THE EUROPEAN DIRECTORATE FOR THE QUALITY OF ......Use of Ph.Eur. Reference Standards Establishment...
Transcript of THE EUROPEAN DIRECTORATE FOR THE QUALITY OF ......Use of Ph.Eur. Reference Standards Establishment...
THE EUROPEAN DIRECTORATE FOR THE QUALITY OF MEDICINES & HEALTHCARE (EDQM)
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Establishment and use of Ph. Eur. Reference standards
Dr. Bart BlanchaertLaboratory Department
EDQM, Council of Europe
EUROPEAN PHARMACOPOEIA TRAINING7-8 July 2020, Webinar
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Outline
Terms and definitions
Establishment and use
RS for finished products monographs
RS for general methods
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Terms and definitions
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Terms and definitions
Terminology Use of Ph.Eur. Reference Standards Establishment of Reference Standards Manufacturing, Labelling, Storage and Distribution of Ph.Eur Reference Standards Re-Test Programme of Ph.Eur. Standards
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ISO GUIDE 30 / Ph.Eur. 5.12.
Reference MaterialMaterial, sufficiently homogeneous and stable with respect to one ormore specified properties*, which has been established to be fit forits intended use in a measurement process.
* quantitative or qualitative
Terms and definitions
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ISO GUIDE 30 / Ph.Eur. 5.12.
Certified Reference Material (CRM)Reference material characterized by a metrologically valid procedurefor one or more specified properties, accompanied by a certificatethat provides the value of the specified property, its associateduncertainty, and a statement of metrological traceability.
Terms and definitions
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ISO GUIDE 30 / Ph.Eur. 5.12.
Primary 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.
Secondary measurement standardStandard whose property value is assigned by comparison with aprimary standard of the same property or quantity.
Terms and definitions
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Ph.Eur. 5.12.
Reference Standard (RS)General term covering reference substances, preparations and spectra.
European Pharmacopoeia reference standard (Ph.Eur. RS)A reference standard established under the aegis of and adopted bythe European Pharmacopoeia Commission.
Terms and definitions
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Ph.Eur. 5.12.
European Pharmacopoeia chemical reference substance (CRS)Substance or mixture of substances intended for use as stated in amonograph or general chapter of the European Pharmacopoeia.
Note: HRS and BRP are other types of RS.
Terms and definitions
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EUROPEAN PHARMACOPOEIACOMPENDIAL STANDARD = MONOGRAPH + REFERENCE STANDARD
Method Specifications
Reference standard
Marketing AuthorisationCertification
Directives 2001/83/EC and 2001/82/EC
Terms and definitions
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Ph.Eur. General Notices
The European Pharmacopoeia Commission establishes the officialreference standards, which are alone authoritative in case ofarbitration.
These reference standards are available from EDQM.
REFERENCE STANDARDSLEGAL ASPECTS
Terms and definitions
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EU guideline for GMP * Part 1 – 6.20Whenever compendial reference standards from an official source exist,these should preferably be used as primary reference standards unless fullyjustified (the use of secondary standards is permitted once their traceability toprimary standards has been demonstrated and is documented).These compendial materials should be used for the purpose described in theappropriate monograph unless otherwise authorised by the National CompetentAuthority.
* Eudralex Volume 4, EU guidelines for good manufacturing practice for medicinal products for human and veterinary use
REFERENCE STANDARDSLEGAL ASPECTS
Terms and definitions
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Establishment and use
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?RS for identification
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Identification of substances subject of a Ph. Eur. monograph
Infrared absorption spectrophotometry (IR) , CRS or Ph. Eur. Reference Spectrum
Nuclear magnetic resonance spectrometry (NMR), if spectrum cannot be interpreted
Chromatographic separation techniques (LC, GC, TLC)
RS for identification
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Example IR
RS for identification
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Example TLC
RS for identification
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Example NMR
RS for identification
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EstablishmentKey quality attribute= identity
Identity: full structural elucidation (NMR, TOF-MS)
Compliance with relevant requirements of the monograph
Intended use
Characterisation less elaborated than for RS used quantitatively
RS for identification
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Assay RS
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Mostly used as external standard in LC or GC method
Substance compliant with relevant requirements of corresponding Ph.Eur. monograph
Exceptional cases: other salt form, other hydrate, lyophilised RS
Content is assigned based on mass balance approach (compendial + complementary tests)
Uncertainty of the assigned value is evaluated and shall be negligible compared to content limits in the monograph
Assay RS
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Assay RS
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EstablishmentKey quality attributes: Identity and content
Identity: full structural elucidation
Compliance with relevant requirements of the monograph
Volatile impurities (LOD, residual solvents (HS-GC) and water)
Inorganic impurities (sulfated ash)
Assay RS
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Establishment (continued) Homogeneity (LOD or water, residual solvents in specific cases)
Confirmation of assigned content by orthogonal methods (DSC, qNMR, elemental analysis)
Inter-laboratory study for parameters with significant contribution to assigned content
Assay RS
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Example: Raltegravir potassium CRS 1
Assay RS
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Example: Raltegravir potassium CRS 1Characterisation EDQM Lab
Test Result RSD nAppearance Almost white powder n/a 1
Mass spectrometry(in-house method)
2.2.43.m/z found in accordance with
sum formula n/a 1
Nuclear magnetic resonance spectrometry
(in-house method)2.2.33.
NMR spectra in accordance with structure n/a 1
Identification reactions of ions and functional groups
2.3.1.Positive reaction b) of
potassium n/a 1
Infrared absorption spectrophotometry
2.2.24.KBr disc and ATR spectra
recorded n/a 1
Related substances by liquid chromatography2.2.29. / 2.2.46.
See inter-laboratory study - -
Semi-micro determination of water2.5.12.
See inter-laboratory study - -
Test Result RSD n
Micro determination of water2.5.32.
0.16 % sd: 0.02 8
Conditions: Direct introduction of about 50 mg - -
Residual solvents by headspace gas chromatography
2.2.28. / 2.4.24.
Acetonitrile and ethanol:see inter-laboratory study
Sum of other residual solvents: below 0.10 %
(Traces of toluene detected)
- -
Quantitative nuclear magnetic resonance spectrometry (in-
house method)2.2.33.
About 99.4 % n/a 3
Internal standard: maleic acid - -
Elemental analysisC: 49.8 % (theory 49.8 %)H: 4.2 % (theory 4.2 %)
N: 17.4 % (theory 17.4 %)n/a 3
Assay RS
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Example: Raltegravir potassium CRS 1LC suitability
Assay RS
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Example: Raltegravir potassium CRS 1LC results
Assay RS
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Example: Raltegravir potassium CRS 1
(100 % - water % - residual solvents %) x [(100 % - sum of impurities by LC %) / 100 %] =
99.1 % of C20H20FKN6O5
Content assignment
Assay RS
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RS for impurity control
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Qualitative RS in impurity control
Chromatographic separation techniques (LC, GC, TLC)
Batch testing: identification of signals (specified impurities or CF)
System suitability testing (no batch related results generated)
Similarities in establishment
RS for impurity control (qualitative)
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Type of RS Pros Cons
Single substanceStability
Concentration easily controlledBatch continuity
May result in high number of RSAvailability
Mixture Representative of what user observes RS batch continuityPeak saturation for API
RS for impurity control (qualitative)
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RS for impurity control (qualitative)
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RS for impurity control (qualitative)
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RS for impurity control (qualitative)RS strategy Single substance <-> mixtures
Alternative to RS: commercial reagent or in situ degradation
If impurities are specified production batches expected to be suitable
A chromatogram is often supplied in the RS leaflet
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Establishment: single substance RS not subject of a Ph. Eur. monograph (e.g. impurity)Key quality attribute: identity
Full structural elucidation
Intended use
Characterisation is less elaborated than for RS used quantitatively
RS for impurity control (qualitative)
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Establishment: mixture RSKey quality attributes: identity of impurities, homogeneity, fitness for
purpose
Identity of impurity peaks
Spiking with authentic impurity samples
Homogeneity
Intended use
RS for impurity control (qualitative)
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Use Mostly in chromatographic methods
External standard for impurities with a response very different fromthat of main substance
RS for impurity control (quantitative)
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Content of RS is critical: ≥ 95.0 % or not?
Salt form has impact on use need for stoichiometric conversion factor?
Single substance RS only
Non-GMP material
RS for impurity control (quantitative)
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RS for impurity control (quantitative)
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EstablishmentKey quality attributes: identity and content
Identity: Structural elucidation
Identity of counter-ion: specific or screening
Related substances: method of intended use (LC/GC)
Volatile impurities: Loss on drying, thermogravimetry or water (+ residual solvents)
RS for impurity control (quantitative)
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Establishment (continued)Inorganic impurities: Sulfated ash (if amount allows) or screening
qNMR
Homogeneity: relevant parameter
Content assignment: mass balance or qNMR
Orthogonal methods
RS for impurity control (quantitative)
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Example: Phenobarbital impurity A CRS 1Analytical resultsIdentity: confirmedLoss on drying: 0.1 %LC-purity: 99.7 %
Content by qNMR (expressed ‘as is’, as free base): 79 %Elemental analysis: does not match the theoretical composition
Investigation Identification of nitrate as the counter ion (not on CoA)Quantification of nitrate by ion-exchange chromatography: 20.6 %
RS for impurity control (quantitative)
Mass balance: 99.6 %No need for assigned content
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RS for finished product monographs
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RS for finished product monographs
Can we use the RS used in the correspondingdrug substance monographs?
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RS for finished product monographs (identification)RS for identification Identity already certified
Independent of method
Use existing substance RS
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RS for finished product monographs (assay)RS strategy depends on the assay and related substances methodsSame methods as substance’s monograph Use existing assay RS
with its assigned content
Different methods from substance’s monograph (assay and/or related substances)Compare selectivity
Similar: Use existing assay RS and its assigned contentNot similar: Use a different RS
One assay RS = one assigned content!
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RS presented as mixturesSpecific related substances for FP (degradation products): separate
RSSame related substances in API and FP monograph: use existing RS
(Different methods add new chromatogram in leaflet)
Impurity RS (quantification)Existing RS and its assigned content can generally be used for FP
monograph, even when methods are different
RS for finished product monographs (impurity control)
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RS for general chapters
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RS for general chaptersReference materials with content traceable to the SI
Elemental impurity CRSChapter 2.4.20 Determination of elemental impuritiesFor accuracy testingLead 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)
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RS for general chaptersElemental impurity CRS
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RS for general chaptersSodium aminosalicylate dihydrate for equipment qualification CRS Used for verification of equipment for2.2.32. Loss on drying2.5.12. Water: semi-micro determination2.5.32. Water: micro determination2.2.34. Thermogravimetric analysis
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RS for general chapters
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RS for general chapters
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