EUROPEAN
`
`PHARMACOPOEIA
`
`Third Edition
`
`Published in accordance with the
`
`Convention on the Elaboration of a European Pharmacopoeia
`(European Treaty Series No. 50)
`
`Council of Europe
`
`Strasbourg
`
`ALKERMES EXH. 2003
`ALKERMES EXH. 2003
`Luye v. Alkermes
`Luye v. Alkermes
`IPRZO16-1095 & |PR2016-1096
`IPR2016-1095 & IPR2016-1096
`
`

`
`© Council of Europe, 67075 Strasbourg Cedex 1996
`
`ISBN: 92-871-2991-6
`
`
`
`All rights reserved. Apart from any fair dealing for the purposes of research or private study, this publication may not be
`reproduced, stored or transmitted in any form or by any means without the prior permission in writing of the publisher.
`
`

`
`Introduction
`
`l
`
`II. INTRODUCTION
`
`
`
`-.—_.o.—i.;L—I-CI:
`
`
`
`Q<{‘&;'ar“'~<U<>.'.-‘co:‘_D.-‘.“D..Y
`
`The European Pharmacopoeia is published in accord-
`ance with the terms of the Convention on the elabora-
`
`tion of a European Pharmacopoeia (European Treaty
`Series No. 50) as amended by the Protocol to the Con-
`vention (European Treaty Series No. 134) under the
`auspices of the Council of Europe, signed by the Gov-
`ernments of Austria, Belgium, Bosnia-Herzegovina,
`Croatia, Cyprus, Denmark, Finland, France, Germany,
`Greece, Iceland, Ireland, Italy, Luxembourg, the Nether-
`lands, Norway, Portugal, Slovakia, Slovenia, Spain, Swe-
`den, Switzerland, “the Former Yugoslav Republic of Mac-
`edonia”, Turkey, the United Kingdom of Great Britain
`and Northern Ireland, and by the European Commu-
`nity.
`
`The preparation of the Pharmacopoeia is the responsi-
`bility of two principal bodies:
`
`1. The Public Health Committee, whose composition
`and functions are set out in Articles 3 and 4 of the
`
`Convention as amended by the Protocol:
`
`Article 3.
`
`“For the purposes of the present Convention, the
`Public Health Committee shall be composed of del-
`egations appointed by the Contracting Parties”.
`
`Article 4.
`
`“1) The Public Health Committee shall exercise a
`general oversight over the activities of the Commis-
`sion and for this purpose the Commission shall sub-
`mit a report on each of its sessions to the Public
`Health Committee.
`
`2) All decisions taken by the Commission, other than
`those of a technical or procedural character, shall
`be subject to the approval of the Public Health Com-
`
`mittee. If the Public Health Committee does not
`
`approve a decision or approves it only partially, the
`Committee shall refer it back to the Commission
`for further consideration.
`
`3) The Public Health Committee, having regard to
`the recommendations of the Commission under Ar-
`
`ticle 6 (d), shall fix the time limits within which
`decisions of a technical character relating to the
`European Pharmacopoeia shall be implemented
`within the territories of the contracting Parties”.
`
`The European Pharmacopoeia Commission is ap-
`pointed in accordance with Article 5 of the above-
`
`mentioned Convention. It is composed of delega-
`tions appointed by the Contracting Parties. Each
`delegation consists of not more than three mem-
`bers chosen for their competence in matters within
`the functions of the Commission.
`
`The functions of the commission established by Ar-
`ticle 6 of the Convention as amended by the Proto-
`col are:
`
`Article 6.
`
`“Subject to the provision of Article 4 of the present
`Convention, the functions of the Commission shall be:
`
`(a) to determine the general principles applicable
`to the elaboration of the European Pharmacopoeia;
`
`(b) to decide upon methods of analysis for that pur-
`pose;
`
`(C) to arrange for the preparation of and to adopt
`monographs to be included in the European Phar-
`macopoeia and;
`
`(d) to recommend the fixing of the time limits within
`which its decisions of a technical character relating
`
`97
`
`1997 - EUROPEAN PHARMACOPOEIA
`
`iii
`
`

`
`Introduction
`
`to the European Pharmacopoeia shall be imple-
`mented within the territories of the Contracting
`Parties.”
`
`In accordance with the terms of the Convention, the
`Contracting Parties undertake to take the necessary
`measures to ensure that the monographs of the Euro-
`pean Pharmacopoeia shall become the official standards
`applicable within their respective territories.
`
`PURPOSE OF THE EUROPEAN PHARMACOPOEIA
`
`The purpose of the European Pharmacopoeia is to pro-
`mote public health by the provision of recognised com-
`mon standards for use by health-care professionals and
`others concerned with the quality of medicines. Such
`standards are to be of appropriate quality as a basis for
`the safe use of medicines by patients and consumers.
`Their existence:
`
`— facilitates the free movement of medicinal products
`in Europe;
`
`-— ensures the quality of medicinal products exported
`from Europe.
`
`European Pharmacopoeia monographs and other texts
`are designed to be appropriate to the needs of:
`
`~ regulatory authorities;
`
`— those engaged in the control of quality;
`
`— manufacturers of starting materials and medicinal
`
`products.
`
`The European Pharmacopoeia is widely used interna-
`tionally and it is the intention of the Pharmacopoeia
`Commission to work more closely with users of the
`Pharmacopoeia in order to better satisfy their needs
`and facilitate their cooperation. To this end improved
`procedures will be sought for obtaining advice on pri-
`orities for elaborating new monographs and enhancing
`the quality of the Pharmacopoeia.
`
`TECHNICAL SECRETARIAT AND LABORATORY
`
`GENERAL PRINCIPLES
`
`General rules for interpretation of the texts of the Phar-
`macopoeia are given in the General Notices. The follow-
`ing information should also be noted.
`
`The general principles applied in the elaboration of the
`European Pharmacopoeia are laid down in the Techni-
`cal Guide for the Elaboration of Monographs available
`
`as a special issue of Pharmeuropa.
`
`It is recognised that general chapters are used elsewhere
`than in the monographs of the Pharmacopoeia; in these
`circumstances users are recommended to consult the
`Technical Guide which gives extensive information on
`the application of many of the methods.
`
`Patents. The description in the Pharmacopoeia of arti-
`cles subject to protection by patent does not confer or
`imply any right to the use of such patents by any per-
`son or persons other than the proprietors of the pat-
`ents concerned.
`
`Use of animals. The Commission is committed to the
`reduction of animal usage, wherever possible, in phar-
`macopoeia testing and encourages those associated with
`its work to seek alternative procedures. An alternative
`or modified method is adopted by the Commission once,
`it has been clearly demonstrated that it offers satisfac-
`tory control for pharmacopoeial purposes.
`
`Hydrates. The degree of hydration is indicated in the
`titles of monographs only where more than one form is
`included in the Pharmacopoeia or where more than one
`form is currently available in commerce.
`
`Chiral substances. The present policy of the Commis-
`sion is to include a test for optical rotation for all chiral
`substances, either to confirm the racemic nature or to
`determine the specific optical rotation where a particu-
`lar enantioner is required by the monograph. In older
`monographs published in the Second Edition and not
`technically revised since the present policy was estab-
`lished, for racemates and racemic mixtures a test to con-
`firm the racemic nature has not usually been included
`unless the optically active form is also described or is
`readily available in commerce.
`
`The European Pharmacopoeia Commission has a Tech-
`nical Secretariat with scientific and administrative staff,
`situated in Strasbourg. The European Pharmacopoeia
`Laboratory is situated within the Secretariat and,
`amongst other duties, is in charge of the establishment
`and monitoring of all reference materials needed for the
`monographs of the Pharmacopoeia.
`
`Polymorphism. Where a substance may show polymor-
`phism, this is usually stated under Characters. In gen-
`eral, no particular crystalline form is required in mono-
`graphs; exceptionally, in a few monographs, the crystal-
`line form required is specified, for example, via an infra-
`red absorption spectrophotometric identification test
`where the spectrum is required to be recorded using
`
`iv
`
`EUROPEAN PHARMACOPOEIA- 1997
`
`

`
`the substance in the solid state without recrystallisation,
`the chemical reference substance provided being of the
`
`type foreseen there. This adaptation of the monographs
`has involved deletion of some monographs on specific
`
`Introduction
`
`types of sutures in favour of a more general approach.
`
`CERTIFICATION PROCEDURE
`
`A procedure for the certification of suitability of mono-
`graphs of the Pharmacopoeia with respect to control of
`the purity of a product from a given source has been
`established [see Public Health Committee (Partial Agree-
`ment) Resolution AP-CSP (93) 5]. Certificates may be
`granted with respect to published monographs or those
`available as definitive texts (see below). Details of the
`
`operation of this scheme are available from the Secre-
`tariat.
`
`PUBLICATIONS
`
`The European Pharmacopoeia is available in English
`and French versions in the form of a book with an an-
`
`nual supplement, and as an annually updated CD-ROM.
`
`Pharmeuropa, the European Pharmacopoeia Forum,
`is published several times each year as an aid in the
`elaboration of monographs and as a vehicle for infor-
`mation on pharmacopoeial and related matters. It is
`available on subscription from the Technical Secretariat.
`
`Definitive texts. Texts adopted by the Commission in
`any given year are published in the first half of the fol-
`lowing year. In the period between adoption and publi-
`cation, they are available from the Technical Secretariat
`as definitive texts in a ‘Prepublication’ brochure.
`
`Implementation. The date on which monographs are to
`be implemented is fixed by the Public Health Commit-
`tee following a recommendation by the Commission. This
`date is usually about six months after publication. Where
`a monograph is to be implemented at a date earlier than
`the next publication date of the Pharmacopoeia or a
`supplement, a Resolution of the Public Health Commit-
`tee gives the full text to be implemented. The text is
`also published in Pharmeuropa for information.
`
`Revision programme. Monographs and other texts of
`the Pharmacopoeia are revised as necessary following a
`decision of the Commission. The current revision pro-
`
`gramme is published in Pharmeuropa.
`
`required crystalline form. However, for substances other
`than these exceptional cases, depending on the use of a
`given substance in a dosage form, it may be necessary
`for a manufacturer to ensure that a particular crystal-
`line form is used. The information given under Charac-
`ters is intended to alert users to the need to evaluate
`
`this aspect during the development of a dosage form.
`
`Specificity of assays. For the elaboration of monographs
`on chemical substances, the approach preferred by the
`Commission is to provide control of impurities via a well
`designed Tests section rather than by the inclusion of
`an assay that is specific for the active principle. It is
`therefore the full set of requirements of a monograph
`that is designed to ensure that the product is of suit-
`able quality.
`
`Impurities. Many monographs, particularly those re-
`cently published, now have appended a list of known or
`potential impurities shown to be controlled by the tests.
`Known impurities (also referred to as ‘actual impuri-
`ties’) are those that have been observed in batches of
`the substance; potential impurities are those that al-
`though they might be expected, from knowledge of the
`manufacturing process, to occur have not in fact been
`observed in batches during elaboration of the mono-
`graph. This list is intended to facilitate use of the mono-
`graph, especially during the licensing process for medi-
`cines (see Impurities in new drug substances, ICH tri-
`partite note for guidance, May 1995). A series of poten-
`tial impurities for a substance obtained by a given manu-
`facturing process may be compared with the list to es-
`tablish whether the monograph provides sufficient con-
`trol. It is the intention of the Commission to include
`
`such lists wherever possible in new monographs and to
`add them to existing monographs during revision.
`
`Medical devices. All editions of the Pharmacopoeia have
`contained monographs on articles that are regarded as
`medical devices, notably surgical sutures and dressings.
`For member States of the European Union, a unified
`framework for standardisation of medical devices is now
`
`provided by a directive. Following an agreement between
`the various parties involved, the Commission has de-
`cided that the monographs on dressings will be deleted
`once standards have been developed as foreseen by the
`directive. Specifications included in the section on con-
`tainers will be adapted or, in some instances, deleted, to
`take account of future standards developed within the
`framework of the directive. The monographs on surgi-
`cal sutures are to remain in the Pharmacopoeia but they
`have been modified to conform to the requirements of
`the directive and are now to be seen as standards of the
`
`1997 - EUROPEAN Pl-IARMACOPOEIA
`
`xv
`
`
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`
`1. GENERAL NOTICES
`
`1.1. GENERAL STATEMENTS
`
`The General Notices apply to all monographs and other texts
`of the European Pharmacopoeia.
`
`In the texts of the European Pharmacopoeia, the word “Phar-
`macopoeia” without qualification means the European Phar-
`macopoeia. 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 rel-
`evant monograph. Such references to monographs in the texts
`of the Pharmacopoeia are shown using the monograph title
`and serial number in italics.
`
`A pharmaceutical preparation must comply throughout its
`period of validity. The subject of any other monograph must
`comply throughout its period of use. The period of validity
`that is assigned to any given article and the time from which
`that period is to‘be calculated are decided by the competent
`authority in the light of experimental results of stability stud-
`ies.
`
`Unless otherwise indicated in the General Notices or in the
`monographs, statements in monographs constitute manda-
`tory 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 informa-
`tion or guidance.
`
`The active ingredients (medicinal substances), excipients (aux-
`iliary substances), pharmaceutical preparations and other ar-
`ticles 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 of all the tests in a
`monograph is necessarily a prerequisite for a manufacturer in
`assessing compliance with the Pharmacopoeia before release
`of a product. The manufacturer may obtain assurance that a
`product is of Pharmacopoeia quality from data derived, for
`example, from validation studies of the manufacturing pro-
`cess and from in-process controls. Parametric release in cir-
`cumstances deemed appropriate by the competent authority
`is thus not precluded by the need to comply with the Pharma-
`copoeia.
`
`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 meth-
`ods 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 analy-'
`sis of the Pharmacopoeia are alone authoritative.
`
`Certain materials that are the subject of a pharmacopoeial
`monograph may exist in different grades suitable for different
`
`1997 - EUROPEAN Pl-IARMACOPOEIA
`
`General notices
`
`purposes. Unless otherwise indicated in the monograph, the
`requirements apply to all grades of the material. In some
`monographs, particularly those on excipients, a list of critical
`properties that are important for the use of the substance
`may be appended to the monograph for information and guid-
`ance. Test methods for determination of one or more of these
`critical properties may be given, also for information and guid-
`ance.
`
`The general monographs on dosage forms apply to all prepa-
`rations of the type defined. The requirements are not neces-
`sarily comprehensive for a given specific preparation and re-
`quirements additional to those prescribed in the general
`monograph may be imposed by the competent authority.
`
`Conventional terms. The term ‘competent authority’ means
`the national, supranational or international body or organi-
`sation vested with the authority for making decisions con-
`cerning 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 com-
`petent 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’ are used to describe a reagent, 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.
`
`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
`than 10 per cent from that stated, is accurately weighed or
`measured and the result is calculated from this exact quan-
`tity. In tests where the limit is not numerical, but usually
`depends upon comparison with the behaviour of a reference
`in the same conditions, the stated quantity is taken for ex-
`amination. Reagents are used in the prescribed amounts.
`
`Quantities are weighed or measured with an accuracy com-
`mensurate 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 inter-
`preted as 0.245 g to 0.255 g). For the measurement of vol-
`umes, if the figure after the decimal point is a zero or ends in
`a zero (for example, 100 ml or 0.50 ml), the volume is
`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 rec-
`
`

`
`General notices
`
`ognised, 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 Stand-
`ardisation.
`
`Unless otherwise prescribed, analytical procedures are car-
`ried out at a temperature between 15 °C and 25 °C.
`
`Unless otherwise prescribed, comparative tests are carried
`out using identical tubes of colourless, transparent, neutral
`glass with a flat base and an internal diameter of 16 mm.
`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.
`
`The term “ethanol” without qualification means absolute al-
`cohol. The term “alcohol” without qualification means alco-
`hol containing about 96 per cent V/V of ethanol (CZHGO).
`Other dilutions of ethanol are indicated by the term
`“alcohol” followed by a statement of the percentage by vol-
`ume of ethanol (CZHGO) required.
`
`EXPRESSION OF CONTENT
`
`In defining content, the expression “per cent” is used accord-
`ing to circumstances with one of two meanings:
`
`— per cent m/m (percentage, mass in mass) expresses the
`number of grams of substance in 100 grams of final prod-
`uct.
`
`— per cent V/V (percentage, volume in volume) expresses
`the number of millilitres of substance in 100 millilitres of
`final product.
`
`The expression “parts per million (ppm)” refers to mass in
`mass, unless otherwise specified.
`
`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.
`
`TEMPERATURE
`
`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 tem-
`perature is near to but not higher than 100 °C or the indi-
`cated temperature.
`
`Drying and ignition to constant mass. The terms “dried to
`constant mass” and “ignited to constant mass” mean that
`two consecutive weighings do not differ by more than 0.5 mg,
`the second weighing following an additional period of drying
`or of ignition respectively appropriate to the nature and quan-
`tity of the residue.
`
`Where an analytical procedure describes temperature with-
`out a figure, the general terms used have the following mean-
`mg:
`
`In a deep-freeze
`In a refrigerator
`Cold or cool
`
`Room temperature
`
`2 °C
`8 °C
`
`15 °C
`
`below — 15 °C
`to
`8 °C
`to
`15 °C
`
`to
`
`25 °C
`
`1.3. GENERAL CHAPTERS
`
`Where drying is prescribed using one of the expressions “in
`a desiccator” or “in vacuo”, it is carried out using the condi-
`tions described under 2.2.32. Loss on drying.
`
`CONTAINERS
`
`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 chapter 4. It is assumed that reagents
`of analytical grade are used; for some reagents, tests to de-
`termine suitability are included in the specifications.
`
`SOLVENTS
`
`Solvents. Where the name of the solvent is not stated, the
`term “solution” implies a solution in water. Where the use of
`water is specified or implied in the analytical procedures de-
`scribed in the Pharmacopoeia or for the preparation
`of reagents, water complying with the requirements of the
`monograph on Purified water (8) is used. The term “distilled
`water” indicates purified water prepared by distillation.
`
`Materials used for containers are described in general chap-
`ter 3. General names used for materials, particularly plastics
`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 de-
`pend on the formulation and are therefore applicable only
`for materials whose formulation is covered by the preamble
`to the specification. The use of materials with different for-
`mulations and the test methods and limits applied to them
`are subject to agreement by the competent authority.
`
`The specifications for containers in general chapter 3, 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 circum-
`stances, of containers that comply with other specifications,
`subject to agreement by the competent authority.
`
`Reference may be made within the monographs of the Phar-
`macopoeia to the definitions and specifications for contain-
`ers provided in this section. The general monographs for phar-
`
`EUROPEAN PHARMACOPOEIA - 1997
`
`
`
`

`
`
`
`General notices
`
`required. A product described in a monograph of the Phar-
`macopoeia is manufactured in accordance with the princi-
`ples of good manufacturing practice and in accordance with
`relevant international agreements and supranational and
`national regulations governing products for human or veteri-
`nary use.
`
`Where in the section under the heading Production a mono-
`graph on a vaccine defines the characteristics of the vaccine
`strain to be used, any test methods given for confirming these
`characteristics are provided for information as examples of
`suitable methods.
`
`CHARACTERS
`
`The statements under the heading Characters are not to be
`interpreted in a strict sense and are not requirements.
`
`Solubility. In statements of solubility in the section headed
`Characters, 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
`
`less than
`Very soluble
`from
`Freely soluble
`from
`Soluble
`from
`Sparingly soluble
`from
`Slightly soluble
`from
`Very slightly soluble
`Practically insoluble more than
`
`1
`1
`10
`30
`100
`1000
`
`to
`to
`to
`to
`to
`
`10
`30
`100
`1000
`10 000 ’
`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.
`
`maceutical dosage forms may, under the heading Definition/
`Production, require the use of certain types of container;
`certain other monographs may, under the heading Storage,
`indicate the type of container that is recommended for use.
`
`1.4. MONOGRAPHS
`
`TITLES
`
`Monograph titles are in English and French in the respective
`versions and there is a Latin subtitle which may be used in
`place of the English or French title as may any synonyms
`declared equivalent by the competent authority.
`
`RELATIVE ATOMIC AND MOLECULAR MASSES
`
`The relative atomic mass (A) or the relative molecular mass
`(M!) is shown, as and where appropriate, at the beginning of
`each monograph. The relative atomic and molecular masses
`and the molecular ‘and graphic formulae do not constitute
`analytical standards for the substances described.
`
`DEFINITION
`
`Statements under the heading Definition constitute an official
`definition of the substance, preparation or other article that
`is the subject of the monograph.
`
`Limits of content. Where limits of content are prescribed,
`they are those determined by the method described under
`Assay.
`r
`
`Vegetable drugs. In monographs on vegetable drugs, the
`definition 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
`example both to the whole drug and the drug in powdered
`form, the definition states this.
`
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`' PRODUCTION
`
`Statements under the heading Production draw attention to
`particular aspects of the manufacturing process but are not
`necessarily comprehensive. They constitute instructions to
`manufacturers. They may relate, for example, to source ma-
`terials, 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 au-
`thority may establish that the instructions have been followed,
`for example, by examination of data received from the manu-
`facturer, by inspection of manufacture or by testing appro-
`priate samples.
`
`The absence of a section on Production does not imply that
`attention to features such as those referred to above is not
`
`1997 - EUROPEAN PHARMACOPOEIA
`
`IDENTIFICATION
`
`The tests given in the identification section are not designed
`to give a full confirmation of the chemical structure or com-
`position of the product; they are intended to give confirma-
`tion, with an acceptable degree of assurance, that the article
`conforms to the description on the label.
`
`Certain monographs have subdivisions entitles ‘First identi-
`fication’ and the ‘Second identification’. The test or tests
`that constitute the ‘Second identification’ may be used in-
`stead of the test or tests of the ‘First identification’ provided
`it can be demonstrated that the substance or preparation is
`fully traceable to a batch certified to comply with all the
`requirements of the monograph.
`
`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 pre-
`
`

`
`General notices
`
`scribed tests is tolerated if common sense and good pharma-
`ceutical practice require that it be absent. See also below
`under Impurities.
`
`Calculation. Where the result of a test or assay is required to
`be calculated with reference to the dried or anhydrous sub-
`stance 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 mono-
`graph.
`
`Limits. The limits prescribed are based on data obtained in
`normal analytical practice; they take account of normal ana-
`lytical 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 ex-
`amined complies with the requirements of the monograph.
`
`In determining compliance with a numerical limit, the calcu-
`lated result of a test or assay is first rounded to the number
`of significant figures stated, unless otherwise prescribed. The
`last figure is increased by one when the part rejected is equal
`to or exceeds one half-unit, whereas it is not modified when
`the part rejected is less than a half-unit.
`
`Indication of permitted limit of impurities. The approximate
`content of impurity tolerated, or the sum of impurities, may
`be indicated in parentheses for information only. If the use
`of a reference substance for the named impurity is not pre-
`scribed, this content may be expressed as a nominal concen-
`tration of the substance used to prepare the reference solu-
`tion specified in the monograph, unless otherwise described.
`Acceptance or rejection is determined on the basis of compli-
`ance or noncompliance with the stated test.
`
`Vegetable drugs. For vegetable drugs, the sulphated ash, total
`ash, water-soluble matter, alcohol-soluble matter, water con-
`tent, 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
`of the Pharmacopoeia only the figures shown are to be used
`in applying the requirements of the monograph.
`
`STORAGE
`
`The information and recommendations given under the head-
`ing 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 possi-
`ble, deterioration. Where special conditions of storage are
`recommended, including the type of container (see General
`Notice on Containers above) and limits of temperature, they
`are stated in the monograph.
`
`The following expressions are used in monographs under
`Storage with the meaning shown.
`
`Protected from moisture means that the product is stored in
`an airtight container. 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 light means that the product is stored either
`in a container made of a material that absorbs actinic light
`sufficiently to protect the contents from change induced by
`such light or in a container enclosed in an outer cover that
`provides such protection or stored in a place from which all
`such light is excluded.
`
`LABELLING
`
`In general, labelling is subject to supranational and national
`regulation and to international agreements. The statements
`under the heading Labelling therefore are not comprehen-
`sive and, moreover, for the purposes of the Pharmacopoeia
`only those statements that are necessary to demonstrate com-
`pliance or non-compliance with the monograph are manda-
`tory. Any other labelling st