european pharmacopoeia · monographs on adjuvants 1664 aluminium hydroxide, hydrated, for...

EUROPEAN 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 EuropeStrasbourg

Direction européennede la qualité du médicament& soins de santé

European Directoratefor the Quality

of Medicines& HealthCare

Free access to supportive pharmacopoeial texts in the field of vaccines for human use

during the coronavirus disease (COVID-19) pandemicUpdated package

The 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 – by openly sharing knowledge and providing access to relevant guidance/standards. To support organisations involved in the development, manufacture or testing of COVID-19 vaccines 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 into account to help build appropriate analytical control strategies for their COVID-19 candidate vaccines and ensure the quality and safety of the final product. Application of such quality requirements may ultimately help to facilitate regulatory acceptance of a subsequent marketing authorisation application.For ease of reading, a summary table listing the pharmacopoeial texts, with information regarding the vaccine types or vaccine platforms concerned (e.g. live attenuated viral vaccine, recombinant viral-vectored vaccines) is provided. The list of texts is not exhaus-tive and will be reviewed regularly and updated as required. The pharmacopoeial texts comprise overarching general texts (general notices, general monographs, dosage form monographs and general chapters) as well as selected indivi-dual vaccine monographs and analytical methods. The texts are from the 10th Edition of the Ph. Eur., including Supplement 10.4. This publication will be available on the EDQM website (https://go.edqm.eu/Pheurvac-cinespackage) until further notice. It will be withdrawn when appropriate.This in no way affects the existing legal status of the European Pharmacopoeia, nor does it imply or confer any demonstrated effectiveness of a particular vaccine type or vaccine platform for the prevention of COVID-19. This is confirmed by the inclusion of the following text at the bottom of pharmacopoeial texts reproduced in this document: “Not official text. Please refer to the current legally effective version of the Pharmacopoeia to ensure 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 private study, this publication may not be reproduced or transmitted in any form or by any means 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].

The 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

http://go.edqm.eu/Pheurvaccinespackagemailto:VaccinesTF%40edqm.eu?subject=Feedback%20on%20vaccines%20packagehttp://go.edqm.eu/Pheurvaccinespackage

TEXT N° TITLE PRODUCT TYPE(S)

General Notices1. General Notices

General monographs2034 Substances for pharmaceutical use All vaccines.2619 Pharmaceutical preparations All vaccines.0153 Vaccines for human use All vaccines.0784 Recombinant DNA technology, products of Recombinant protein-based vaccines.1483 Products with risk of transmitting agents of

animal spongiform encephalopathiesVaccines produced using material of animal origin.

Dosage form monographs0520 Parenteral preparations Vaccines for parenteral administration.0676 Nasal preparations Vaccines for nasal administration.

General chapters5.2.1 Terminology used in monographs on biological

productsAll vaccines.

5.2.2 Chicken flocks free from specified pathogens for the production and quality control of vaccines

Vaccines produced in specified pathogen-free primary avian tissues.

5.2.3 Cell substrates for the production of vaccines for human use

Vaccines using cell cultures for production.

2.6.16 Tests for extraneous agents in viral vaccines for human use

Live attenuated viral vaccines, inactivated viral vaccines, recombinant viral vectored vaccines.

5.1.7 Viral safety Vaccines produced using material of human or animal origin.

5.2.8 Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products

Vaccines produced using material of animal origin.

5.14 Gene transfer medicinal products for human use

Certain considerations may be relevant to recom-binant viral vectored vaccines using adenovirus or poxvirus as backbone, and to DNA vaccines.


methods of analysis2.6.1 Sterility All vaccines1.5.1.6 Alternative methods for control of microbiolo-

gical qualityAll vaccines2.

2.6.2 Mycobacteria Vaccines using cell cultures or primary avian tissues for production.

2.6.7 Mycoplasmas Vaccines using cell cultures or primary avian tissues for production.

5.1.3 Efficacy of antimicrobial preservation Multi-dose vaccines containing a preservative.2.6.14 Bacterial endotoxins All vaccines1.5.1.10 Guidelines for using the test for bacterial

endotoxinsAll vaccines1.

2.7.2 Microbiological assay of antibiotics Where antibiotics are used during the production process3, the residual antibiotic concentration may be determined by a microbiological assay adapted from chapter 2.7.2 or by other suitable methods (e.g. liquid chromatography).

2.6.34 Host-cell protein assays Recombinant protein-based vaccines and purified recombinant viral vectored vaccines.

2.5.33 Total protein Certain live attenuated viral vaccines and recombinant viral vectored vaccines that are less amenable to purification.

2.6.35 Quantification and characterisation of residual host-cell DNA

Vaccines produced in continuous cell lines4.

2.2.29 Liquid chromatography When the method is selected.2.6.21 Nucleic acid amplification techniques When the method is selected.2.7.1 Immunochemical methods When the method is selected.2.7.24 Flow cytometry When the method is selected.2.2.1 Clarity and degree of opalescence of liquids Vaccines in liquid form, lyophilised vaccines after

reconstitution.2.2.2 Degree of coloration of liquids Vaccines in liquid form, lyophilised vaccines after

reconstitution.2.2.3 Potentiometric determination of pH Vaccines in liquid form, lyophilised vaccines after

reconstitution.2.2.35 Osmolality Vaccines for parenteral administration.2.5.12 Water: semi-micro determination Lyophilised vaccines.2.9.17 Test for extractable volume of parenteral

preparationsVaccines for parenteral administration.

2.9.20 Particulate contamination: visible particles Vaccines in liquid form, lyophilised vaccines after reconstitution.

1 2

3

4

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 prerequi-site 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 is penicillin or streptomycin used.See also General Chapter 5.2.3. Cell substrates for the production of vaccines for human use.


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 as guidance and should be considered for vaccines in a similar class without a specific monograph.2441 Human papillomavirus vaccine (rDNA) Recombinant protein-based vaccines. Production

in an insect cell / baculovirus expression vector system.

1056 Hepatitis B vaccine (rDNA) Recombinant protein-based vaccines. Production in CHO cells.

0214 Poliomyelitis vaccine (inactivated) Inactivated viral vaccines.0537 Yellow fever vaccine (live) Live attenuated viral vaccines.

Certain considerations may be relevant to recom-binant viral vectored vaccines using yellow fever virus or other viruses as backbone.

0213 Measles vaccine (live) Live attenuated viral vaccines.Certain considerations may be relevant to recom-binant viral vectored vaccines using measles virus or other viruses as backbone.

2772 Influenza vaccine (live, nasal) Live attenuated viral vaccines for nasal adminis-tration.Certain considerations may be relevant to recom-binant viral vectored vaccines using influenza virus or other viruses as backbone.

Monographs on adjuvants1664 Aluminium hydroxide, hydrated, for

adsorption Vaccines containing aluminium hydroxide as adjuvant.

2805 Squalene Vaccines containing a squalene-based adjuvant.

General Notices


1. General Notices

Please refer to the current legally effective version of the Pharmacopoeia to access the official standards.

EUROPEAN PHARMACOPOEIA 1. General notices

07/2014:10000corrected 10.0

1. GENERAL NOTICES1.1. GENERAL STATEMENTSThe General Notices apply to all monographs and other textsof the European Pharmacopoeia.The official texts of the European Pharmacopoeia arepublished in English and French. Translations in otherlanguages may be prepared by the signatory States of theEuropean Pharmacopoeia Convention. In case of doubtor dispute, the English and French versions are aloneauthoritative.In the texts of the European Pharmacopoeia, the word‘Pharmacopoeia’ without qualification means the EuropeanPharmacopoeia. The official abbreviation Ph. Eur. may beused to indicate the European Pharmacopoeia.The use of the title or the subtitle of a monograph impliesthat the article complies with the requirements of the relevantmonograph. Such references to monographs in the texts ofthe Pharmacopoeia are shown using the monograph title andreference number in italics.A preparation must comply throughout its period of validity ;a distinct period of validity and/or specifications for openedor broached containers may be decided by the competentauthority. The subject of any other monograph must complythroughout its period of use. The period of validity that isassigned to any given article and the time from which thatperiod is to be calculated are decided by the competentauthority in light of experimental results of stability studies.Unless otherwise indicated in the General Notices or in themonographs, statements in monographs constitute mandatoryrequirements. General chapters become mandatory whenreferred to in a monograph, unless such reference is made in away that indicates that it is not the intention to make the textreferred to mandatory but rather to cite it for information.The active substances, excipients, pharmaceutical preparationsand other articles described in the monographs are intendedfor human and veterinary use (unless explicitly restricted toone of these uses).Quality systems. The quality standards represented bymonographs are valid only where the articles in question areproduced within the framework of a suitable quality system.The quality system must assure that the articles consistentlymeet the requirements of the Pharmacopoeia.Alternative methods. The tests and assays describedare the official methods upon which the standards of thePharmacopoeia are based. With the agreement of thecompetent authority, alternative methods of analysis maybe used for control purposes, provided that the methodsused enable an unequivocal decision to be made as towhether compliance with the standards of the monographswould be achieved if the official methods were used. In theevent of doubt or dispute, the methods of analysis of thePharmacopoeia are alone authoritative.Demonstration of compliance with the Pharmacopoeia(1) An article is not of Pharmacopoeia quality unless itcomplies with all the requirements stated in the monograph.This does not imply that performance of all the tests in amonograph is necessarily a prerequisite for a manufacturer inassessing compliance with the Pharmacopoeia before releaseof a product. The manufacturer may obtain assurance thata product is of Pharmacopoeia quality on the basis of itsdesign, together with its control strategy and data derived, forexample, from validation studies of the manufacturing process.

(2) An enhanced approach to quality control could utiliseprocess 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.(3) Reduction of animal testing : the European Pharmacopoeiais dedicated to phasing out the use of animals for test purposes,in accordance with the 3Rs (Replacement, Reduction,Refinement) set out in the European Convention for theProtection of Vertebrate Animals used for Experimental andOther Scientific Purposes. In demonstrating compliance withthe Pharmacopoeia as indicated above (1), manufacturersmay consider establishing additional systems to monitorconsistency of production. With the agreement of thecompetent authority, the choice of tests performed to assesscompliance with the Pharmacopoeia when animal tests areprescribed is established in such a way that animal usage isminimised as much as possible.Grade of materials. Certain materials that are the subject ofa pharmacopoeial monograph may exist in different gradessuitable for different purposes. Unless otherwise indicatedin the monograph, the requirements apply to all grades ofthe material. In some monographs, particularly those onexcipients, a list of functionality-related characteristics that arerelevant to the use of the substance may be appended to themonograph for information. Test methods for determinationof one or more of these characteristics may be given, also forinformation.General monographs. Substances and preparations that arethe subject of an individual monograph are also requiredto comply with relevant, applicable general monographs.Cross-references to applicable general monographs are notnormally given in individual monographs.General monographs apply to all substances and preparationswithin the scope of the Definition section of the generalmonograph, except where a preamble limits the application,for example to substances and preparations that are the subjectof a monograph of the Pharmacopoeia.General monographs on dosage forms apply to all preparationsof the type defined. The requirements are not necessarilycomprehensive for a given specific preparation andrequirements additional to those prescribed in the generalmonograph may be imposed by the competent authority.General monographs and individual monographs arecomplementary. If the provisions of a general monograph donot apply to a particular product, this is expressly stated in theindividual monograph.Validation of pharmacopoeial methods. The test methodsgiven in monographs and general chapters have been validatedin accordance with accepted scientific practice and currentrecommendations on analytical validation. Unless otherwisestated in the monograph or general chapter, validation of thetest methods by the analyst is not required.Implementation of pharmacopoeial methods. Whenimplementing a pharmacopoeial method, the user must assesswhether and to what extent the suitability of the methodunder the actual conditions of use needs to be demonstratedaccording to relevant monographs, general chapters andquality systems.Conventional terms. The term ‘competent authority’means the national, supranational or international body ororganisation vested with the authority for making decisionsconcerning the issue in question. It may, for example, be anational pharmacopoeia authority, a licensing authority oran official control laboratory.The expression ‘unless otherwise justified and authorised’means that the requirements have to be met, unless the

General Notices (1) apply to all monographs and other texts 1Please refer to the current legally effective version of the Pharmacopoeia to access the official standards.

1. General notices EUROPEAN PHARMACOPOEIA

competent 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 is

measured using a pipette, a volumetric flask or a burette, asappropriate ; otherwise, a graduated measuring cylinder or agraduated pipette may be used. Volumes stated in microlitresare measured using a micropipette or microsyringe.It is recognised, however, that in certain cases the precisionwith which quantities are stated does not correspond to thenumber of significant figures stated in a specified numericallimit. The weighings and measurements are then carried outwith a sufficiently improved accuracy.Apparatus and procedures. Volumetric glassware complieswith Class A requirements of the appropriate InternationalStandard issued by the International Organisation forStandardisation.Unless otherwise prescribed, analytical procedures are carriedout at a temperature between 15 °C and 25 °C.Unless otherwise prescribed, comparative tests are carried outusing identical tubes of colourless, transparent, neutral glasswith a flat base ; the volumes of liquid prescribed are for usewith tubes having an internal diameter of 16 mm, but tubeswith a larger internal diameter may be used provided thevolume of liquid used is adjusted (2.1.5). Equal volumes ofthe liquids to be compared are examined down the verticalaxis of the tubes against a white background, or if necessaryagainst a black background. The examination is carried out indiffuse light.Any solvent required in a test or assay in which an indicator isto be used is previously neutralised to the indicator, unless ablank test is prescribed.Water-bath. The term ‘water-bath’ means a bath of boilingwater unless water at another temperature is indicated.Other methods of heating may be substituted provided thetemperature is near to but not higher than 100 °C or theindicated temperature.Drying and ignition to constant mass. The terms ‘driedto constant mass’ and ‘ignited to constant mass’ mean that2 consecutive weighings do not differ by more than 0.5 mg,the 2nd weighing following an additional period of drying orof ignition respectively appropriate to the nature and quantityof the residue.Where drying is prescribed using one of the expressions ‘in adesiccator’ or ‘in vacuo’, it is carried out using the conditionsdescribed in chapter 2.2.32. Loss on drying.Reagents. The proper conduct of the analytical proceduresdescribed in the Pharmacopoeia and the reliability of theresults depend, in part, upon the quality of the reagents used.The reagents are described in general chapter 4. It is assumedthat reagents of analytical grade are used ; for some reagents,tests to determine suitability are included in the specifications.Solvents. Where the name of the solvent is not stated, theterm ‘solution’ implies a solution in water.Where the use of water is specified or implied in theanalytical procedures described in the Pharmacopoeia orfor the preparation of reagents, water complying with therequirements of the monograph Purified water (0008) isused, except that for many purposes the requirements forbacterial endotoxins (Purified water in bulk) and microbialcontamination (Purified water in containers) are not relevant.The term ‘distilled water’ indicates purified water preparedby distillation.The term ‘ethanol’ without qualification means anhydrousethanol. The term ‘alcohol’ without qualification meansethanol (96 per cent). Other dilutions of ethanol are indicatedby the term ‘ethanol’ or ‘alcohol’ followed by a statement of thepercentage by volume of ethanol (C2H6O) required.Expression of content. In defining content, the expression‘per cent’ is used according to circumstances with one of2 meanings :– per cent m/m (percentage, mass in mass) expresses the

number of grams of substance in 100 g of final product ;

2 See the information section on general monographs (cover pages)Please refer to the current legally effective version of the Pharmacopoeia to access the official standards.


– per cent V/V (percentage, volume in volume) expressesthe number of millilitres of substance in 100 mL of finalproduct.

The expression ‘parts per million’ (or ppm) refers to mass inmass, unless otherwise specified.Temperature. Where an analytical procedure describestemperature without a figure, the general terms used have thefollowing meaning :– in a deep-freeze : below − 15 °C;– in a refrigerator : 2 °C to 8 °C;– cold or cool : 8 °C to 15 °C ;– room temperature : 15 °C to 25 °C.

1.3. GENERAL CHAPTERSContainers. Materials used for containers are describedin general chapter 3.1. General names used for materials,particularly plastic materials, each cover a range of productsvarying not only in the properties of the principal constituentbut also in the additives used. The test methods and limitsfor materials depend on the formulation and are thereforeapplicable only for materials whose formulation is covered bythe preamble to the specification. The use of materials withdifferent formulations, and the test methods and limits appliedto them, are subject to agreement by the competent authority.The specifications for containers in general chapter 3.2have been developed for general application to containersof the stated category, but in view of the wide variety ofcontainers available and possible new developments, thepublication of a specification does not exclude the use, injustified circumstances, of containers that comply withother specifications, subject to agreement by the competentauthority.Reference may be made within the monographs of thePharmacopoeia to the definitions and specifications forcontainers provided in chapter 3.2. Containers. The generalmonographs for pharmaceutical dosage forms may, underthe heading Definition/Production, require the use of certaintypes of container ; certain other monographs may, underthe heading Storage, indicate the type of container that isrecommended for use.

1.4. MONOGRAPHSTITLESMonograph titles are in English and French in the respectiveversions and there is a Latin subtitle.

RELATIVE ATOMIC AND MOLECULAR MASSESThe relative atomic mass (Ar) or the relative molecularmass (Mr) is shown, as and where appropriate, at the beginningof each monograph. The relative atomic and molecular massesand the molecular and graphic formulae do not constituteanalytical standards for the substances described.

CHEMICAL ABSTRACTS SERVICE (CAS) REGISTRYNUMBERCAS registry numbers are included for information inmonographs, where applicable, to provide convenient accessto useful information for users. CAS Registry Number® is aregistered trademark of the American Chemical Society.

DEFINITIONStatements under the heading Definition constitute an officialdefinition of the substance, preparation or other article that isthe subject of the monograph.

Limits of content. Where limits of content are prescribed,they are those determined by the method described underAssay.Herbal drugs. In monographs on herbal drugs, the definitionindicates whether the subject of the monograph is, forexample, the whole drug or the drug in powdered form.Where a monograph applies to the drug in several states, forexample both to the whole drug and the drug in powderedform, the definition states this.

PRODUCTIONStatements under the heading Production draw attentionto particular aspects of the manufacturing process but arenot necessarily comprehensive. They constitute mandatoryrequirements for manufacturers, unless otherwise stated.They may relate, for example, to source materials ; to themanufacturing process itself and its validation and control ; toin-process testing ; or to testing that is to be carried out by themanufacturer on the final article, either on selected batchesor on each batch prior to release. These statements cannotnecessarily be verified on a sample of the final article by anindependent analyst. The competent authority may establishthat the instructions have been followed, for example, byexamination of data received from the manufacturer, byinspection of manufacture or by testing appropriate samples.

The absence of a Production section does not imply thatattention to features such as those referred to above is notrequired.Choice of vaccine strain, Choice of vaccine composition.The Production section of a monograph may define thecharacteristics of a vaccine strain or vaccine composition.Unless otherwise stated, test methods given for verification ofthese characteristics are provided for information as examplesof suitable methods. Subject to approval by the competentauthority, other test methods may be used without validationagainst the method shown in the monograph.

POTENTIAL ADULTERATIONDue to the increasing number of fraudulent activities andcases of adulteration, information may be made available toPh. Eur. users to help detect adulterated materials (i.e. activesubstances, excipients, intermediate products, bulk productsand finished products).To this purpose, a method for the detection of potentialadulterants and relevant limits, together with a reminder thatall stages of production and sourcing are subjected to a suitablequality system, may be included in this section of monographson substances for which an incident has occurred or thatpresent a risk of deliberate contamination. The frequency oftesting by manufacturers or by users (e.g. manufacturers ofintermediate products, bulk products and finished products,where relevant) depends on a risk assessment, taking intoaccount the level of knowledge of the whole supply chain andnational requirements.

This section constitutes requirements for the whole supplychain, from manufacturers to users (e.g. manufacturers ofintermediate products, bulk products and finished products,where relevant). The absence of this section does not implythat attention to features such as those referred to above isnot required.

CHARACTERSThe statements under the heading Characters are not to beinterpreted in a strict sense and are not requirements.



Solubility. In statements of solubility in the Characterssection, the terms used have the following significance,referred to a temperature between 15 °C and 25 °C.

Descriptive term Approximate volume of solvent in millilitresper gram of solute

Very soluble less than 1

Freely soluble from 1 to 10

Soluble from 10 to 30

Sparingly soluble from 30 to 100

Slightly soluble from 100 to 1000

Very slightly soluble from 1000 to 10 000

Practically insoluble more than 10 000

The term ‘partly soluble’ is used to describe a mixture whereonly some of the components dissolve. The term ‘miscible’ isused to describe a liquid that is miscible in all proportionswith the stated solvent.IDENTIFICATIONScope. The tests given in the Identification section are notdesigned to give a full confirmation of the chemical structureor composition of the product ; they are intended to giveconfirmation, with an acceptable degree of assurance, that thearticle conforms to the description on the label.First and second identifications. Certain monographshave subdivisions entitled ‘First identification’ and ‘Secondidentification’. The test or tests that constitute the ‘Firstidentification’ may be used in all circumstances. The test ortests that constitute the ‘Second identification’ may be usedin pharmacies provided it can be demonstrated that thesubstance or preparation is fully traceable to a batch certifiedto comply with all the other requirements of the monograph.Certain monographs give two or more sets of tests for thepurpose of the first identification, which are equivalentand may be used independently. One or more of these setsusually contain a cross-reference to a test prescribed in theTests section of the monograph. It may be used to simplifythe work of the analyst carrying out the identification andthe prescribed tests. For example, one identification setcross-refers to a test for enantiomeric purity while the otherset gives a test for specific optical rotation : the intendedpurpose of the two is the same, that is, verification that thecorrect enantiomer is present.Powdered herbal drugs. Monographs on herbal drugs maycontain schematic drawings of the powdered drug. Thesedrawings complement the description given in the relevantidentification test.TESTS AND ASSAYSScope. The requirements are not framed to take account of allpossible impurities. It is not to be presumed, for example, thatan impurity that is not detectable by means of the prescribedtests is tolerated if common sense and good pharmaceuticalpractice require that it be absent. See also below underImpurities.Calculation. Where the result of a test or assay is requiredto be calculated with reference to the dried or anhydroussubstance or on some other specified basis, the determinationof loss on drying, water content or other property is carriedout by the method prescribed in the relevant test in themonograph. The words ‘dried substance’ or ‘anhydroussubstance’ etc. appear in parentheses after the result.Where a quantitative determination of a residual solvent iscarried out and a test for loss on drying is not carried out,the content of residual solvent is taken into account for thecalculation of the assay content of the substance, the specificoptical rotation and the specific absorbance. No furtherindication is given in the specific monograph.

Limits. The limits prescribed are based on data obtainedin normal analytical practice ; they take account of normalanalytical errors, of acceptable variations in manufacture andcompounding and of deterioration to an extent consideredacceptable. No further tolerances are to be applied to the limitsprescribed to determine whether the article being examinedcomplies with the requirements of the monograph.In determining compliance with a numerical limit, thecalculated result of a test or assay is first rounded to thenumber of significant figures stated, unless otherwiseprescribed. The limits, regardless of whether the values areexpressed as percentages or as absolute values, are consideredsignificant to the last digit shown (for example 140 indicates 3significant figures). The last figure of the result is increased byone when the part rejected is equal to or exceeds one half-unit,whereas it is not modified when the part rejected is less than ahalf-unit.Indication of permitted limit of impurities. The acceptancecriteria for related substances are expressed in monographseither in terms of comparison of peak areas (comparative tests)or as numerical values. For comparative tests, the approximatecontent of impurity tolerated, or the sum of impurities, maybe indicated in brackets for information only. Acceptanceor rejection is determined on the basis of compliance ornon-compliance with the stated test. If the use of a referencesubstance for the named impurity is not prescribed, thiscontent may be expressed as a nominal concentration of thesubstance used to prepare the reference solution specified inthe monograph, unless otherwise described.Herbal drugs. For herbal drugs, the sulfated ash, total ash,water-soluble matter, alcohol-soluble matter, water content,content of essential oil and content of active principle arecalculated with reference to the drug that has not beenspecially dried, unless otherwise prescribed in the monograph.Equivalents. Where an equivalent is given, for the purposesof the Pharmacopoeia only the figures shown are to be used inapplying the requirements of the monograph.Culture media. The culture media described in monographsand general chapters have been found to be satisfactory forthe intended purpose. However, the components of media,particularly those of biological origin, are of variable quality,and it may be necessary for optimal performance to modulatethe concentration of some ingredients, notably :– peptones and meat or yeast extracts, with respect to their

nutritive properties ;– buffering substances ;– bile salts, bile extract, deoxycholate, and colouring matter,

depending on their selective properties ;– antibiotics, with respect to their activity.

STORAGEThe information and recommendations given under theheading Storage do not constitute a pharmacopoeialrequirement but the competent authority may specifyparticular storage conditions that must be met.The articles described in the Pharmacopoeia are storedin such a way as to prevent contamination and, as far aspossible, deterioration. Where special conditions of storageare recommended, including the type of container (see section1.3. General chapters) and limits of temperature, they arestated in the monograph.The following expressions are used in monographs underStorage with the meaning shown.In an airtight container means that the product is stored in anairtight container (3.2). Care is to be taken when the containeris opened in a damp atmosphere. A low moisture contentmay be maintained, if necessary, by the use of a desiccant inthe container provided that direct contact with the productis avoided.



Protected from light means that the product is stored eitherin a container made of a material that absorbs actinic lightsufficiently to protect the contents from change induced bysuch light, or in a container enclosed in an outer cover thatprovides such protection, or is stored in a place from which allsuch light is excluded.LABELLINGIn general, labelling of medicines is subject to supranationaland national regulation and to international agreements. Thestatements under the heading Labelling are not thereforecomprehensive and, moreover, for the purposes of thePharmacopoeia only those statements that are necessaryto demonstrate compliance or non-compliance with themonograph are mandatory. Any other labelling statements areincluded as recommendations. When the term ‘label’ is usedin the Pharmacopoeia, the labelling statements may appearon the container, the package, a leaflet accompanying thepackage, or a certificate of analysis accompanying the article,as decided by the competent authority.WARNINGSMaterials described in monographs and reagents specifiedfor use in the Pharmacopoeia may be injurious to healthunless adequate precautions are taken. The principles ofgood quality control laboratory practice and the provisionsof any appropriate regulations are to be observed at alltimes. Attention is drawn to particular hazards in certainmonographs by means of a warning statement ; absence of sucha statement is not to be taken to mean that no hazard exists.IMPURITIESA list of all known and potential impurities that have beenshown to be detected by the tests in a monograph may begiven. See also chapter 5.10. Control of impurities in substancesfor pharmaceutical use. The impurities are designated by aletter or letters of the alphabet. Where a letter appears tobe missing, the impurity designated by this letter has beendeleted from the list during monograph development prior topublication or during monograph revision.FUNCTIONALITY-RELATED CHARACTERISTICS OFEXCIPIENTSMonographs on excipients may have a section onfunctionality-related characteristics. The characteristics, anytest methods for determination and any tolerances are notmandatory requirements ; they may nevertheless be relevantfor use of the excipient and are given for information (see alsosection 1.1. General statements).REFERENCE STANDARDSCertain monographs require the use of reference standards(chemical reference substances, herbal reference standards,biological reference preparations, reference spectra). Seealso chapter 5.12. Reference standards. The EuropeanPharmacopoeia Commission establishes the officialreference standards, which are alone authoritative in caseof arbitration. These reference standards are available fromthe European Directorate for the Quality of Medicines &HealthCare (EDQM). Information on the available referencestandards and a batch validity statement can be obtained viathe EDQM website.

1.5. ABBREVIATIONS AND SYMBOLSA Absorbance

A1 cm1 per cent Specific absorbance

Ar Relative atomic mass

α[ ]D20 Specific optical rotation

bp Boiling pointBRP Biological reference preparation

CRS Chemical reference substance

d2020 Relative density

λ WavelengthHRS Herbal reference standardIU International UnitM MolarityMr Relative molecular massmp Melting point

nD20 Refractive index

Ph. Eur. U. European Pharmacopoeia Unitppb Parts per billion (micrograms per kilogram)ppm Parts per million (milligrams per kilogram)R Substance or solution defined under

4. ReagentsRF Retardation factor (see chapter 2.2.46)Rst Used in chromatography to indicate the

ratio of the distance travelled by a substanceto the distance travelled by a referencesubstance

RV Substance used as a primary standard involumetric analysis (chapter 4.2.1)

Abbreviations used in the monographs onimmunoglobulins, immunosera and vaccinesCFU Colony-forming unitsLD50 The statistically determined quantity of a

substance that, when administered by thespecified route, may be expected to causethe death of 50 per cent of the test animalswithin a given period

MLD Minimum lethal doseL+/10 dose The smallest quantity of a toxin that, in the

conditions of the test, when mixed with0.1 IU of antitoxin and administered by thespecified route, causes the death of the testanimals within a given period

L+ dose The smallest quantity of a toxin that, in theconditions of the test, when mixed with1 IU of antitoxin and administered by thespecified route, causes the death of the testanimals within a given period

lr/100 dose The smallest quantity of a toxin that, inthe conditions of the test, when mixedwith 0.01 IU of antitoxin and injectedintracutaneously causes a characteristicreaction at the site of injection within agiven period

Lp/10 dose The smallest quantity of toxin that, in theconditions of the test, when mixed with0.1 IU of antitoxin and administered by thespecified route, causes paralysis in the testanimals within a given period

Lo/10 dose The largest quantity of a toxin that, in theconditions of the test, when mixed with0.1 IU of antitoxin and administered by thespecified route, does not cause symptoms oftoxicity in the test animals within a givenperiod

Lf dose The quantity of toxin or toxoid thatflocculates in the shortest time with 1 IU ofantitoxin



CCID50 The statistically determined quantity ofvirus that may be expected to infect 50 percent of the cell cultures to which it is added

EID50 The statistically determined quantity ofvirus that may be expected to infect 50 percent of the fertilised eggs into which it isinoculated

ID50 The statistically determined quantity ofa virus that may be expected to infect50 per cent of the animals into which it isinoculated

PD50 The statistically determined dose of avaccine that, in the conditions of the test,may be expected to protect 50 per cent ofthe animals against a challenge dose of themicro-organisms or toxins against which itis active

ED50 The statistically determined dose of avaccine that, in the conditions of thetest, may be expected to induce specificantibodies in 50 per cent of the animals forthe relevant vaccine antigens

PFU Pock-forming units or plaque-forming unitsSPF Specified-pathogen-free

Collections of micro-organismsATCC American Type Culture Collection

10801 University BoulevardManassas, Virginia 20110-2209, USA

C.I.P. Collection de Bactéries de l’Institut PasteurB.P. 52, 25 rue du Docteur Roux75724 Paris Cedex 15, France

IMI International Mycological InstituteBakeham LaneSurrey TW20 9TY, Great Britain

I.P. Collection Nationale de Culture deMicroorganismes (C.N.C.M.)Institut Pasteur25, rue du Docteur Roux75724 Paris Cedex 15, France

NCIMB National Collection of Industrial andMarine Bacteria Ltd23 St Machar DriveAberdeen AB2 1RY, Great Britain

NCPF National Collection of Pathogenic FungiLondon School of Hygiene and TropicalMedicineKeppel StreetLondon WC1E 7HT, Great Britain

NCTC National Collection of Type CulturesCentral Public Health LaboratoryColindale AvenueLondon NW9 5HT, Great Britain

NCYC National Collection of Yeast CulturesAFRC Food Research InstituteColney LaneNorwich NR4 7UA, Great Britain

NITE Biological Resource CenterDepartment of BiotechnologyNational Institute of Technology andEvaluation2-5-8 Kazusakamatari, Kisarazu-shi, Chiba,292-0818Japan

S.S.I. Statens Serum Institut80 Amager Boulevard, Copenhagen,Denmark

1.6. UNITS OF THE INTERNATIONAL SYSTEM (SI) USEDIN THE PHARMACOPOEIA AND EQUIVALENCE WITHOTHER UNITSINTERNATIONAL SYSTEM OF UNITS (SI)The International System of Units comprises 2 main classesof units, namely base units and derived units(1). The base unitsare the metre, the kilogram, the second, the ampere, thekelvin, the mole and the candela.The derived units are formed as products of powers of thebase units according to the algebraic relationships linking thecorresponding quantities. Some of these derived units havespecial names and symbols. The derived units used in thePharmacopoeia are shown in Table 1.6.-1.Some important and widely used units outside theInternational System are shown in Table 1.6.-2.The prefixes shown in Table 1.6.-3 are used to form the namesand symbols of the decimal multiples and submultiples ofSI units.

Table 1.6.-1. – Derived units used in the European Pharmacopoeia and equivalence with other units

Quantity Unit

Name Symbol Name Symbol Expression inSI base units

Expression inother SI units

Conversion of other units into SI units

Wave number ν one per metre 1/m m− 1

Wavelength λ micrometrenanometre

μm nm

10− 6m10− 9m

Area A, S square metre m2 m2

Volume V cubic metre m3 m3 1 mL = 1 cm3 = 10− 6 m3

Frequency ν hertz Hz s− 1

Density ρ kilogram percubic metre

kg/m3 kg·m− 3 1 g/mL = 1 g/cm3 = 103 kg·m− 3

Velocity, speed v metre persecond

m/s m·s− 1

(1) The definitions of the units used in the International System are given in the booklet ‘Le Système International d’Unités (SI)’, published by the Bureau International des Poidset Mesures, Pavillon de Breteuil, F-92310 Sèvres.



Quantity Unit

Name Symbol Name Symbol Expression inSI base units

Expression inother SI units

Conversion of other units into SI units

Force F newton N m·kg·s− 2 1 dyne = 1 g·cm·s− 2 = 10− 5 N1 kp = 9.806 65 N

Pressure, stress p pascal Pa m− 1·kg·s− 2 N·m− 2 1 dyne/cm2 = 10− 1 Pa = 10− 1 N·m− 2

1 atm = 101 325 Pa = 101.325 kPa1 bar = 105 Pa = 0.1 MPa1 mm Hg = 133.322 387 Pa1 Torr = 133.322 368 Pa1 psi = 6.894 757 kPa

Dynamicviscosity

η pascal second Pa·s m− 1·kg·s− 1 N·s·m− 2 1 P = 10− 1 Pa·s = 10− 1 N·s·m− 2

1 cP = 1 mPa·s

Kinematicviscosity

ν square metreper second

m2/s m2·s− 1 Pa·s·m3·kg− 1

N·m·s·kg− 11 St = 1 cm2·s− 1 = 10− 4 m2·s− 1

Energy W joule J m2·kg·s− 2 N·m 1 erg = 1 cm2·g·s− 2 = 1 dyne·cm = 10− 7 J1 cal = 4.1868 J

Power,radiant flux

P watt W m2·kg·s− 3 N·m·s− 1

J·s− 11 erg/s = 1 dyne·cm·s− 1 = 10− 7 W = 10− 7 N·m·s− 1 = 10− 7 J·s− 1

Absorbed dose(of radiantenergy)

D gray Gy m2·s− 2 J·kg− 1 1 rad = 10− 2 Gy

Electricpotentialdifference,voltage

U volt V m2· kg·s− 3·A− 1 W·A− 1

Electricresistance

R ohm Ω m2· kg·s− 3·A− 2 V·A− 1

Electric charge Q coulomb C A·s

Activityreferred to aradionuclide

A becquerel Bq s− 1 1 Ci = 37·109 Bq = 37·109 s− 1

Concentration(of amount ofsubstance),

molarconcentration

c mole per cubicmetre

mol/m3 mol·m− 3 1 mol/L = 1 M = 1 mol/dm3 = 103 mol·m− 3

Massconcentration

ρ kilogram percubic metre

kg/m3 kg·m− 3 1 g/L = 1 g/dm3 = 1 kg·m− 3

Catalyticactivity

Ζ katal kat mol·s-1

NOTES1. In the Pharmacopoeia, the Celsius temperature is used

(symbol t). This is defined by the following equation :

t T T0= -where T0 = 273.15 K by definition. The Celsius orcentigrade temperature is expressed in degrees Celsius(symbol °C). The unit ‘degree Celsius’ is equal to the unit‘kelvin’.

2. The practical expressions of concentrations used in thePharmacopoeia are defined in the General Notices.

3. The radian is the plane angle between two radii of a circlethat cut off on the circumference an arc equal in lengthto the radius.

4. In the Pharmacopoeia, conditions of centrifugation aredefined by reference to the acceleration due to gravity (g) :

g = 9.806 65 m·s-2

5. Certain quantities without dimensions are used in thePharmacopoeia : relative density (2.2.5), absorbance(2.2.25), specific absorbance (2.2.25) and refractive index(2.2.6).

6. The microkatal is defined as the enzymic activity that,under defined conditions, produces the transformation(e.g. hydrolysis) of 1 micromole of the substrate per second.



Table 1.6.-2. – Non-SI units accepted for use with the SI unitsQuantity Unit Value in SI units

Name SymbolTime minute min 1 min = 60 s

hour h 1 h = 60 min = 3600 sday d 1 d = 24 h = 86 400 s

Plane angle degree ° 1° = (π/180) radVolume litre L 1 L = 1 dm3 = 10− 3 m3

Mass tonne t 1 t = 103 kgdalton Da 1 Da = 1.660539040(20) × 10-27 kg

Rotationalfrequency

revolutionper minute

r/min 1 r/min = (1/60) s− 1

Energy electronvolt eV 1eV=1.602176634 × 10-19J

Table 1.6.-3. – Decimal multiples and sub-multiples of SI unitsFactor Prefix Symbol Factor Prefix Symbol

1018 exa E 10− 1 deci d

1015 peta P 10− 2 centi c

1012 tera T 10− 3 milli m

109 giga G 10− 6 micro μ

106 mega M 10− 9 nano n

103 kilo k 10− 12 pico p

102 hecto h 10− 15 femto f

101 deca da 10− 18 atto a


General monographs


2034 Substances for pharmaceutical use All vaccines.

2619 Pharmaceutical preparations All vaccines.

0153 Vaccines for human use All vaccines.

0784 Recombinant DNA technology, products of Recombinant protein-based vaccines.

1483 Products with risk of transmitting agents of animal spongiform encephalopathiesVaccines produced using material of animal origin.

Please refer to the current legally effective version of the Pharmacopoeia to access the official standards.

EUROPEAN PHARMACOPOEIA Substances for pharmaceutical use

01/2021:2034

SUBSTANCESFOR PHARMACEUTICAL USE

Corpora ad usum pharmaceuticumDEFINITIONSubstances for pharmaceutical use are any organic or inorganicsubstances that are used as active substances or excipients forthe production of medicinal products for human or veterinaryuse. They may be obtained from natural sources or producedby extraction from raw materials, fermentation or synthesis.This general monograph does not apply to herbal drugs,herbal drugs for homoeopathic preparations, herbal drugpreparations, herbal drug extracts, or mother tincturesfor homoeopathic preparations, which are the subject ofseparate general monographs (Herbal drugs (1433), Herbaldrugs for homoeopathic preparations (2045), Herbal drugpreparations (1434), Herbal drug extracts (0765), Mothertinctures for homoeopathic preparations (2029)). It does notapply to raw materials for homoeopathic preparations, exceptwhere there is an individual monograph for the substance inthe non-homoeopathic part of the Pharmacopoeia.This monograph does not apply to chemical precursorsfor radiopharmaceutical preparations which are thesubject of a separate monograph (Chemical precursors forradiopharmaceutical preparations (2902)).Where a substance for pharmaceutical use not described inan individual monograph of the Pharmacopoeia is used in amedicinal product prepared for the special needs of individualpatients, the need for compliance with the present generalmonograph is decided in the light of a risk assessment thattakes account of the available quality of the substance and itsintended use.Where medicinal products are manufactured using substancesfor pharmaceutical use of human or animal origin, therequirements of chapter 5.1.7. Viral safety apply.Substances for pharmaceutical use may be used as such oras starting materials for subsequent formulation to preparemedicinal products. Depending on the formulation, certainsubstances may be used either as active substances or asexcipients. Solid substances may be compacted, coated,granulated, powdered to a certain fineness, or processedin other ways. A monograph is applicable to a substanceprocessed with an excipient only where such processing ismentioned in the definition section of the monograph.Substance for pharmaceutical use of special grade. Unlessotherwise indicated or restricted in the individualmonographs, a substance for pharmaceutical use is intendedfor human and veterinary use, and is of appropriate quality forthe manufacture of all dosage forms in which it can be used.Polymorphism. Individual monographs do not usually specifycrystalline or amorphous forms, unless bioavailability isaffected. All forms of a substance for pharmaceutical usecomply with the requirements of the monograph, unlessotherwise indicated.

PRODUCTIONSubstances for pharmaceutical use are manufactured byprocedures that are designed to ensure a consistent quality andcomply with the requirements of the individual monograph orapproved specification.The manufacture of active substances must take place underconditions of good manufacturing practice.The provisions of general chapter 5.10 apply to the control ofimpurities in substances for pharmaceutical use.

Whether or not it is specifically stated in the individualmonograph that the substance for pharmaceutical use :– is a recombinant protein or another substance obtained

as a direct gene product based on genetic modification,where applicable, the substance also complies with therequirements of the general monograph Products ofrecombinant DNA technology (0784) ;

– is obtained from animals susceptible to transmissiblespongiform encephalopathies other than by experimentalchallenge, where applicable, the substance also complieswith the requirements of the general monograph Productswith risk of transmitting agents of animal spongiformencephalopathies (1483) ;

– is a substance derived from a fermentation process,whether or not the micro-organisms involved are modifiedby traditional procedures or recombinant DNA (rDNA)technology, where applicable, the substance also complieswith the requirements of the general monograph Productsof fermentation (1468).

If solvents are used during production, they are of suitablequality. In addition, their toxicity and their residual levelare taken into consideration (5.4). If water is used duringproduction, it is of suitable quality.The identity of elemental impurities derived from intentionallyadded catalysts and reagents is known, and strategies forcontrolling them should be established using the principles ofrisk management.If substances are produced or processed to yield a certainform or grade, that specific form or grade of the substancecomplies with the requirements of the monograph. Certainfunctionality-related tests may be described to controlproperties that may influence the suitability of the substanceand subsequently the properties of dosage forms preparedfrom it.Powdered substances may be processed to obtain a certaindegree of fineness (2.9.35).Compacted substances are processed to increase the particlesize or to obtain particles of a specific form and/or to obtaina substance with a higher bulk density.Coated active substances consist of particles of the activesubstance coated with one or more suitable excipients.Granulated active substances are particles of a specifiedsize and/or form produced from the active substance bygranulation directly or with one or more suitable excipients.If substances are processed with excipients, these excipientscomply with the requirements of the relevant monograph or,where no such monograph exists, the approved specification.Where active substances have been processed with excipientsto produce, for example, coated or granulated substances,the processing is carried out under conditions of goodmanufacturing practice and the processed substances areregarded as intermediates in the manufacture of a medicinalproduct.

CHARACTERSThe statements under the heading Characters (e.g. statementsabout the solubility or a decomposition point) are not to beinterpreted in a strict sense and are not requirements. Theyare given for information.Where a substance may show polymorphism, this may bestated under Characters in order to draw this to the attentionof the user who may have to take this characteristic intoconsideration during formulation of a preparation.

IDENTIFICATIONWhere under Identification an individual monographcontains subdivisions entitled ‘First identification’ and‘Second identification’, the test or tests that constitute the‘First identification’ may be used in all circumstances. Thetest or tests that constitute the ‘Second identification’ may be


Substances for pharmaceutical use EUROPEAN PHARMACOPOEIA

used in pharmacies only, provided it can be demonstratedthat the substance or preparation is fully traceable to a batchcertified to comply with all the other requirements of themonograph. The implementation of the tests under the secondidentification is subject to national regulation.Certain monographs give two or more sets of tests for thepurpose of the first identification, which are equivalentand may be used independently. One or more of these setsusually contain a cross-reference to a test prescribed in theTests section of the monograph. It may be used to simplifythe work of the analyst carrying out the identification andthe prescribed tests. For example, one identification setcross-refers to a test for enantiomeric purity while the otherset gives a test for specific optical rotation : the intendedpurpose of the two is the same, that is, verification that thecorrect enantiomer is present.

TESTSPolymorphism (5.9). If the nature of a crystalline oramorphous form imposes restrictions on its use inpreparations, the nature of the specific crystalline oramorphous form is identified, its morphology is adequatelycontrolled and its identity is stated on the label.Related substances. Unless otherwise prescribed or justifiedand authorised, organic impurities in active substances areto be reported, identified wherever possible, and qualified asindicated in Table 2034.-1 or in Table 2034.-2 for peptidesobtained by chemical synthesis.

Table 2034.-1. – Reporting, identification and qualification oforganic impurities in active substances

Use Maximumdailydose

Report-ing

threshold

Identificationthreshold

Qualificationthreshold

Humanuse orhumanand

veterinaryuse

≤ 2 g/day > 0.05 percent

> 0.10 percent or a

daily intakeof > 1.0 mg(whichever isthe lower)

> 0.15 percent or a

daily intakeof > 1.0 mg(whichever isthe lower)

Humanuse orhumanand

veterinaryuse

> 2 g/day > 0.03 percent

> 0.05 percent

> 0.05 percent

Veterinaryuse only

Notapplicable

> 0.10 percent

> 0.20 percent

> 0.50 percent

Table 2034.-2. – Reporting, identification and qualification oforganic impurities in peptides obtained by chemical synthesis

Reportingthreshold

Identificationthreshold

Qualificationthreshold

> 0.1 per cent > 0.5 per cent > 1.0 per cent

Specific thresholds may be applied for impurities knownto be unusually potent or to produce toxic or unexpectedpharmacological effects.For DNA reactive impurities, the requirements of ICHGuideline M7 Assessment and Control of DNA Reactive(Mutagenic) Impurities in Pharmaceuticals to Limit PotentialCarcinogenic Risk must be complied with for active substancesto be used in medicinal products for human use, in casesdefined in the scope of the guideline.If the individual monograph does not provide suitablecontrol for a new impurity, a suitable test for control must bedeveloped and included in the specification for the substance.The requirements above do not apply to biological andbiotechnological products, oligonucleotides, products offermentation and semi-synthetic products derived therefrom,to crude products of animal or plant origin or herbal products.

Elemental impurities. Permitted daily exposures forelemental impurities (e.g. as included in the ICH Q3Dguideline, the principles of which are reproduced ingeneral chapter 5.20. Elemental impurities) apply to themedicinal product. Individual monographs on substances forpharmaceutical use therefore do not contain specifications forelemental impurities unless otherwise prescribed.Residual solvents are limited according to the principlesdefined in chapter 5.4, using general method 2.4.24 or anothersuitable method. Where a quantitative determination of aresidual solvent is carried out and a test for loss on drying isnot carried out, the content of residual solvent is taken intoaccount for calculation of the assay content of the substance,the specific optical rotation and the specific absorbance.Microbiological quality. Individual monographs giveacceptance criteria for microbiological quality wherever suchcontrol is necessary. Table 5.1.4.-2. – Acceptance criteriafor microbiological quality of non-sterile substances forpharmaceutical use in chapter 5.1.4. Microbiological qualityof non-sterile pharmaceutical preparations and substances forpharmaceutical use gives recommendations on microbiologicalquality that are of general relevance for substances subject tomicrobial contamination. Depending on the nature of thesubstance and its intended use, different acceptance criteriamay be justified.Sterility (2.6.1). If intended for use in the manufacture ofsterile dosage forms without a further appropriate sterilisationprocedure, or if offered as sterile grade, the substance forpharmaceutical use complies with the test for sterility.Bacterial endotoxins (2.6.14). The substance forpharmaceutical use complies with the test for bacterialendotoxins if it is labelled as a bacterial endotoxin-free gradeor if it is intended for use in the manufacture of parenteralpreparations or preparations for irrigation without a furtherappropriate procedure for the removal of bacterial endotoxins.The limit, when not indicated in the individual monograph,is determined in accordance with the recommendationsof general chapter 5.1.10. Guidelines for using the test forbacterial endotoxins.Pyrogens (2.6.8). If the test for pyrogens is justified ratherthan the test for bacterial endotoxins and if a pyrogen-freegrade is offered, the substance for pharmaceutical usecomplies with the test for pyrogens. The limit and test methodare stated in the individual monograph or approved by thecompetent authority. Based on appropriate test validationfor bacterial endotoxins and pyrogens, the test for bacterialendotoxins may replace the test for pyrogens.Additional properties. Control of additional properties (e.g.physical characteristics, functionality-related characteristics)may be necessary for individual manufacturing processesor formulations. Grades (such as sterile, endotoxin-free,pyrogen-free) may be produced with a view to manufactureof preparations for parenteral administration or other dosageforms and appropriate requirements may be specified in anindividual monograph.

ASSAYUnless justified and authorised, contents of substances forpharmaceutical use are determined. Suitable methods areused.

LABELLINGIn general, labelling is subject to supranational and nationalregulation and to international agreements. The statementsunder the heading Labelling therefore are not comprehensiveand, moreover, for the purposes of the Pharmacopoeia onlythose statements that are necessary to demonstrate complianceor non-compliance with the monograph are mandatory. Anyother labelling statements are included as recommendations.When the term ‘label’ is used in the Pharmacopoeia, thelabelling statements may appear on the container, the package,


EUROPEAN PHARMACOPOEIA Substances for pharmaceutical use

a leaflet accompanying the package or a certificate of analysisaccompanying the article, as decided by the competentauthority.Where appropriate, the label states that the substance is :– intended for a specific use ;– of a distinct crystalline form;– of a specific degree of fineness ;– compacted ;– coated ;

– granulated;– sterile ;– free from bacterial endotoxins ;– free from pyrogens ;– containing gliding agents.Where applicable, the label states :– the degree of hydration ;– the name and concentration of any excipient.


EUROPEAN PHARMACOPOEIA Pharmaceutical preparations

04/2019:2619

PHARMACEUTICAL PREPARATIONS

PharmaceuticaINTRODUCTIONThis monograph is intended to be a reference sourceof standards in the European Pharmacopoeia on activesubstances, excipients and dosage forms, which are to beapplied in the manufacture/preparation of pharmaceuticals,but not a guide on how to manufacture as there is specificguidance available covering methods of manufacture andassociated controls.It does not cover investigational medicinal products, butcompetent authorities may refer to pharmacopoeial standardswhen authorising clinical trials using investigational medicinalproducts.

DEFINITIONPharmaceutical preparations are medicinal products generallyconsisting of active substances that may be combined withexcipients, formulated into a dosage form suitable for theintended use, where necessary after reconstitution, presentedin a suitable and appropriately labelled container.Pharmaceutical preparations may be licensed by the competentauthority, or unlicensed and made to the specific needs ofpatients according to legislation. There are 2 categories ofunlicensed pharmaceutical preparations :– extemporaneous preparations, i.e. pharmaceutical

preparations individually prepared for a specific patient orpatient group, supplied after preparation ;

– stock preparations, i.e. pharmaceutical preparationsprepared in advance and stored until a request for a supplyis received.

In addition to this monograph, pharmaceutical preparationsalso comply with the General Notices and with the relevantgeneral chapters of the Pharmacopoeia. General chapters arenormally given for information and become mandatory whenreferred to in a general or specific monograph, unless suchreference is made in a way that indicates that it is not theintention to make the text referred to mandatory but rather tocite it for information.Where relevant, pharmaceutical preparations also complywith the dosage form monographs (e.g. Capsules (0016),Tablets (0478)) and general monographs relating topharmaceutical preparations (e.g. Allergen products (1063),Herbal teas (1435), Homoeopathic preparations (1038),Homoeopathic pillules, coated (2786), Homoeopathicpillules, impregnated (2079), Immunosera for human use,animal (0084), Immunosera for veterinary use (0030), Livebiotherapeutic products for human use (3053), Monoclonalantibodies for human use (2031), Radiopharmaceuticalpreparations (0125), Vaccines for human use (0153), Vaccinesfor veterinary use (0062)).

ETHICAL CONSIDERATIONS AND GUIDANCE IN THEPREPARATION OF UNLICENSED PHARMACEUTICALPREPARATIONSThe underlying principle of legislation for pharmaceuticalpreparations is that, subject to specific exemptions, nopharmaceutical preparation may be placed on the marketwithout an appropriate marketing authorisation. Theexemptions from the formal licensing requirement allowthe supply of unlicensed products to meet the special needsof individual patients. However, when deciding to use anunlicensed preparation all health professionals involved

(e.g. the prescribing practitioners and/or the preparingpharmacists) have, within their area of responsibilities, a dutyof care to the patient receiving the pharmaceutical preparation.In considering the preparation of an unlicensed pharmaceuticalpreparation, a suitable level of risk assessment is undertaken.The risk assessment identifies :– the criticality of different parameters (e.g. quality of

active substances, excipients and containers ; designof the preparation process ; extent and significance oftesting ; stability of the preparation) to the quality of thepreparation ; and

– the risk that the preparation may present to a particularpatient group.

Based on the risk assessment, the person responsible for thepreparation must ensure, with a suitable level of assurance,that the pharmaceutical preparation is, throughout itsshelf-life, of an appropriate quality and suitable and fit forits purpose. For stock preparations, storage conditions andshelf-life have to be justified on the basis of, for example,analytical data or professional judgement, which may be basedon literature references.

PRODUCTIONManufacture/preparation must take place within theframework of a suitable quality system and be compliant withthe standards relevant to the type of product being made.Licensed products must comply with the requirements oftheir licence. For unlicensed products a risk assessment asoutlined in the section ‘Ethical considerations and guidancein the preparation of unlicensed pharmaceutical preparations’is of special importance, as these products are not previouslyassessed by the competent authority.Where pharmaceutical preparations are manufactured/prepared using materials of human or animal origin,the general requirements of general chapters 5.1.7. Viralsafety and 5.2.6. Evaluation of safety of veterinary vaccinesand immunosera and of the general monograph Productswith risk of transmitting agents of animal spongiformencephalopathies (1483) apply, where appropriate.Formulation. During pharmaceutical development or priorto manufacture/preparation, suitable ingredients, processes,tests and specifications are identified and justified in order toensure the suitability of the product for the intended purpose.This includes consideration of the properties required in orderto identify whether specific ingredient properties or processsteps are critical to the required quality of the pharmaceuticalpreparation.Active substances and excipients. Active substancesand excipients used in the formulation of pharmaceuticalpreparations comply with the requirements of the relevantgeneral monographs, e.g. Substances for pharmaceuticaluse (2034), Essential oils (2098), Herbal drug extracts (0765),Herbal drugs (1433), Herbal drug preparations (1434),Herbal drugs for homoeopathic preparations (2045), Mothertinctures for homoeopathic preparations (2029), Methods ofpreparation of homoeopathic stocks and potentisation (2371),Products of fermentation (1468), Products of recombinant DNAtechnology (0784), Vegetable fatty oils (1579).In addition, where specific monographs exist, the quality ofthe active substances and excipients used complies with thecorresponding monographs.Where no specific monographs exist, the required qualitymust be defined, taking into account the intended use andthe involved risk.When physicochemical characteristics of active substancesand functionality-related characteristics (FRCs) of excipients(e.g. particle-size distribution, viscosity, polymorphism) arecritical in relation to their role in the manufacturing processand quality attributes of the pharmaceutical preparation, theymust be identified and controlled.


Pharmaceutical preparations EUROPEAN PHARMACOPOEIA

Detailed information on FRCs is given in general chapter 5.15.Functionality-related characteristics of excipients.Microbiological quality. The formulation of thepharmaceutical preparation and its container must ensure thatthe microbiological quality is suitable for the intended use.During development, it shall be demonstrated that theantimicrobial activity of the preparation as such or, ifnecessary, with the addition of a suitable preservative orpreservatives, or by the selection of an appropriate container,provides adequate protection from adverse effects that mayarise from microbial contamination or proliferation duringthe storage and use of the preparation. A suitable test methodtogether with criteria for evaluating the preservative propertiesof the formulation are provided in general chapter 5.1.3.Efficacy of antimicrobial preservation.If preparations do not have adequate antimicrobial efficacyand do not contain antimicrobial preservatives they aresupplied in single-dose containers, or in multidose containersthat prevent microbial contamination of the contents afteropening.In the manufacture/preparation of non-sterile pharmaceuticalpreparations, suitable measures are taken to ensure theirmicrobial quality ; recommendations on this aspect areprovided in general chapters 5.1.4. Microbiological qualityof non-sterile pharmaceutical preparations and substancesfor pharmaceutical use and 5.1.8. Microbiological quality ofherbal medicinal products for oral use and extracts used intheir preparation.Sterile preparations are manufactured/prepared usingmaterials and methods designed to ensure sterility and toavoid the introduction of contaminants and the growthof micro-organisms; recommendations on this aspect areprovided in general chapter 5.1.1. Methods of preparation ofsterile products.Containers. A suitable container is selected. Consideration isgiven to the intended use of the preparation, the properties ofthe container, the required shelf-life, and product/containerincompatibilities. Where applicable, containers forpharmaceutical preparations comply with the requirementsfor containers (3.2 and subsections) and materials used for themanufacture of containers (3.1 and subsections).Stability. Stability requirements of pharmaceuticalpreparations are dependent on their intended use and on thedesired storage time.Where applicable, the probability and criticality of possibledegradation products of the active substance(s) and/orreaction products of the active substance(s) with an excipientand/or the immediate container must be assessed. Dependingon the result of this assessment, limits of degradation and/orreaction products are set and monitored in the pharmaceuticalpreparation. Licensed products require a stability exercise.Methods used for the purpose of stability testing for allrelevant characteristics of the preparation are validated asstability indicating, i.e. the methods allow the quantification ofthe relevant degradation products and physical characteristicchanges.

TESTSRelevant tests to apply in order to ensure the appropriatequality of a particular dosage form are described in the specificdosage form monographs.Where it is not practical, for unlicensed pharmaceuticalpreparations, to carry out the tests (e.g. batch size, timerestraints), other suitable methods are implemented to ensurethat the appropriate quality is achieved in accordance with therisk assessment carried out and any local guidance or legalrequirements.Stock preparations are normally tested to a greater extent thanextemporaneous preparations.

The following tests are applicable to many preparations andare therefore listed here.Appearance. The appearance (e.g. size, shape and colour) ofthe pharmaceutical preparation is controlled.Identity and purity tests. Where applicable, the followingtests are carried out on the pharmaceutical preparation:– identification of the active substance(s) ;– identification of specific excipient(s), such as preservatives ;– purity tests (e.g. investigation of degradation products,

residual solvents (2.4.24) or other related impurities,sterility (2.6.1)) ;

– safety tests (e.g. safety tests for biological products).Elemental impurities. General chapter 5.20. Elementalimpurities applies to pharmaceutical preparations exceptproducts for veterinary use, unlicensed preparations and otherproducts that are excluded from the scope of this chapter.For pharmaceutical preparations outside the scope of generalchapter 5.20, manufacturers of these products remainresponsible for controlling the levels of elemental impuritiesusing the principles of risk management.If appropriate, testing is performed using suitable analyticalprocedures according to general chapter 2.4.20. Determinationof elemental impurities.Uniformity (2.9.40 or 2.9.5/2.9.6). Pharmaceuticalpreparations presented in single-dose units comply with thetest(s) as prescribed in the relevant specific dosage formmonograph. If justified and authorised, general chapter 2.9.40can be applicable only at the time of release.Special uniformity requirements apply in the following cases :– for herbal drugs and herbal drug preparations, compliance

with general chapter 2.9.40 is not required ;– for homoeopathic preparations, the provisions of general

chapters 2.9.6 and 2.9.40 are normally not appropriate,however in certain circumstances compliance with thesechapters may be required by the competent authority ;

– for single- and multivitamin and trace-elementpreparations, compliance with general chapters 2.9.6 and2.9.40 (content uniformity only) is not required ;

– in justified and authorised circumstances, for otherpreparations, compliance with general chapters 2.9.6 and2.9.40 may not be required by the competent authority.

Reference standards. Reference standards may be neededat various stages for quality control of pharmaceuticalpreparations. They are established and monitored taking dueaccount of general chapter 5.12. Reference standards.

ASSAYUnless otherwise justified and authorised, contents of activesubstances and specific excipients such as preservatives aredetermined in pharmaceutical preparations. Limits must bedefined and justified.Suitable and validated methods are used. If assay methodsprescribed in the respective active substance monographs areused, it must be demonstrated that they are not affected by thepresence of the excipients and/or by the formulation.Reference standards. See Tests.

LABELLING AND STORAGEThe relevant labelling requirements given in the generaldosage form monographs apply. In addition, relevantEuropean Union or other applicable regulations apply.

GLOSSARYFormulation : the designing of an appropriate formula(including materials, processes, etc.) that will ensure that thepatient receives the suitable pharmaceutical preparation in anappropriate form that has the required quality and that will bestable and effective for the required length of time.


EUROPEAN PHARMACOPOEIA Pharmaceutical preparations

Licensed pharmaceutical preparation : a medicinal productthat has been granted a marketing authorisation by acompetent authority. Synonym: authorised pharmaceuticalpreparation.Manufacture : all operations of purchase of materials andproducts, Production, Quality Control, release, storage,distribution of medicinal products and the related controls.Preparation (of an unlicensed pharmaceuticalpreparation) : the ‘manufacture’ of unlicensed pharmaceuticalpreparations by or at the request of pharmacies or otherhealthcare establishments (the term ‘preparation’ is usedinstead of ‘manufacture’ in order clearly to distinguish itfrom the industrial manufacture of licensed pharmaceuticalpreparations).

Reconstitution : manipulation to enable the use or applicationof a medicinal product with a marketing authorisation inaccordance with the instructions given in the summary ofproduct characteristics or the patient information leaflet.Risk assessment : the identification of hazards and the analysisand evaluation of risks associated with exposure to thosehazards.Unlicensed pharmaceutical preparation : a medicinalproduct that is exempt from the need of having a marketingauthorisation issued by a competent authority but is made forspecific patients’ needs according to legislation.


EUROPEAN PHARMACOPOEIA Vaccines for human use

07/2018:0153corrected 10.0

VACCINES FOR HUMAN USEVaccina ad usum humanum

DEFINITIONVaccines for human use are preparations containing antigenscapable of inducing a specific and active immunity in managainst an infecting agent or the toxin or antigen elaboratedby it. Immune responses include the induction of the innateand the adaptive (cellular, humoral) parts of the immunesystem. Vaccines for human use shall have been shown to haveacceptable immunogenic activity and safety in man with theintended vaccination schedule.Vaccines for human use may contain : whole micro-organisms(bacteria, viruses or parasites), inactivated by chemicalor physical means that maintain adequate immunogenicproperties ; whole live micro-organisms that are naturallyavirulent or that have been treated to attenuate their virulencewhilst retaining adequate immunogenic properties ; antigensextracted from the micro-organisms or secreted by themicro-organisms or produced by genetic engineering orchemical synthesis. The antigens may be used in their nativestate or may be detoxified or otherwise modified by chemicalor physical means and may be aggregated, polymerised orconjugated to a carrier to increase their immunogenicity.Vaccines may contain an adjuvant. Where the antigen isadsorbed on a mineral adjuvant, the vaccine is referred to as‘adsorbed’.Terminology used in monographs on vaccines for human useis defined in general chapter 5.2.1.Bacterial vaccines containing whole cells are suspensions ofvarious degrees of opacity in colourless or almost colourlessliquids, or may be freeze-dried. They may be adsorbed. Theconcentration of living or inactivated bacteria is expressed interms of International Units of opacity or, where appropriate,is determined by direct cell count or, for live bacteria, byviable count.Bacterial vaccines containing bacterial components aresuspensions or freeze-dried products. They may be adsorbed.The antigen content is determined by a suitable validated assay.Bacterial toxoids are prepared from toxins by diminishing theirtoxicity to an acceptable level or by completely eliminatingit by physical or chemical procedures whilst retainingadequate immunogenic properties. The toxins are obtainedfrom selected strains of micro-organisms. The method ofproduction is such that the toxoid does not revert to toxin.The toxoids are purified. Purification is performed beforeand/or after detoxification. Toxoid vaccines may be adsorbed.Viral vaccines are prepared from viruses grown in animals, infertilised eggs, in suitable cell cultures or in suitable tissues, orby culture of genetically engineered cells. They are liquids thatvary in opacity according to the type of preparation or maybe freeze-dried. They may be adsorbed. Liquid preparationsand freeze-dried preparations after reconstitution may becoloured if a pH indicator such as phenol red has been usedin the culture medium.Synthetic antigen vaccines are generally clear or colourlessliquids. The concentration of the components is usuallyexpressed in terms of specific antigen content.Combined vaccines are multicomponent preparationsformulated so that different antigens are administeredsimultaneously. The different antigenic components areintended to protect against different strains or types ofthe same organism and/or against different organisms. Acombined vaccine may be supplied by the manufacturer either

as a single liquid or freeze-dried preparation or as severalconstituents with directions for admixture before use. Wherethere is no monograph to cover a particular combination, thevaccine complies with the monograph for each individualcomponent, with any necessary modifications approved bythe competent authority.Adsorbed vaccines are suspensions and may form a sedimentat the bottom of the container.

PRODUCTIONGeneral provisions. The production method for a givenproduct must have been shown to yield consistently batchescomparable with the batch of proven clinical efficacy,immunogenicity and safety in man. Product specificationsincluding in-process testing should be set. Specificrequirements for production including in-process testingare included in individual monographs. Where justified andauthorised, certain tests may be omitted where it can bedemonstrated, for example by validation studies, that theproduction process consistently ensures compliance with thetest.Unless otherwise justified and authorised, vaccines areproduced using a seed-lot system. The methods of preparationare designed to maintain adequate immunogenic properties, torender the preparation harmless and to prevent contaminationwith extraneous agents.Where vaccines for human use are manufactured usingmaterials of human or animal origin, the general requirementsof general chapter 5.1.7. Viral safety apply in conjunction withthe more specific requirements relating to viral safety in thismonograph, in general chapters 5.2.2. Chicken flocks free fromspecified pathogens for the production and quality control ofvaccines, 5.2.3. Cell substrates for the production of vaccinesfor human use and 2.6.16. Tests for extraneous agents in viralvaccines for human use, and in i

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