EUROPEANPHARMACOPOEIAFree access to supportive pharmacopoeial texts inthe field of vaccines for human useduring the coronavirus disease (COVID-19)pandemicUpdated package - October 2020Published in accordance with theConvention on the Elaboration of a European Pharmacopoeia(European Treaty Series No. 50)European Directoratefor the Qualityof Medicines& HealthCareDirection européennede la qualitédu médicament& soins de santéCouncil of EuropeStrasbourg
Free access to supportive pharmacopoeial textsin the field of vaccines for human useduring the coronavirus disease (COVID-19) pandemicUpdated packageThe EDQM is committed to supporting users during the coronavirus disease (COVID-19)pandemic – as well as contributing to the wider global effort to combat the virus – byopenly sharing knowledge and providing access to relevant guidance/standards.To support organisations involved in the development, manufacture or testing of COVID-19vaccines worldwide, many of which are universities and small and medium-sized enterprises,the EDQM is offering temporary free access to texts of the European Pharmacopoeia(Ph. Eur.) in the field of vaccines.This package includes quality standards for vaccines which developers can take intoaccount to help build appropriate analytical control strategies for their COVID-19candidate vaccines and ensure the quality and safety of the final product. Applicationof such quality requirements may ultimately help to facilitate regulatory acceptance of asubsequent marketing authorisation application.For ease of reading, a summary table listing the pharmacopoeial texts, with informationregarding the vaccine types or vaccine platforms concerned (e.g. live attenuated viralvaccine, recombinant viral-vectored vaccines) is provided. The list of texts is not exhaustive and will be reviewed regularly and updated as required.The pharmacopoeial texts comprise overarching general texts (general notices, generalmonographs, dosage form monographs and general chapters) as well as selected individual vaccine monographs and analytical methods. The texts are from the 10th Edition ofthe Ph. Eur., including Supplement 10.4.This publication will be available on the EDQM website (https://go.edqm.eu/Pheurvaccinespackage) until further notice. It will be withdrawn when appropriate.This in no way affects the existing legal status of the European Pharmacopoeia, nor doesit imply or confer any demonstrated effectiveness of a particular vaccine type or vaccineplatform for the prevention of COVID-19. This is confirmed by the inclusion of thefollowing text at the bottom of pharmacopoeial texts reproduced in this document: “Notofficial text. Please refer to the current legally effective version of the Pharmacopoeia toensure compliance.”The package was updated on 25 October 2020 to include additional Ph. Eur. texts.All rights reserved. Apart from any fair dealing for the purposes of research or privatestudy, this publication may not be reproduced or transmitted in any form or by anymeans without the prior permission in writing of the publisher.If you have any questions or comments please contact the EDQM via the mailbox:[email protected] European Pharmacopoeia is published by the European Directorate for the Quality of Medicines &HealthCare of the Council of Europe (EDQM). Council of Europe, 67075 Strasbourg Cedex, France - 2020
TEXT N 220.127.116.11.85.14TITLEGeneral NoticesPRODUCT TYPE(S)General NoticesGeneral monographsSubstances for pharmaceutical usePharmaceutical preparationsVaccines for human useRecombinant DNA technology, products ofProducts with risk of transmitting agents ofanimal spongiform encephalopathiesParenteral preparationsNasal preparationsAll vaccines.All vaccines.All vaccines.Recombinant protein-based vaccines.Vaccines produced using material of animal origin.Dosage form monographsVaccines for parenteral administration.Vaccines for nasal administration.General chaptersTerminology used in monographs on biologicalproductsChicken flocks free from specified pathogensfor the production and quality control ofvaccinesCell substrates for the production of vaccinesfor human useTests for extraneous agents in viral vaccines forhuman useViral safetyAll vaccines.Vaccines produced in specified pathogen-free primaryavian tissues.Vaccines using cell cultures for production.Live attenuated viral vaccines, inactivated viralvaccines, recombinant viral vectored vaccines.Vaccines produced using material of human or animalorigin.Vaccines produced using material of animal origin.Minimising the Risk of Transmitting AnimalSpongiform Encephalopathy Agents via Humanand Veterinary Medicinal ProductsGene transfer medicinal products for humanCertain considerations may be relevant to recomusebinant viral vectored vaccines using adenovirus orpoxvirus as backbone, and to DNA vaccines.
TEXT N 18.104.22.168.6TITLEPRODUCT TYPE(S)methods of analysis2.6.2SterilityAlternative methods for control of microbiological 102.7.2Efficacy of antimicrobial preservationBacterial endotoxinsGuidelines for using the test for bacterialendotoxinsMicrobiological assay of antibiotics2.6.34Host-cell protein assays2.5.33Total ation and characterisation of residualhost-cell DNALiquid chromatographyNucleic acid amplification techniquesImmunochemical methodsFlow cytometryClarity and degree of opalescence of liquids2.2.2Degree of coloration of liquids2.2.3Potentiometric determination of pH2.2.322.214.171.124.17OsmolalityWater: semi-micro determinationTest for extractable volume of parenteralpreparationsParticulate contamination: visible particles2.9.2012 3 4All vaccines1.All vaccines2.Vaccines using cell cultures or primary avian tissuesfor production.Vaccines using cell cultures or primary avian tissuesfor production.Multi-dose vaccines containing a preservative.All vaccines1.All vaccines1.Where antibiotics are used during the productionprocess3, the residual antibiotic concentration may bedetermined by a microbiological assay adapted fromchapter 2.7.2 or by other suitable methods (e.g. liquidchromatography).Recombinant protein-based vaccines and purifiedrecombinant viral vectored vaccines.Certain live attenuated viral vaccines and recombinantviral vectored vaccines that are less amenable topurification.Vaccines produced in continuous cell lines4.When the method is selected.When the method is selected.When the method is selected.When the method is selected.Vaccines in liquid form, lyophilised vaccines afterreconstitution.Vaccines in liquid form, lyophilised vaccines afterreconstitution.Vaccines in liquid form, lyophilised vaccines afterreconstitution.Vaccines for parenteral administration.Lyophilised vaccines.Vaccines for parenteral administration.Vaccines in liquid form, lyophilised vaccines afterreconstitution.Unless otherwise justified and authorised, as described in the General Monograph Vaccines for human use (0153).A comprehensive validation package, including the demonstration of equivalence with the compendial test, is a prerequisite when opting to use alternative microbiological methods for sterility.It is preferable to have a production free from antibiotics. Unless otherwise justified, at no stage during production ispenicillin or streptomycin used.See also General Chapter 5.2.3. Cell substrates for the production of vaccines for human use.
TEXT N TITLEPRODUCT TYPE(S)Individual vaccine monographsExamples of individual monographs for various types of vaccines.The following examples demonstrate the applicable requirements for specific products. They can be taken asguidance and should be considered for vaccines in a similar class without a specific monograph.2441Human papillomavirus vaccine (rDNA)Recombinant protein-based vaccines. Productionin an insect cell / baculovirus expression vectorsystem.1056Hepatitis B vaccine (rDNA)Recombinant protein-based vaccines. Productionin CHO cells.0214Poliomyelitis vaccine (inactivated)Inactivated viral vaccines.0537Yellow fever vaccine (live)Live attenuated viral vaccines.Certain considerations may be relevant to recombinant viral vectored vaccines using yellow fevervirus or other viruses as backbone.0213Measles vaccine (live)Live attenuated viral vaccines.Certain considerations may be relevant to recombinant viral vectored vaccines using measles virusor other viruses as backbone.2772Influenza vaccine (live, nasal)Live attenuated viral vaccines for nasal administration.Certain considerations may be relevant to recombinant viral vectored vaccines using influenzavirus or other viruses as backbone.16642805Monographs on adjuvantsAluminium hydroxide, hydrated, foradsorptionSqualeneVaccines containing aluminium hydroxide asadjuvant.Vaccines containing a squalene-based adjuvant.
General NoticesTEXT N 1.TITLEPRODUCT TYPE(S)General NoticesPlease refer to the current legally effective version of the Pharmacopoeia to access the official standards.
EUROPEAN PHARMACOPOEIA1. General notices07/2014:10000 (2) An enhanced approach to quality control could utilisecorrected 10.0 process analytical technology (PAT) and/or real-time releasetesting (including parametric release) strategies as alternativesto end-product testing alone. Real-time release testingin circumstances deemed appropriate by the competentauthority is thus not precluded by the need to comply with thePharmacopoeia.1. GENERAL NOTICES(3) Reduction of animal testing : the European Pharmacopoeiais dedicated to phasing out the use of animals for test purposes,1.1. GENERAL STATEMENTSThe General Notices apply to all monographs and other texts in accordance with the 3Rs (Replacement, Reduction,Reﬁnement) set out in the European Convention for theof the European Pharmacopoeia.Protection of Vertebrate Animals used for Experimental andThe ofﬁcial texts of the European Pharmacopoeia areOther Scientiﬁc Purposes. In demonstrating compliance withpublished in English and French. Translations in otherthe Pharmacopoeia as indicated above (1), manufacturerslanguages may be prepared by the signatory States of themay consider establishing additional systems to monitorEuropean Pharmacopoeia Convention. In case of doubtconsistency of production. With the agreement of theor dispute, the English and French versions are alonecompetent authority, the choice of tests performed to assessauthoritative.compliance with the Pharmacopoeia when animal tests areprescribed is established in such a way that animal usage isIn the texts of the European Pharmacopoeia, the wordminimised as much as possible.‘Pharmacopoeia’ without qualiﬁcation means the EuropeanPharmacopoeia. The ofﬁcial abbreviation Ph. Eur. may beGrade of materials. Certain materials that are the subject ofused to indicate the European Pharmacopoeia.a pharmacopoeial monograph may exist in different gradesThe use of the title or the subtitle of a monograph impliessuitable for different purposes. Unless otherwise indicatedthat the article complies with the requirements of the relevant in the monograph, the requirements apply to all grades ofmonograph. Such references to monographs in the texts ofthe material. In some monographs, particularly those onthe Pharmacopoeia are shown using the monograph title and excipients, a list of functionality-related characteristics that arereference number in italics.relevant to the use of the substance may be appended to theA preparation must comply throughout its period of validity ; monograph for information. Test methods for determinationof one or more of these characteristics may be given, also fora distinct period of validity and/or speciﬁcations for openedinformation.or broached containers may be decided by the competentauthority. The subject of any other monograph must complyGeneral monographs. Substances and preparations that arethroughout its period of use. The period of validity that isthe subject of an individual monograph are also requiredassigned to any given article and the time from which thatto comply with relevant, applicable general monographs.period is to be calculated are decided by the competentCross-references to applicable general monographs are notauthority in light of experimental results of stability studies.normally given in individual monographs.Unless otherwise indicated in the General Notices or in theGeneral monographs apply to all substances and preparationsmonographs, statements in monographs constitute mandatory within the scope of the Deﬁnition section of the generalrequirements. General chapters become mandatory whenmonograph, except where a preamble limits the application,referred to in a monograph, unless such reference is made in a for example to substances and preparations that are the subjectway that indicates that it is not the intention to make the text of a monograph of the Pharmacopoeia.referred to mandatory but rather to cite it for information.General monographs on dosage forms apply to all preparationsThe active substances, excipients, pharmaceutical preparations of the type deﬁned. The requirements are not necessarilyand other articles described in the monographs are intendedcomprehensive for a given speciﬁc preparation andfor human and veterinary use (unless explicitly restricted torequirements additional to those prescribed in the generalone of these uses).monograph may be imposed by the competent authority.Quality systems. The quality standards represented byGeneral monographs and individual monographs aremonographs are valid only where the articles in question arecomplementary. If the provisions of a general monograph doproduced within the framework of a suitable quality system.not apply to a particular product, this is expressly stated in theThe quality system must assure that the articles consistentlyindividual monograph.meet the requirements of the Pharmacopoeia.Validation of pharmacopoeial methods. The test methodsAlternative methods. The tests and assays describedgiven in monographs and general chapters have been validatedare the ofﬁcial methods upon which the standards of thein accordance with accepted scientiﬁc practice and currentPharmacopoeia are based. With the agreement of therecommendations on analytical validation. Unless otherwisecompetent authority, alternative methods of analysis maystated in the monograph or general chapter, validation of thebe used for control purposes, provided that the methodstest methods by the analyst is not required.used enable an unequivocal decision to be made as toImplementation of pharmacopoeial methods. Whenwhether compliance with the standards of the monographsimplementing a pharmacopoeial method, the user must assesswould be achieved if the ofﬁcial methods were used. In thewhether and to what extent the suitability of the methodevent of doubt or dispute, the methods of analysis of theunder the actual conditions of use needs to be demonstratedPharmacopoeia are alone authoritative.according to relevant monographs, general chapters andDemonstration of compliance with the Pharmacopoeiaquality systems.(1) An article is not of Pharmacopoeia quality unless itConventional terms. The term ‘competent authority’complies with all the requirements stated in the monograph.means the national, supranational or international body orThis does not imply that performance of all the tests in aorganisationvested with the authority for making decisionsmonograph is necessarily a prerequisite for a manufacturer inconcerning the issue in question. It may, for example, be aassessing compliance with the Pharmacopoeia before releasenational pharmacopoeia authority, a licensing authority orof a product. The manufacturer may obtain assurance thatan ofﬁcial control laboratory.a product is of Pharmacopoeia quality on the basis of itsdesign, together with its control strategy and data derived, for The expression ‘unless otherwise justiﬁed and authorised’example, from validation studies of the manufacturing process. means that the requirements have to be met, unless theGeneral Notices (1) apply to all monographs and other textsPlease refer to the current legally effective version of the Pharmacopoeia to access the official standards.1
1. General noticescompetent authority authorises a modiﬁcation or anexemption where justiﬁed in a particular case.Statements containing the word ‘should’ are informative oradvisory.In certain monographs or other texts, the terms ‘suitable’ and‘appropriate’ are used to describe a reagent, micro-organism,test method etc. ; if criteria for suitability are not described inthe monograph, suitability is demonstrated to the satisfactionof the competent authority.Medicinal product. (a) Any substance or combination ofsubstances presented as having properties for treating orpreventing disease in human beings and/or animals ; or (b)any substance or combination of substances that may be usedin or administered to human beings and/or animals with aview either to restoring, correcting or modifying physiologicalfunctions by exerting a pharmacological, immunological ormetabolic action, or to making a medical diagnosis.Herbal medicinal product. Any medicinal product, exclusivelycontaining as active ingredients one or more herbal drugs orone or more herbal drug preparations, or one or more suchherbal drugs in combination with one or more such herbaldrug preparations.Active substance. Any substance intended to be used inthe manufacture of a medicinal product and that, when soused, becomes an active ingredient of the medicinal product.Such substances are intended to furnish a pharmacologicalactivity or other direct effect in the diagnosis, cure, mitigation,treatment or prevention of disease, or to affect the structureand function of the body.Excipient (auxiliary substance). Any constituent of a medicinalproduct that is not an active substance. Adjuvants, stabilisers,antimicrobial preservatives, diluents, antioxidants, forexample, are excipients.Interchangeable methods. Certain general chapters containa statement that the text in question is harmonised withthe corresponding text of the Japanese Pharmacopoeiaand/or the United States Pharmacopeia and that these textsare interchangeable. This implies that if a substance orpreparation is found to comply with a requirement using aninterchangeable method from one of these pharmacopoeiasit complies with the requirements of the EuropeanPharmacopoeia. In the event of doubt or dispute, the text ofthe European Pharmacopoeia is alone authoritative.References to regulatory documents. Monographs andgeneral chapters may contain references to documentsissued by regulatory authorities for medicines, for exampledirectives and notes for guidance of the European Union.These references are provided for information for users forthe Pharmacopoeia. Inclusion of such a reference does notmodify the status of the documents referred to, which may bemandatory or for guidance.1.2. OTHER PROVISIONS APPLYING TO GENERALCHAPTERS AND MONOGRAPHSQuantities. In tests with numerical limits and assays, thequantity stated to be taken for examination is approximate.The amount actually used, which may deviate by not morethan 10 per cent from that stated, is accurately weighed ormeasured and the result is calculated from this exact quantity.In tests where the limit is not numerical, but usually dependsupon comparison with the behaviour of a reference substancein the same conditions, the stated quantity is taken forexamination. Reagents are used in the prescribed amounts.Quantities are weighed or measured with an accuracycommensurate with the indicated degree of precision. Forweighings, the precision corresponds to plus or minus 5 unitsafter the last ﬁgure stated (for example, 0.25 g is to beinterpreted as 0.245 g to 0.255 g). For the measurement ofvolumes, if the ﬁgure after the decimal point is a zero or endsin a zero (for example, 10.0 mL or 0.50 mL), the volume is2EUROPE
PHARMACOPOEIA Free access to supportive pharmacopoeial texts in the field of vaccines for human use during the coronavirus disease (COVID-19) pandemic Updated package - October 2020 Published in accordance with the Convention on the Elaboration of a European Pharmacopoeia (European Treaty Series No. 50) Council of Europe Strasbourg