acid:AL 2016 EDQM, Council of Europe. All rights CRSAL 2016 EDQM, Council of Europe.

7 All rights Eur. assay Reference Standards why no uncertainty?ISO GUIDE 34 : 2009 GUIDE 31 : 2015 some cases that are covered by specific legislation ( most Pharmacopoeia assay Standards ) the uncertainties of the assigned values are not stated since they are considered to be negligible in relation to the defined limits of the method specific assays for which they are 2016 EDQM, Council of Europe. All rights Standard LeafletAL 2016 EDQM, Council of Europe. All rights (retest-programme) After establishment and adoption there is a standardizedtesting procedure in order to assure the fitness for use ofthe Reference Standards .

8 Depending on the use and the known or predicted stability,substances are retested every 12, 24, 36 or 60 months Items of retesting: All properties which might be subject tochange in the life cycle of a CRS, :- Water content- Purity by LC, GC or TLC- Possibly IR, UVNo expiry date is given: see batch validity statementAL 2016 EDQM, Council of Europe. All rights STANDARDSAL 2016 EDQM, Council of Europe. All rights Standards - paragraph 4-5. (for information)A secondary standard should exhibit the same property orproperties as the primary standard, relevant for the test(s) for whichit is established.

9 The extent of testing is not so great as is requiredfor the establishment of a primary standard. The secondarystandard is established by comparison with the primary standard towhich it istraceable. An official primary standard is used whereverpossible for establishment of secondary Standards . It is the responsibility of the user to justify/document thesuitability of secondary 2016 EDQM, Council of Europe. All rights 2016 EDQM, Council of Europe. All rights GMP Annex VI - Whenever compendial Reference Standards from an officialsource exist, these should preferably be used as primaryreference Standards unless fully justifiedthe use of secondary Standards is permitted once theirtraceability to primary standardshas been demonstratedand is traceabilityproperty of ameasurement resultwhereby the result can berelated to a Reference through a documented unbroken chain ofcalibrations.

10 Each contributing to themeasurement uncertaintyInternational vocabulary of metrology Basic and general concepts and associated terms(VIM) 3rd editionTRACEABILITYAL 2016 EDQM, Council of Europe. All rights Secondary Standards Example: Paracetamol CRS (no assigned content value)Used in monograph 0049 Paracetamol for: Identification by IRAssay determination in the monograph: TitrationAL 2016 EDQM, Council of Europe. All rights StandardsTraceability???AL 2016 EDQM, Council of Europe. All rights Eur. CRS official, legally binding Standards , an essential part of Ph.