European Pharmacopoeia Reference Standards

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European PharmacopoeiaReference StandardsDr Jochen PauwelsLaboratory Department,EDQM, Council of EuropeJ. Pauwels 2018 EDQM, Council of Europe. All rights reserved.TOPICS Ph.Eur. Reference Standards - References andDefinitions Establishment of quantitative standards Establishment of qualitative standards Labelling and use of Ph.Eur. Reference Standards Secondary StandardsJ. Pauwels 2018 EDQM, Council of Europe. All rights reserved.1

TERMS AND DEFINITIONSISO GUIDE 30Reference MaterialMaterial, sufficiently homogeneous and stable with respectto one or more specified properties*, which has beenestablished to be fit for its intended use in a measurementprocess.* quantitative or qualitativeJ. Pauwels 2018 EDQM, Council of Europe. All rights reserved.TERMS AND DEFINITIONSISO GUIDE 30Certified Reference Material (CRM)Reference material characterized by a metrologically validprocedure for one or more specified properties,accompanied by a certificate that provides the value ofthe specified property, its associated uncertainty, and astatement of metrological traceability.J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.2

TERMS AND DEFINITIONSWhat is a Ph.Eur. Reference Standard? Reference standard” (RS) is a general term covering referencesubstances, preparations and spectra. European Pharmacopoeia reference standardA reference standard established under the aegis of and adopted bythe European Pharmacopoeia Commission. European Pharmacopoeia chemical reference substance(CRS)A substance or mixture of substances intended for use as stated in amonograph or general chapter of the European Pharmacopoeia.Ph.Eur. Chapter 5.12.J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.EUROPEAN PHARMACOPOEIACOMPENDIAL STANDARD MONOGRAPH REFERENCE ting AuthorisationCertificationDirectives 2001/83/EC and 2001/82/ECJ. Pauwels 2018 EDQM, Council of Europe. All rights reserved.3

TERMS AND DEFINITIONSPrimary measurement standardA standard designated or widely acknowledged as having the highestmetrological qualities and whose property value is acceptedwithout reference to other standards of the same property orquantity, within a specific context.ISO Guide 30 (2015) / Ph. Eur. Chapter 5.12.Secondary measurement standardStandard whose property value is assigned by comparison with aprimary standard of the same property or quantity.ISO GUIDE 30 (2015) / Ph. Eur. Chapter 5.12.J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.Ph.Eur. Chapter 5.12. –Reference Standards (07/2018) Terminology Use of Ph.Eur. Reference Standards Establishment of Reference Standards Primary StandardsPh.Eur CRSPh.Eur HRSPh.Eur. BRP and Chemical RS for Biologicals Manufacturing, Labelling, Storage and Distribution ofPh.Eur Reference Standards Re-Test Programme of Ph.Eur. StandardsJ. Pauwels 2018 EDQM, Council of Europe. All rights reserved.4

Ph.Eur. General NoticesThe European Pharmacopoeia Commission establishesthe official reference standards, which are aloneauthoritative in case of arbitration.These reference standards are available from EDQM.J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.5

6.20Reference standards should be established as suitable for theirintended use. Their qualification and certification as such shouldbe clearly stated and documented.Whenever compendial reference standards from anofficial source exist, these should preferably be used asprimary reference standards unless fully justified (the use ofsecondary standards is permitted once their traceability toprimary standards has been demonstrated and is documented).These compendial materials should be used for the purposedescribed in the appropriate monograph unless otherwiseauthorised by the National Competent Authority.J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.Use of Ph.Eur. Reference StandardBATCH TESTINGe.g. IdentificationAssay, PurityEVALUATION OF AMEASUREMENTEVALUATIONOF ASYSTEMMEASUREMENTSYSTEMe.g. Systemsuitability testESTABLISHMENT OF ASECONDARY STANDARDe.g. WorkingstandardsVERIFICATION OFA MEASUREMENTSYSTEMe.g. TGA, KF, LODequipmentJ. Pauwels 2018 EDQM, Council of Europe. All rights reserved.6

Establishment of quantitative RSNeed for a new RS or a replacement on-profileFillingEstablishment / content assignmentApproval / AdoptionRelease of RS for distributionJ. Pauwels 2018 EDQM, Council of Europe. All rights reserved.REFERENCE STANDARDSUSED ASEXTERNAL STANDARDSIN THEASSAYJ. Pauwels 2018 EDQM, Council of Europe. All rights reserved.7

Establishment / Content assignmentStructure elucidationCompliance with the relevant requirements of the monographVerification of batch homogeneityInter-laboratory study to assign a content (if required)- water determination / loss on drying- related substances (LC, GC, CE)- other minor components e.g. inorganic impurities, residualsolvents etc. Content assigned by “mass balance” Assigned value checked by orthogonal techniques(e.g. qNMR where applicable). J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.Example: Raltegravir Potassium CRS 1J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.8

Example: Raltegravir Potassium CRS 1Characterisation EDQM LabJ. Pauwels 2018 EDQM, Council of Europe. All rights reserved.S. Almeling 2018 EDQM, Council of Europe. All rights reserved.Example: Raltegravir Potassium CRS 1Inter-Laboratory study (example LC - suitability):J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.9

Example: Raltegravir Potassium CRS 1Inter-Laboratory study (example LC - results):J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.Example: Raltegravir Potassium CRS 1Content assignment:(100% - water% - residual solvents%) x [(100% - sum of impurities by LC%) / 100%] 99.1% of C20H20FKN6O5The estimated uncertainty of this value is 0.10%J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.10

Example: Raltegravir Potassium CRS 1Estimated uncertainty: . uIS standard uncertainty of inter-laboratory study standard deviation water standard deviation LCn number of participants Uexp.uISuhomk expanded uncertainty standard uncertainty of inter-laboratory study standard uncertainty homogeneity coverage factorNote: The stability component of the uncertainty is not included as considered negligible based on existing data.J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.11

ASSIGNED CONTENTPowder-filled CRSContent (m/m) assigned on an “ as is ” basis.TO BE WEIGHED - NO NEED TO DRYFreeze-dried CRSThe value assigned corresponds to the amount per vial, for example2.05 mg/vial.TO BE RECONSTITUTED, NOT WEIGHEDJ. Pauwels 2018 EDQM, Council of Europe. All rights reserved.PH.EUR. REFERENCE STANDARDS not necessarily suitable for other purposes.If a reference standard is to be used for anypurpose other than that for which it has beenestablished, its suitability for the new use hasto be fully demonstrated.Any value assigned to a reference standard is valid for theintended use and not necessarily for other uses.[Ph.Eur. Chapter 5.12.]J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.12

Ph.Eur. Chapter 5.12.Reference StandardsA European Pharmacopoeia reference standard with an assignedcontent/potency for use in the assay of a substance forpharmaceutical use ( ) may be suitable to determine thecontent/potency of that substance in a pharmaceuticalpreparation provided all of the following conditions are fulfilled:– the chromatographic assay method described in the activesubstance monograph is employed;– the applicability of the method to the particular pharmaceuticalpreparation (absence of interference) is verified by the user;–any pre-treatment of the sample (e.g. extraction, filtration) isvalidated for the particular pharmaceutical preparation.J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.Risks related to off-label use:Artemisinin RS established for LC assayLC-UV assay method: RP C18 column – Isocratic elutionDetection wavelength: 210 nmLimits: 97.0 to 102.0%Content of the reference standard for assay:mass balance: 99.9%by qNMR:99.9%CAN THE STANDARD BE USEDIN A DIRECT UV ASSAY METHOD AT 210 nm?J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.13

Risks related to off-label use :LC vs direct UV assay of ArtemisininArtemisininImpurity A(Artemisitene)At 210 nm impurity A needs a correction factor of 0.027corresponding to a response factor of 37!J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.Risks related to off-label use :LC vs direct UV assay of ArtemisininThe presence of 0.1% of impurity A results in a UV signal at 210nm which is equivalent to 3.7% of artemisinin.Conclusion:The standard with an assignedcontent of 99.9% is not suitablefor use in a direct UV assay methodJ. Pauwels 2018 EDQM, Council of Europe. All rights reserved.14

REFERENCE STANDARDSUSED ASEXTERNAL STANDARDSIN THERELATED SUBSTANCES TEST(IMPURITIES)J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.ESTABLISHMENT OF IMPURITY RSA candidate impurity RS used as external standard ischaracterised for: identity (structure elucidation) identity of / screening for counter-ionpurity (method of intended use)loss on drying / TGA or water ( residual solvents)homogeneityconfirmation of assigned content / purity by orthogonalmethods.Note: A content is assigned only if below 95.0%.J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.15

ESTABLISHMENT OF IMPURITY RSCOUNTER-IONExample: Phenobarbital impurity AAnalytical results: Loss on drying: below 0.1% LC-purity: 99.7%But: Content by qNMR: 79% Elemental analysis: does not match the theoretical composition Identification of nitrate as the counter ion Quantification of nitrate by ion-exchange chromatography: 20.6%Content assignment: 79.1%J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.ESTABLISHMENT OF IMPURITY RSStoichiometric Conversion FactorApplied for new impurity RS to be used as external standardsprovided the RS is supplied in a different salt form than thesubstance to be examined.If required, a stoichiometric conversion factor will be providedin the leaflet accompanying the RS.The stoichiometric conversion factor will in any case be givenseparate from the assigned content.J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.16

ESTABLISHMENT OF IMPURITY RSStoichiometric Conversion Factor - Example Impurity A CRS is used in the monographs of the base and thesulfate salt of the same API. Impurity A CRS 1 is supplied as sulfate salt. The sulfate salt of impurity A has a molecular mass (Mr) of400.0, impurity A as a base has a Mr of 302.0. The calculated stoichiometric conversion factor for use in the APIbase monograph is: 400/302 1.324J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.ESTABLISHMENT OF IMPURITY RSStoichiometric Conversion Factor - ExampleInformation provided with the CRS:“ XXXX impurity A CRS 1 is provided as a sulfate salt.For the calculation of the amount of impurity A in monograph xxxx (base), multiplythe peak area of impurity A obtained with reference solution (b) by a stoichiometricconversion factor of Mr 400.0 / Mr 302.0 1.3.For the calculation of the amount of impurity A in monograph xxxx (sulfate), nostoichiometric conversion is required.Note: Molecular masses used for the calculation of the stoichiometric correctionfactor in this leaflet:xxxx impurity A sulfate: (CxHyNz * H2SO4) 400.0 g/molxxxx impurity A base: (CxHyNz) 302.0 g/mol”J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.17

REFERENCE STANDARDSUSED ASREFERENCE MATERIALJ. Pauwels 2018 EDQM, Council of Europe. All rights reserved.NEW:Ph.Eur. ELEMENTAL IMPURITY CRSFour new elemental impurity CRS areavailable in the Ph.Eur. catalogue: Lead solution CRS (1.00 mg/g) Cadmium solution CRS (1.00 mg/g) Mercury solution CRS (1.00 mg/g) Arsenic solution CRS (1.00 mg/g)J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.18

NEW:Ph.Eur. ELEMENTAL IMPURITY CRSThese elements occurring in nature are amongst the greatestpotential sources of elemental contamination in medicinalproducts and substances for pharmaceutical use; the newreference standards are traceable to the SI (InternationalSystem of units of measurements) and enable metrologicallysound determination of lead, cadmium, mercury and arsenic aselemental impurities in medicinal products and substances forpharmaceutical use in relation with Ph.Eur. Chapter 2.4.20.describing the determination of elemental impurities.J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.New: Sodium aminosalicylate dihydratefor equipment qualification CRSSodium aminosalicylate dihydrate for equipment qualification CRS 1replaces the former Amoxicillin trihydrate for performanceverification CRS, which has been discontinued since 1 April 2018in the Ph.Eur.The new reference standard (RS) comes with enhanced featurescompared to the former beta-lactam based RS.In addition to simpler and faster sample preparation, the new CRSallows for a broader spectrum of applications as, unlike theprevious RS, it can be used for all applications described in the Ph.Eur. chapter on micro determination of water (2.5.32) and not onlythe oven technique.J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.19

Sodium aminosalicylate dihydrate forequipment qualification CRS2.2.32. LOSS ON DRYINGMethod. Place the prescribed quantity of the substance to be examined in a weighing bottle previously dried under the conditionsprescribed for the substance to be examined. Dry the substance to constant mass or for the prescribed time by one of the followingprocedures. Where the drying temperature is indicated by a single value rather than a range, drying is carried out at the prescribedtemperature 2 C. d) “in an oven within a specified temperature range”: the drying is carried outin an oven within the temperature range prescribed in the monograph;instrument qualification is carried out according to established quality systemprocedures, for example using a suitable certified reference material (sodiumaminosalicylate dihydrate for equipment qualification CRS may beused); J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.Sodium aminosalicylate dihydrate forequipment qualification CRSRS leaflet – 2.2 analytical information: 2.2.32. – Loss on dryingCertified loss on drying value: 169.6 mg/gUncertainty: 0.4 mg/gTest procedure:Determine the loss on drying in triplicate using 1000 mg of substance perdetermination. Drying conditions: 105 C until constant mass (Ph. Eur. method2.2.32. d)).Container dimensions (recommended): diameter about 50 mm; height about 30mm. J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.20

Sodium aminosalicylate dihydrate forequipment qualification CRSDetermination of the suggested acceptance criteria (1):According to ISO Guide 33 two factors contribute to thedifference between the certified value and themeasurement result: the uncertainty of the certified value. the uncertainty of the results of the measurementprocess being assessed expressed by its standarddeviation ( ).J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.Sodium aminosalicylate dihydrate forequipment qualification CRSDetermination of the suggested acceptance criteria (2):The standard deviation of a measurement process ( ), which is caused by anunavoidable random error inherent in every measurement process is composedof: within-laboratory variability (short term fluctuation), expressed as repeatabilitystandard deviation ( ) between laboratory fluctuation, expressed as intermediate precision or),reproducibility standard deviation (Consequently, the uncertainty of a measurement process ( ) can be calculatedas follows: J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.21

Sodium aminosalicylate dihydrate forequipment qualification CRSRS leaflet – 2.4 instructions for use:Taking into account the inter-laboratory standard deviation as wellas the mean intra-laboratory standard deviation obtained in theinter-laboratory study for the value assignment, the result of ameasurement (following the indicated experimental conditions) maybe considered acceptable if the mean of 3 replicate determinationsfalls within the following limits:Loss on drying (2.2.32.) 167.2 mg/g to 172.0 mg/g J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.REFERENCE STANDARDS FORQUALITATIVE USEJ. Pauwels 2018 EDQM, Council of Europe. All rights reserved.22

RS FOR QUALITATIVE USEPurposeIdentification of monograph substance (not further discussed).Identification of impurities of the monograph substance, often in atest for related substances using a chromatographic method (LC, GCor TLC), e.g. because of specific limit for impurity, correction factorfor impurity System suitability test of an analytical method, e.g.:- selectivity: resolution, peak-to-valley ratio;- sensitivity. Individual substance (“impurity”) or mixture RSJ. Pauwels 2018 EDQM, Council of Europe. All rights reserved.‘SINGLE COMPOUNDS – IMPURITY’ExampleJ. Pauwels 2018 EDQM, Council of Europe. All rights reserved.23

‘SINGLE COMPOUNDS – IMPURITY’EstablishmentKey quality attribute identity.Verification of the identity and intended use.Overall, less elaborate than for impurities used quantitatively.J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.‘MIXTURES’ExampleJ. Pauwels 2018 EDQM, Council of Europe. All rights reserved.24

‘MIXTURES’Composition (see monograph): several impurities with/without main compoundName: for system suitability CRS, for peak identification CRS, impurity mixture CRS, EstablishmentIdentity of impurities:normally confirmed by spiking with individual impuritysamples.Fitness for purpose:using method of intended useimpurities present in sufficient amount for peak identificationsystem suitability assessment.Homogeneity:for compounded mixtures.J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.LABELLINGANDUSEJ. Pauwels 2018 EDQM, Council of Europe. All rights reserved.25

LabellingIncludes: name of the reference standard; name of the supplier; batch number; any other information necessary to the properuse of the reference standard.J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.LabellingIf used as an assay standard the following information isalso given: the assigned percentage content; or, the content in mg or mL of the chemical entity in thecontainer; or, the assigned potency (for biological assays ormicrobiological assays) in units either per mg or per vial.An explanatory leaflet is considered as part of the labelling.J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.26

Reference Standard LeafletsAssignedcontentvalueJ. Pauwels 2018 EDQM, Council of Europe.All rights reserved.WHAT IS EXPECTED FROM THE USERImmediately before using a Ph.Eur. Reference Standard,the following shall be checked: that the reference standard batch number be current at thetime of use. A real-time batch validity statement is availableonline; that the container/closure system integrity be kept, i.e.absence of visible defects originating from shipping; that the reference standard after receipt has been stored atthe conditions prescribed in the Ph.Eur. RS catalogue;Moreover, allow the RS to equilibrate to lab temperature beforeopening.J. Pauwels 2018 EDQM, Council of Europe. All rights reserved.27

REFERENCE STANDARDS CATALOGUEAvailable online. Updated daily. English only.http://crs.edqm.eu/db/4DCGI/web catalog CRS(for searching database: https://crs.edqm.eu)J. Pauwels 2018 EDQM, Council of Europe. All

Reference standards should be established as suitable for their intended use. Their qualification and certification as such should be clearly stated and documented. Whenever compendial reference standards from an official source exist, these should preferably be used as primary reference standards unless fully justified (the use of

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