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The European Pharmacopoeia (Ph. Eur.) THE EUROPEAN DIRECTORATE FOR THE QUALITY OF MEDICINES & HEALTHCARE (EDQM) European Directorate for the Quality of Medicines & HealthCare • A Council of Europe Directorate, based on the Convention on the Elaboration of a European Pharmacopoeia (PA, 1964) • Mission: to contribute to a basic human right: access to good quality medicines and healthcare • See www.edqm.eu for further information 2 ©2020 EDQM, Council of Europe. All rights reserved. Key players for the quality of medicines in Europe National Authorities EU Coordination of scientific DG Health and resources from MS Food Safety Licensing Authorities Inspectorates Control Laboratories Pharmacopoeia Authorities Pharmaceutical legislation National Authorities EU & non-EU European Pharmacopoeia OMCL, Certification, Healthcare…. 3 ©2020 EDQM, Council of Europe. All rights reserved. •EDQM Laboratory •Established in 1967 •Located in Strasbourg, France • - Analytical Chemistry Division • - Biological Section 4 ©2020 EDQM, Council of Europe. All rights reserved. Role of the EDQM Laboratory European • establish/monitor Ph. Eur. reference substances (CRS) Pharmacopoeia • support elaboration of Ph. Eur. monographs / chapters (Ph. Eur.) • support the biological standardisation programme European • support the annual PTS programme OMCL network WHO • establish/monitor ICRS (Ref. Standards for the Ph. Int.) • establish/monitor ISA (Int’l Standards for Antibiotics) • participate in int’l studies on RS 5 ©2020 EDQM, Council of Europe. All rights reserved. European Pharmacopoeia Reference Standards for Biologicals Frank Jung, Ph.D. EDQM Laboratory Department Biological Section 6 ©2020 EDQM, Council of Europe. All rights reserved. The European Pharmacopoeia (Ph. Eur.) A compendium of quality standards for substances for pharmaceutical use and medicinal products Legally binding in 39 countries signatories of the Ph. Eur. Convention + the EU (> 600 million people); Applied in >100 countries worldwide 10h Edition: > 2300 monographs > 350 general texts ca. 3000 reference standards 7 ©2020 EDQM, Council of Europe. All rights reserved. Marketing Authorisation for Medicinal products QUALITY Marketing Authorisation Application SAFETY EFFICACY 8 ©2020 EDQM, Council of Europe. All rights reserved. Role of Ph. Eur. reference standards General chapters Specific monographs Reference General monographs standards Where a RS is referred to in a Ph. Eur. text, it represents the official standard that is alone authoritative... [Ph. Eur. chapter 5.12.] 9 ©2020 EDQM, Council of Europe. All rights reserved. The Ph. Eur. quality triangle Reference Standards Methods Specifications 10 ©2020 EDQM, Council of Europe. All rights reserved. Ph. Eur. RS portfolio for biologicals • About 140 Reference Standards for Enzyme Synthetic 9% Products Biologicals (CRS and BRP): 4% of Ph. peptides from 19% extraction Cell line Eur. RS portfolio 8% 2% rDNA Vaccines • 21% monographs on rDNA derived proteins and Sera 21% 22% biotherapeutics Blood products 17% NAT 2% 11 ©2020 EDQM, Council of Europe. All rights reserved. Ph. Eur. monographs on rDNA biotherapeutics – smaller molecules mol mass units CALCITONIN (rDNA and synthetic) 3432 mg GLUCAGON 3483 mg TERIPARATIDE 4118 mg HUMAN INSULIN (rDNA and enzymatic modification) 5808 mg PEPTIDES INSULIN LISPRO 5808 mg INSULIN ASPART 5826 mg INSULIN GLARGINE 6063 mg Content expressed in mass (mg) 12 ©2020 EDQM, Council of Europe. All rights reserved. Ph. Eur. monographs on rDNA biotherapeutics – larger molecules mol mass units MOLGRAMOSTIM 14477 IU INTERFERON GAMMA-1B 16465 IU FILGRASTIM 18799 IU INTERFERON ALFA-2 19241-19271 IU SOMATROPIN 22125 mg INTERFERON BETA-1a ca 22500 IU PROTEINS FOLLITROPIN 30000-40000 IU HUMAN COAGULATION FACTOR VIIa ca 50000 IU HUMAN COAGULATION FACTOR XIa ca 55000 IU ETANERCEPT 51200 (w/o glycosylation) IU HUMAN COAGULATION FACTOR VIIIa average 264725 IU mol mass units mAb INFLIXIMAB 145000 (w/o glycosylation) IU Content usually expressed in IU (biological assay) 13 ©2020 EDQM, Council of Europe. All rights reserved. rDNA biotherapeutics – increasing complexity Peptides Proteins Glycoproteins Infliximab Etanercept Follitropin Filgrastim Insulin glargine 1328 Teriparatide 934 203 175 53 34 Number of amino acids Structural inhomogeneity 14 ©2020 EDQM, Council of Europe. All rights reserved. Ph. Eur. monographs on rDNA biotherapeutics – continued Bioassay (arbitrary unitage) International Standard (WHO) • Activity assigned by the WHO (International Units) Ph. Eur. Biological Reference Preparations (”BRP”) • Calibrated in International Units against a WHO International Standard In the Ph. Eur. potency is expressed in I.U. per mg of protein The protein content is usually determined by UV spectrophotometry, using either a specific absorbance value given in the monograph (example: infliximab) or a Ph. Eur. CRS (example: etanercept). 15 ©2020 EDQM, Council of Europe. All rights reserved. Intended use of Ph. Eur. reference standards Ph. Eur. ref. standards for rDNA biotherapeutics are to be used for the intended use(s) described in the respective monographs They are not to be used in defining biosimilarity, and should not be inferred as serving this purpose Reference biotherapeutic product (RBP) “A reference biotherapeutic product is used as the comparator for head-to-head comparability studies with the similar biotherapeutic product in order to show similarity in terms of quality, safety and efficacy. Only an originator product licensed on the basis of a full registration dossier can serve as a RBP. It does not refer to measurement standards such as international, pharmacopoeial, or national standards or reference standards.” WHO GUIDELINES ON EVALUATION OF SIMILAR BIOTHERAPEUTIC PRODUCTS (SBPs), 2009 16 ©2020 EDQM, Council of Europe. All rights reserved. Ph. Eur. Reference standards for rDNA biotherapeutics Reference Substances for physico-chemical tests 17 ©2020 EDQM, Council of Europe. All rights reserved. CRS for assay Example: INSULIN ASPART Insulin aspart is a 2-chain peptide, A-chain is composed of 21 amino acids B-chain is composed of 30 amino acids. Assay is by LC, by comparison with insulin aspart CRS. Insulin aspart CRS is presented as a vial containing a lyophilisate. The candidate bulk material has been characterised as a primary standard using a variety of physico- chemical techniques to confirm structure, identity and purity. The batch of lyophilised vials has been tested for homogeneity, stability and suitability for the intended use. A content value has been assigned based on an international collaborative study, applying the mass- balance approach. 18 ©2020 EDQM, Council of Europe. All rights reserved. CRS for peptide mapping Example: ETANERCEPT Peptide mapping involves chemical / enzymatic treatment to form peptide fragments that are separated (e.g. by LC) and identified. It is an identity test for proteins. This is why it is described in the identification section of the monograph. Peptide mapping is a comparative procedure. By comparing the info obtained with a reference substance treated similarly, the primary structure of the protein can be confirmed, alterations in structure can be detected, process consistency can be demonstrated in the course of development. Compliance with the Ph. Eur. is a mandatory requirement (no flexibility) 19 ©2020 EDQM, Council of Europe. All rights reserved. CRS for identification - Peptide mapping <2.2.55> - ETANERCEPT A valid LC method is described in the monograph, where Etanercept CRS is used to prepare the reference solution. The profile obtained with the test solution corresponds (in retention times, peak responses, number of peaks, overall elution pattern) to that obtained with the ref. solution. 20 ©2020 EDQM, Council of Europe. All rights reserved. Infliximab 2 glycosylation sites (one per hc); exact composition of glycans can vary C6462H9960N1728O2036S44 Mr approx. 145 kDa (without glycosylation) 21 ©2020 EDQM, Council of Europe. All rights reserved. CRS for system suitability Example: INFLIXIMAB Glycan mapping The glycan profile depends on the manufacturing process; ex. murine or CHO cells may be used. This is why glycan analysis is described in the production section of the monograph. Flexibility is given as far as the method’s choice, however a valid LC method is described in the monograph, where peak ID relies on comparison with the chromatogram of the monograph (documentary standard) and Infliximab CRS (material standard) is used to compare the LC profile to assess system suitability. The LC profile of the batch under test is then compared with that of a in-house reference standard, representative of the manufacturing process, whereas quantification is made by area normalization (no RS needed). 22 ©2020 EDQM, Council of Europe. All rights reserved. CRS for system suitability Example: INFLIXIMAB Glycan mapping LC-electrochemical detection 1. Peaks are identified using the monograph chromatogram 2. The LC profile is compared to that of infliximab CRS; peaks 1 to 7 are clearly visible 3. The LC profile and RTs are compared to those of a suitable in-house RS, no additional peaks are to be observed. 4. Glycans are quantified by area normalization, no acceptance criteria given in the monograph (as approved by competent authorities). 23 ©2020 EDQM, Council of Europe. All rights reserved. Intended use of Ph. Eur. RS in glycan analysis To control the performance of the method, including glycan cleavage, recovery and analysis -> system suitability “The system suitability tests represent an integral
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