1. General notices

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EUROPEAN PHARMACOPOEIA 8.01. General notices 01/2013:10000 1. GENERAL NOTICES 1.1. GENERAL STATEMENTS The General Notices apply to all monographs and other texts of the European Pharmacopoeia. The official texts of the European Pharmacopoeia are published in English and French. Translations in other languages may be prepared by the signatory States of the European Pharmacopoeia Convention. In case of doubt or dispute, the English and French versions are alone authoritative. In the texts of the European Pharmacopoeia, the word ‘Pharmacopoeia’ without qualification means the European Pharmacopoeia. The official abbreviation Ph. Eur. may be used to indicate the European Pharmacopoeia. The use of the title or the subtitle of a monograph implies that the article complies with the requirements of the relevant monograph. Such references to monographs in the texts of the Pharmacopoeia are shown using the monograph title and reference number initalics. A preparation must comply throughout its period of validity; a distinct period of validity and/or specifications for opened or broached containers may be decided by the competent authority. The subject of any other monograph must comply throughout its period of use. The period of validity that is assignedtoanygivenarticleandthetimefromwhichthat period is to be calculated are decided by the competent authority in light of experimental results of stability studies. Unless otherwise indicated in the General Notices or in the monographs, statements in monographs constitute mandatory requirements. General chapters become mandatory when referred to in a monograph, unless such reference is made in a way that indicates that it is not the intention to make the text referred to mandatory but rather to cite it for information. The active substances, excipients, pharmaceutical preparations and other articles described in the monographs are intended for human and veterinary use (unless explicitly restricted to one of these uses). An article is not of Pharmacopoeia quality unless it complies with all the requirements stated in the monograph. This does not imply that performance ofallthetestsinamonographisnecessarilyaprerequisite for a manufacturer in assessing compliance with the Pharmacopoeia before release of a product. The manufacturer mayobtainassurancethataproductisofPharmacopoeia quality from data derived, for example, from validation studies of the manufacturing process and from in-process controls. Parametric release in circumstances deemed appropriate by thecompetentauthorityisthusnotprecludedbytheneedto comply with the Pharmacopoeia. The tests and assays described are the official methods upon which the standards of the Pharmacopoeia are based. With the agreement of the competent authority, alternative methods of analysis may be used for control purposes, provided that the methods used enable an unequivocal decision to be made as to whether compliance with the standards of the monographs would be achieved if the official methods were used. In the event of doubt or dispute, the methods of analysis of the Pharmacopoeia are alone authoritative. Certain materials that are the subject of a pharmacopoeial monograph may exist in different grades suitable for different purposes. Unless otherwise indicated in the monograph, therequirementsapplytoallgradesofthematerial.In some monographs, particularly those on excipients, a list of functionality-related characteristics that are relevant to the useofthesubstancemaybeappendedtothemonographfor information. Test methods for determination of one or more of these characteristics may be given, also for information. Quality systems.Thequalitystandardsrepresentedby monographs are valid only where the articles in question are produced within the framework of a suitable quality system. General monographs. Substances and preparations that are the subject of an individual monograph are also required to comply with relevant, applicable general monographs. Cross-references to applicable general monographs are not normallygiveninindividualmonographs. General monographs apply to all substances and preparations within the scope of the Definition section of the general monograph, except where a preamble limits the application, for example to substances and preparations that are the subject of a monograph of the Pharmacopoeia. General monographs on dosage forms apply to all preparations ofthetypedefined.Therequirementsarenotnecessarily comprehensive for a given specific preparation and requirements additional to those prescribed in the general monograph may be imposed by the competent authority. General monographs and individual monographs are complementary. If the provisions of a general monograph do not apply to a particular product, this is expressly stated in the individual monograph. Validation of pharmacopoeial methods.Thetestmethods giveninmonographsandgeneralchaptershavebeenvalidated in accordance with accepted scientific practice and current recommendations on analytical validation. Unless otherwise stated in the monograph or general chapter, validation of the test methods by the analyst is not required. Implementation of pharmacopoeial methods.When implementing a pharmacopoeial method, the user must assess whether and to what extent the suitability of the method under the actual conditions of use needs to be demonstrated according to relevant monographs, general chapters and quality systems. Conventional terms. The term ‘competent authority’ means the national, supranational or international body or organisation vested with the authority for making decisions concerning the issue in question. It may, for example, be a national pharmacopoeia authority, a licensing authority or an official control laboratory. The expression ‘unless otherwise justified and authorised’ means that the requirements have to be met, unless the competent authority authorises a modification or an exemption where justified in a particular case. Statements containing the word ‘should’ are informative or advisory. In certain monographs or other texts, the terms ‘suitable’ and ‘appropriate’areusedtodescribeareagent,micro-organism, test method etc.; if criteria for suitability are not described in the monograph, suitability is demonstrated to the satisfaction of the competent authority. Medicinal product.(a)Anysubstanceorcombinationof substances presented as having properties for treating or pre v enting disease in human beings and/or animals; or (b) any substance or combination of substances that may be used in or administered to human beings and/or animals with a view either to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis. Herbal medicinal product. Any medicinal product, exclusively containing as active ingredients one or more herbal drugs or one or more herbal drug preparations, or one or more such herbal drugs in combination with one or more such herbal drug preparations. Active substance.Anysubstanceintendedtobeusedin the manufacture of a medicinal product and that, when so used, becomes an active ingredient of the medicinal product. Such substances are intended to furnish a pharmacological General Notices (1) apply to all monographs and other texts3 1. General noticesEUROPEAN PHARMACOPOEIA 8.0 activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to affect the structure and function of the body. Excipient(auxiliary substance). Any constituent of a medicinal productthatisnotanactivesubstance.Adjuvants,stabilisers, antimicrobial preservatives, diluents, antioxidants, for example, are excipients. Interchangeable methods. Certain general chapters contain astatementthatthetextinquestionisharmonisedwith thecorrespondingtextoftheJapanesePharmacopoeia and/or the United States Pharmacopeia and that these texts are interchangeable. This implies that if a substance or preparation is found to comply with a requirement using an interchangeable method from one of these pharmacopoeias it complies with the requirements of the European Pharmacopoeia. In the event of doubt or dispute, the text of the European Pharmacopoeia is alone authoritative. References to regulatory documents.Monographsand general chapters may contain references to documents issued by regulatory authorities for medicines, for example directives and notes for guidance of the European Union. These references are provided for information for users for the Pharmacopoeia. Inclusion of such a reference does not modify the status of the documents referred to, which may be mandatory or for guidance. 1.2. OTHER PROVISIONS APPLYING TO GENERAL CHAPTERS AND MONOGRAPHS Quantities. In tests with numerical limits and assays, the quantity stated to be taken for examination is approximate. The amount actually used, which may deviate by not more than10percentfromthatstated,isaccuratelyweighedor measured and the result is calculated from this exact quantity. In tests where the limit is not numerical, but usually depends upon comparison with the behaviour of a reference substance in the same conditions, the stated quantity is taken for examination. Reagents are used in the prescribed amounts. Quantities are weighed or measured with an accuracy commensurate with the indicated degree of precision. For weighings, the precision corresponds to plus or minus 5 units after the last figure stated (for example, 0.25 g is to be interpreted as 0.245 g to 0.255 g). For the measurement of volumes, if the figure after the decimal point is a zero or ends inazero(forexample,10.0mLor0.50mL),thevolumeis measured using a pipette, a volumetric flask or a burette, as appropriate; otherwise, a graduated measuring cylinder or a graduated pipette may be used. Volumes stated in microlitres are measured using a micropipette or microsyringe. It is recognised, however, that in certain cases the precision with which quantities are stated does not correspond to the number of significant figures stated in a specified numerical limit. The weighings and measurements are then carried out with a sufficiently improved accuracy. Apparatus and procedures. Volumetric glassware complies with Class A requirements of the appropriate International Standard issued by the International Organisation for Standardisation. Unless otherwise prescribed, analytical procedures are carried out at a temperature between 15 °C and 25 °C. Unlessotherwiseprescribed,comparativetestsarecarriedout using identical tubes of colourless, transparent, neutral glass with a flat base; the volumes of liquid prescribed are for use with tubes having an internal diameter of 16 mm, but tubes with a larger internal diameter may be used provided the volume of liquid used is adjusted (2.1.5). Equal volumes of the liquids to be compared are examined down the vertical axis of the tubes against a white background, or if necessary against a black background. The examination is carried out in diffuse light. Any solvent required in a test or assay in which an indicator is to be used is previously neutralised to the indicator, unless a blank test is prescribed. Water-bath. The term ‘water-bath’ means a bath of boiling water unless water at another temperature is indicated. Other methods of heating may be substituted provided the temperatureisneartobutnothigherthan100°Corthe indicated temperature. Drying and ignition to constant mass.Theterms‘dried to constant mass’ and ‘ignited to constant mass’ mean that 2 consecutive weighings do not differ by more than 0.5 mg, the 2 nd weighing following an additional period of drying or of ignition respectively appropriate to the nature and quantity of the residue. Wheredryingisprescribedusingoneoftheexpressions‘ina desiccator’ or ‘in vacuo’, it is carried out using the conditions described in chapter2.2.32.Loss on drying. Reagents. The proper conduct of the analytical procedures described in the Pharmacopoeia and the reliability of the results depend, in part, upon the quality of the reagents used. The reagents are described in general chapter4.Itisassumed that reagents of analytical grade are used; for some reagents, tests to determine suitability are included in the specifications. Solvents.Wherethenameofthesolventisnotstated,the term ‘solution’ implies a solution in water. Where the use of water is specified or implied in the analytical procedures described in the Pharmacopoeia or forthepreparationofreagents,watercomplyingwiththe requirements of the monographPurified water (0008)is used, except that for many purposes the requirements for bacterial endotoxins (Purified water in bulk)andmicrobial contamination (Purified water in containers)are not relevant. The term ‘distilled water’ indicates purified water prepared by distillation. The term ‘ethanol’ without qualification means anhydrous ethanol. The term ‘alcohol’ without qualification means ethanol (96 per cent). Other dilutions of ethanol are indicated by the term ‘ethanol’ or ‘alcohol’ followed by a statement of the percentage by volume of ethanol (C 2 H 6 O) required. Expression of content. In defining content, the expression ‘per cent’ is used according to circumstances with one of 2 meanings: –percentm/m(percentage, mass in mass) expresses the number of grams of substance in 100 g of final product; –percentV/V(percentage, volume in volume) expresses the number of millilitres of substance in 100 mL of final product. The expression ‘parts per million’ (or ppm) refers to mass in mass, unless otherwise specified. Temperature. Where an analytical procedure describes temperature without a figure, the general terms used have the following meaning: – in a deep-freeze: below − 15 °C; –inarefrigerator:2°Cto8°C; – coldorcool:8°Cto15°C; – roomtemperature:15°Cto25°C. 1.3. GENERAL CHAPTERS Containers. Materials used for containers are described in general chapter3.1. General names used for materials, particularly plastic materials, each cover a range of products varying not only in the properties of the principal constituent but also in the additives used. The test methods and limits for materials depend on the formulation and are therefore applicable only for materials whose formulation is covered by 4See the information section on general monographs (cover pages) EUROPEAN PHARMACOPOEIA 8.01. General notices the preamble to the specification. The use of materials with different formulations, and the test methods and limits applied to them, are subject to agreement by the competent authority. The specifications for containers in general chapter3.2 have been developed for general application to containers of the stated category, but in view of the wide variety of containers available and possible new developments, the publication of a specification does not exclude the use, in justified circumstances, of containers that comply with other specifications, subject to agreement by the competent authority. Reference may be made within the monographs of the Pharmacopoeia to the definitions and specifications for containers provided in chapter3.2.Containers.Thegeneral monographs for pharmaceutical dosage forms may, under the heading Definition/Production, require the use of certain types of container; certain other monographs may, under theheadingStorage,indicatethetypeofcontainerthatis recommended for use. 1.4. MONOGRAPHS TITLES Monograph titles are in English and French in the respective versions and there is a Latin subtitle. RELATIVE ATOMIC AND MOLECULAR MASSES The relative atomic mass (A r ) or the relative molecular mass (M r )isshown,asandwhereappropriate,atthebeginning of each monograph. The relative atomic and molecular masses and the molecular and graphic formulae do not constitute analytical standards for the substances described. CHEMICAL ABSTRACTS SERVICE (CAS) REGISTRY NUMBER CAS registry numbers are included for information in monographs, where applicable, to provide convenient access to useful information for users. CAS Registry Number® is a registered trademark of the American Chemical Society. DEFINITION Statements under the heading Definition constitute an official definition of the substance, preparation or other article that is thesubjectofthemonograph. Limits of content. Where limits of content are prescribed, they are those determined by the method described under Assay. Herbal drugs.Inmonographsonherbaldrugs,thedefinition indicates whether the subject of the monograph is, for example, the whole drug or the drug in powdered form. Where a monograph applies to the drug in several states, for examplebothtothewholedrugandthedruginpowdered form, the definition states this. PRODUCTION Statements under the heading Production draw attention toparticularaspectsofthemanufacturingprocessbutare not necessarily comprehensive. They constitute mandatory requirements for manufacturers, unless otherwise stated. They may relate, for example, to source materials; to the manufacturing process itself and its validation and control; to in-process testing; or to testing that is to be carried out by the manufacturer on the final article, either on selected batches or on each batch prior to release. These statements cannot necessarily be verified on a sample of the final article by an independent analyst. The competent authority may establish that the instructions have been followed, for example, by examination of data received from the manufacturer, by inspection of manufacture or by testing appropriate samples. The absence of a Production section does not imply that attention to features such as those referred to above is not required. Choice of vaccine strain, Choice of vaccine composition. The Production section of a monograph may define the characteristics of a vaccine strain or vaccine composition. Unless otherwise stated, test methods given for verification of these characteristics are provided for information as examples of suitable methods. Subject to approval by the competent authority, other test methods may be used without validation against the method shown in the monograph. POTENTIAL ADULTERATION Due to the increasing number of fraudulent activities and cases of adulteration, information may be made available to Ph.Eur.userstohelpdetectadulteratedmaterials(i.e.active substances, excipients, intermediate products, bulk products and finished products). To this purpose, a method for the detection of potential adulterants and relevant limits, together with a reminder that all stages of production and sourcing are subjected to a suitable quality system, may be included in this section of monographs on substances for which an incident has occurred or that present a risk of deliberate contamination. The frequency of testing by manufacturers or by users (e.g. manufacturers of intermediate products, bulk products and finished products, where relevant) depends on a risk assessment, taking into account the level of knowledge of the whole supply chain and national requirements. This section constitutes requirements for the whole supply chain, from manufacturers to users (e.g. manufacturers of intermediate products, bulk products and finished products, where relevant). The absence of this section does not imply that attention to features such as those referred to above is not required. CHARACTERS ThestatementsundertheheadingCharactersarenottobe interpreted in a strict sense and are not requirements. Solubility.InstatementsofsolubilityintheCharacters section, the terms used have the following significance, referred to a temperature between 15 °C and 25 °C. Descriptive term Approximate volume of solvent in millilitres per gram of solute Very solubleless than 1 Freely solublefrom 1 to 10 Solublefrom 10 to 30 Sparingly solublefrom 30 to 100 Slightly solublefrom 100 to 1000 Very slightly solublefrom 1000 to 10 000 Practically insolublemore than 10 000 The term ‘partly soluble’ is used to describe a mixture where only some of the components dissolve. The term ‘miscible’ is used to describe a liquid that is miscible in all proportions with the stated solvent. IDENTIFICATION Scope. The tests given in the Identification section are not designedtogiveafullconfirmationofthechemicalstructure or composition of the product; they are intended to give confirmation, with an acceptable degree of assurance, that the article conforms to the description on the label. First and second identifications.Certainmonographs have subdivisions entitled ‘First identification’ and ‘Second identification’. The test or tests that constitute the ‘First identification’ may be used in all circumstances. The test or tests that constitute the ‘Second identification’ may be used in pharmacies provided it can be demonstrated that the substance or preparation is fully traceable to a batch certified to comply with all the other requirements of the monograph. Certain monographs give two or more sets of tests for the purpose of the first identification, which are equivalent General Notices (1) apply to all monographs and other texts5 1. General noticesEUROPEAN PHARMACOPOEIA 8.0 andmaybeusedindependently.Oneormoreofthesesets usually contain a cross-reference to a test prescribed in the Tests section of the monograph. It may be used to simplify the work of the analyst carrying out the identification and the prescribed tests. For example, one identification set cross-refers to a test for enantiomeric purity while the other set gives a test for specific optical rotation: the intended purpose of the two is the same, that is, verification that the correct enantiomer is present. Powdered herbal drugs.Monographsonherbaldrugsmay contain schematic drawings of the powdered drug. These drawings complement the description given in the relevant identification test. TESTS AND ASSAYS Scope. The requirements are not framed to take account of all possible impurities. It is not to be presumed, for example, that an impurity that is not detectable by means of the prescribed tests is tolerated if common sense and good pharmaceutical practicerequirethatitbeabsent.Seealsobelowunder Impurities. Calculation. Where the result of a test or assay is required to be calculated with reference to the dried or anhydrous substance or on some other specified basis, the determination of loss on drying, water content or other property is carried out by the method prescribed in the relevant test in the monograph. The words ‘dried substance’ or ‘anhydrous substance’ etc. appear in parentheses after the result. Where a quantitative determination of a residual solvent is carried out and a test for loss on drying is not carried out, the content of residual solvent is taken into account for the calculation of the assay content of the substance, the specific optical rotation and the specific absorbance. No further indication is given in the specific monograph. Limits. The limits prescribed are based on data obtained in normal analytical practice; they take account of normal analytical errors, of acceptable variations in manufacture and compounding and of deterioration to an extent considered acceptable. No further tolerances are to be applied to the limits prescribed to determine whether the article being examined complies with the requirements of the monograph. In determining compliance with a numerical limit, the calculated result of a test or assay is first rounded to the number of significant figures stated, unless otherwise prescribed. The limits, regardless of whether the values are expressed as percentages or as absolute values, are considered significant to the last digit shown (for example 140 indicates 3 significantfigures).Thelastfigureoftheresultisincreasedby onewhenthepartrejectedisequaltoorexceedsonehalf-unit, whereas it is not modified when the part rejected is less than a half-unit. Indication of permitted limit of impurities. The acceptance criteria for related substances are expressed in monographs either in terms of comparison of peak areas (comparative tests) or as numerical values. For comparative tests, the approximate content of impurity tolerated, or the sum of impurities, may be indicated in brackets for information only. Acceptance orrejectionisdeterminedonthebasisofcomplianceor non-compliance with the stated test. If the use of a reference substance for the named impurity is not prescribed, this content may be expressed as a nominal concentration of the substance used to prepare the reference solution specified in the 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 are calculated with reference to the drug that has not been specially dried, unless otherwise prescribed in the monograph. Equivalents. Where an equivalent is given, for the purposes ofthePharmacopoeiaonlythefiguresshownaretobeusedin applying the requirements of the monograph. Culture media. The culture media described in monographs and general chapters have been found to be satisfactory for the intended purpose. However, the components of media, particularlythoseofbiologicalorigin,areofvariablequality, and it may be necessary for optimal performance to modulate the concentration of some ingredients, notably: – peptones and meat or yeast extracts, with respect to their nutritive properties; –bufferingsubstances; – bile salts, bile extract, deoxycholate, and colouring matter, depending on their selective properties; – antibiotics, with respect to their activity. STORAGE The information and recommendations given under the heading Storage do not constitute a pharmacopoeial requirement but the competent authority may specify particular storage conditions that must be met. The articles described in the Pharmacopoeia are stored in such a way as to prevent contamination and, as far as possible, deterioration. Where special conditions of storage are recommended, including the type of container (see section 1.3. General chapters) and limits of temperature, they are stated in the monograph. The following expressions are used in monographs under Storage with the meaning shown. In an airtight containermeansthattheproductisstoredinan airtight container (3.2). Care is to be taken when the container is opened in a damp atmosphere. A low moisture content may be maintained, if necessary, by the use of a desiccant in the container provided that direct contact with the product is avoided. Protected from lightmeans that the product is stored either in a container made of a material that absorbs actinic light sufficientlytoprotectthecontentsfromchangeinducedby such light, or in a container enclosed in an outer cover that provides such protection, or is stored in a place from which all such light is excluded. LABELLING In general, labelling of medicines is subject to supranational and national regulation and to international agreements. The statements under the heading Labelling are not therefore comprehensive and, moreover, for the purposes of the Pharmacopoeia only those statements that are necessary to demonstrate compliance or non-compliance with the monograph are mandatory. Any other labelling statements are included as recommendations. When the term ‘label’ is used in the Pharmacopoeia, the labelling statements may appear on the container, the package, a leaflet accompanying the package, or a certificate of analysis accompanying the article, as de cided by the competent authority. WARNINGS Materials described in monographs and reagents specified for use in the Pharmacopoeia may be injurious to health unless adequate precautions are taken. The principles of good quality control laboratory practice and the provisions ofanyappropriateregulationsaretobeobservedatall times. Attention is drawn to particular hazards in certain monographs by means of a warning statement; absence of such a statement is not to be taken to mean that no hazard exists. IMPURITIES A list of all known and potential impurities that have been shown to be detected by the tests in a monograph may be given. See also chapter5.10.Control of impurities in substances for pharmaceutical use. The impurities are designated by a letter or letters of the alphabet. Where a letter appears to be missing, the impurity designated by this letter has been deleted from the list during monograph development prior to publication or during monograph revision. 6See the information section on general monographs (cover pages) EUROPEAN PHARMACOPOEIA 8.01. General notices FUNCTIONALITY-RELATED CHARACTERISTICS OF EXCIPIENTS Monographs on excipients may have a section on functionality-related characteristics. The characteristics, any test methods for determination and any tolerances are not mandatory requirements; they may nevertheless be relevant for use of the excipient and are given for information (see also section 1.1. General statements). REFERENCE STANDARDS Certain monographs require the use of reference standards (chemical reference substances, herbal reference standards, biological reference preparations, reference spectra). See also chapter5.12.Reference standards.TheEuropean Pharmacopoeia Commission establishes the official reference standards, which are alone authoritative in case of arbitration. These reference standards are available from the European Directorate for the Quality of Medicines & HealthCare (EDQM). Information on the available reference standards and a batch validity statement can be obtained via the EDQM website. 1.5. ABBREVIATIONS AND SYMBOLS A Absorbance Specific absorbance A r Relative atomic mass Specific optical rotation bpBoiling point BRP Biological reference preparation CRS Chemical reference substance Relative density λWavelength HRS Herbal reference standard IU International Unit M Molarity M r Relative molecular mass mp Melting point Refractive index Ph.Eur.U. EuropeanPharmacopoeiaUnit ppbParts per billion (micrograms per kilogram) ppm Parts per million (milligrams per kilogram) R Substance or solution defined under 4.Reagents R F Retardation factor (see chapter2.2.46) R st Used in chromatography to indicate the ratio of the distance travelled by a substance to the distance travelled by a reference substance RV Substance used as a primary standard in volumetric analysis (chapter4.2.1) Abbreviations used in the monographs on immunoglobulins, immunosera and vaccines LD 50 The statistically determined quantity of a substance that, when administered by the specified route, may be expected to cause the death of 50 per cent of the test animals within a given period MLD Minimum lethal dose L+/10 dose The smallest quantity of a toxin that, in the conditions of the test, when mixed with 0.1 IU of antitoxin and administered by the specified route, causes the death of the test animalswithinagivenperiod L+ doseThe smallest quantity of a toxin that, in the conditions of the test, when mixed with 1 IU of antitoxin and administered by the specified route, causes the death of the test animalswithinagivenperiod lr/100 dose The smallest quantity of a toxin that, in the conditions of the test, when mixed with 0.01 IU of antitoxin and injected intracutaneously causes a characteristic reaction at the site of injection within a given period Lp/10 dose The smallest quantity of toxin that, in the conditions of the test, when mixed with 0.1 IU of antitoxin and administered by the specified route, causes paralysis in the test animalswithinagivenperiod Lo/10 dose The largest quantity of a toxin that, in the conditions of the test, when mixed with 0.1 IU of antitoxin and administered by the specified route, does not cause symptoms of toxicity in the test animals within a given period Lf doseThe quantity of toxin or toxoid that flocculates in the shortest time with 1 IU of antitoxin CCID 50 The statistically determined quantity of virus that may be expected to infect 50 per cent of the cell cultures to which it is added EID 50 The statistically determined quantity of virus that may be expected to in fect 50 per cent of the fertilised eggs into which it is inoculated ID 50 The statistically determined quantity of avirusthatmaybeexpectedtoinfect 50 per cent of the animals into which it is inoculated PD 50 The statistically determined dose of a vaccine that, in the conditions of the test, maybeexpectedtoprotect50percentof the animals against a challenge dose of the micro-organisms or toxins against which it is active ED 50 The statistically determined dose of a vaccine that, in the conditions of the test, may be expected to induce specific antibodies in 50 per cent of the animals for the relevant vaccine antigens PFU Pock-forming units or plaque-forming units SPF Specified-pathogen-free Collections of micro-organisms ATCC American Type Culture Collection 10801 University Boulevard Manassas, Virginia 20110-2209, USA C.I.P. Collection de Bactéries de l’Institut Pasteur B.P. 52, 25 rue du Docteur Roux 75724 Paris Cedex 15, France IMI International Mycological Institute Bakeham Lane Surrey TW20 9TY, Great Britain General Notices (1) apply to all monographs and other texts7 1. General noticesEUROPEAN PHARMACOPOEIA 8.0 I.P. Collection Nationale de Culture de Microorganismes (C.N.C.M.) Institut Pasteur 25, rue du Docteur Roux 75724 Paris Cedex 15, France NCIMB National Collection of Industrial and Marine Bacteria Ltd 23 St Machar Drive Aberdeen AB2 1RY, Great Britain NCPF National Collection of Pathogenic Fungi London School of Hygiene and Tropical Medicine Keppel Street London WC1E 7HT, Great Britain NCTC National Collection of Type Cultures Central Public Health Laboratory Colindale Avenue London NW9 5HT, Great Britain NCYC National Collection of Yeast Cultures AFRC Food Research Institute Colney Lane Norwich NR4 7UA, Great Britain NITE Biological Resource Center Department of Biotechnology National Institute of Technology and Evaluation 2-5-8 Kazusakamatari, Kisarazu-shi, Chiba, 292-0818 Japan S.S.I.Statens Serum Institut 80 Amager Boulevard, Copenhagen, Denmark 1.6. UNITS OF THE INTERNATIONAL SYSTEM (SI) USED IN THE PHARMACOPOEIA AND EQUIVALENCE WITH OTHER UNITS INTERNATIONAL SYSTEM OF UNITS (SI) The International System of Units comprises 3 classes of units, namely base units, derived units and supplementary units (1) . The base units and their definitions are set out in Table 1.6-1. The derived units may be formed by combining the base units according to the algebraic relationships linking the corresponding quantities. Some of these derived units have special names and symbols. The SI units used in the PharmacopoeiaareshowninTable1.6-2. Some important and widely used units outside the International System are shown in Table 1.6-3. The prefixes shown in Table 1.6-4 are used to form the names and symbols of the decimal multiples and submultiples of SI units. NOTES 1. In the Pharmacopoeia, the Celsius temperature is used (symbolt). This is defined by the following equation: whereT 0 = 273.15 K by definition. The Celsius or centigrade 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 the Pharmacopoeia are defined in the General Notices. 3. The radian is the plane angle between two radii of a circle that cut off on the circumference an arc equal in length to the radius. 4. In the Pharmacopoeia, conditions of centrifugation are defined by reference to the acceleration due to gravity (g): · 5. Certain quantities without dimensions are used in the Pharmacopoeia: relative density (2.2.5), absorbance (2.2.25), specific absorbance (2.2.25)andrefractiveindex (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.-1. –SI base units Quantity Unit Name Symbol Name Symbol Definition Lengthl metre m The metre is the length of the path travelled by light in a vacuum during a time interval of 1/299 792 458 of a second. Mass m kilogramkgThe kilogram is equal to the mass of the international prototype of the kilogram. Time t second s Thesecondisthedurationof9192631770periodsoftheradiationcorresponding to the transition between the two hyperfine levels of the ground state of the caesium-133 atom. Electric current I ampere A The ampere is that constant current which, maintained in two straight parallel conductors of infinite length, of negligible circular cross-section and placed 1 metre apart in vacuum would produce between these conductors a force equal to 2 × 10 −7 newton per metre of length. Thermodynamic temperature T kelvin K The kelvin is the fraction 1/273.16 of the thermodynamic temperature of the triple point of water. Amount of substance n molemolThe mole is the amount of substance of a system containing as many elementary entities as there are atoms in 0.012 kilogram of carbon-12*. Luminous intensityI v candelacdThe candela is the luminous intensity in a given direction of a source emitting monochromatic radiation with a frequency of 540 × 10 12 hertz and whose energy intensity in that direction is 1/683 watt per steradian. * When the mole is used, the elementary entities must be specified and may be atoms, molecules, ions, electrons, other particles or specified groups of such particles. (1) ThedefinitionsoftheunitsusedintheInternationalSystemaregiveninthebooklet‘LeSystèmeInternationald’Unités(SI)’,publishedbytheBureau International des Poids et Mesures, Pavillon de Breteuil, F-92310 Sèvres. 8See the information section on general monographs (cover pages) EUROPEAN PHARMACOPOEIA 8.01. General notices Table 1.6.-2. –SI units used in the European Pharmacopoeia and equivalence with other units Quantity Unit Name Symbol Name Symbol Expression in SI base units Expression in other SI units Conversion of other units into SI units Wave number ν one per metre 1/m m −1 Wavelengthλ micrometre nanometre μm nm 10 −6 m 10 −9 m Area A, S square metre m 2 m 2 Volume V cubic metre m 3 m 3 1mL=1cm 3 =10 −6 m 3 Frequency ν hertz Hz s −1 Density ρ kilogram per cubic metre kg/m 3 kg·m −3 1g/mL=1g/cm 3 =10 3 kg·m −3 Velocity v metre per second m/s m·s −1 ForceF newton N m·kg·s −2 1dyne=1g·cm·s −2 =10 −5 N 1 kp = 9.806 65 N Pressure p pascal Pa m −1 ·kg·s −2 N·m −2 1dyne/cm 2 =10 −1 Pa = 10 −1 N·m −2 1 atm = 101 325 Pa = 101.325 kPa 1bar=10 5 Pa = 0.1 MPa 1 mm Hg = 133.322 387 Pa 1 Torr = 133.322 368 Pa 1psi=6.894757kPa Dynamic viscosity η pascal second Pa·s m −1 ·kg·s −1 N·s·m −2 1P=10 −1 Pa·s = 10 −1 N·s·m −2 1cP=1mPa·s Kinematic viscosity ν square metre per second m 2 /s m 2 ·s −1 Pa·s·m 3 ·kg −1 N·m·s·kg −1 1St=1cm 2 ·s −1 =10 −4 m 2 ·s −1 EnergyW joule J m 2 ·kg·s −2 N·m 1erg=1cm 2 ·g·s −2 = 1 dyne·cm = 10 −7 J 1 cal = 4.1868 J Power Radiant flux P watt W m 2 ·kg·s −3 N·m·s −1 J·s −1 1 erg/s = 1 dyne·cm·s −1 = 10 −7 W=10 −7 N·m·s −1 =10 −7 J·s −1 Absorbed dose (of radiant energy) D gray Gy m 2 ·s −2 J·kg −1 1rad=10 −2 Gy Electric potential, electromotive force U volt V m 2 ·kg·s −3 ·A −1 W·A −1 Electric resistance R ohm Ω m 2 ·kg·s −3 ·A −2 V·A −1 Quantity of electricity Q coulomb CA·s Activity of a radionuclide A becquerel Bq s −1 1 Ci = 37·10 9 Bq = 37·10 9 s −1 Concentration (of amount of substance), molar concentration c mole per cubic metre mol/m 3 mol·m −3 1mol/L=1M=1mol/dm 3 =10 3 mol·m −3 Mass concentration ρ kilogram per cubic metre kg/m 3 kg·m −3 1g/L=1g/dm 3 =1kg·m −3 Table 1.6.-3. –Units used with the International System Quantity Unit Value in SI units Name Symbol Time minutemin1 min = 60 s hourh1 h = 60 min = 3600 s dayd1 d = 24 h = 86 400 s Plane angledegree ° 1° = (π/180) rad Volumelitre L 1L=1dm 3 =10 −3 m 3 Mass tonnet 1t=10 3 kg Rotational frequency revolution per minute r/min 1 r/min = (1/60) s −1 Table 1.6.-4. –Decimal multiples and sub-multiples of units Factor PrefixSymbol Factor PrefixSymbol 10 18 exa E 10 −1 decid 10 15 peta P 10 −2 centi c 10 12 tera T 10 −3 milli m 10 9 giga G 10 −6 micro μ 10 6 mega M 10 −9 nanon 10 3 kilok 10 −12 pico p 10 2 hectoh 10 −15 femtof 10 1 decada 10 −18 atto a General Notices (1) apply to all monographs and other texts9 EUROPEAN PHARMACOPOEIA 8.02.1.3. Ultraviolet ray lamps for analytical purposes 2.1. APPARATUS 01/2008:20101 2.1.1. DROPPERS The term ‘drops’ means standard drops delivered from a standard dropper as described below. Standard droppers (Figure 2.1.1-1) are constructed of practically colourless glass. The lower extremity has a circular orifice in a flat surface at right angles to the axis. Figure 2.1.1.-1. –Standard dropper Dimensions in millimetres Other droppers may be used provided they comply with the following test. 20 drops ofwater Rat 20 ± 1 °C flowing freely from the dropper held in the vertical position at a constant rate of 1 drop per second weighs 1000 ± 50 mg. The dropper must be carefully cleaned before use. Carry out 3 determinations on any given dropper. No result may deviate by more than 5 per cent from the mean of the 3 determinations. 01/2008:20102 2.1.2. COMPARATIVE TABLE OF POROSITY OF SINTERED-GLASS FILTERS (1) Table 2.1.2.-1 Porosity number (Ph. Eur.) (2) Maximum diameter of pores in micrometres Germany France United Kingdom 1.6 less than 1.65f –– – 1-2.5 5 – 5 4 1.6 - 4 ––– – 4-6 – 5 – 104 - 10 4f – 4 1610 - 16 44 – 4016 - 40333 – 40 - 50 –– 2 10040 - 10022 – – 100 - 120 –– 1 160100 - 16011 – – 150 - 20000 – 250160 - 250 ––– – 200 - 500 – 00 – Special Uses Diameters in micrometres <2.5 Bacteriological filtration 4-10 Ultra-fine filtration, separation of micro-organisms of large diameter 10 - 40 Analytical filtration, very fine filtration of mercury, very fine dispersion of gases 40 - 100 Fine filtration, filtration of mercury, fine dispersion of gases 100 - 160 Filtration of coarse materials, dispersion and washing of gases, support for other filter materials 160 - 500 Filtration of very coarse materials, dispersion and washing of gases. 01/2008:20103 2.1.3. ULTRAVIOLET RAY LAMPS FOR ANALYTICAL PURPOSES Mercury vapour in quartz lamps is used as the source of ultraviolet light. A suitable filter may be fitted to eliminate the visible part of the spectrum emitted by the lamp. When the Pharmacopoeia prescribes in a test the use of ultraviolet light of wavelength 254 nm or 365 nm, an instrument consisting of a mercury vapour lamp and a filter which gives an emission band with maximum intensity at about 254 nm or 365 nm is used. The lamp used should be capable of revealing without doubt a standard spot of sodium salicylate with a diameter of about 5 mm on a support ofsilica gel G R,thespotbeing examined while in a position normal to the radiation. For this purpose apply 5 μL of a 0.4 g/L solution ofsodium salicylate Rinalcohol R (3) for lamps of maximum output at 254nmand5μLofa2g/Lsolutioninalcohol R (3) for lamps of maximumoutputat365nm.Thedistancebetweenthelamp and the chromatographic plate under examination used in a pharmacopoeial test should never exceed the distance used to carry out the above test. (1) The given limits are only approximate. (2) The European Pharmacopoeia has adopted the system proposed by the International Organization for Standardization (ISO). (3) Thealcohol Rused must be free from fluorescence. General Notices (1) apply to all monographs and other texts15

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