欧洲药典(Ph. Eur.)是指导欧洲药品质量标准的根本性法规文件,而其第一章通用凡例(General Notices)则是整部药典的总纲与法律基石。凡例中的每一条款都具有普遍约束力,为所有各论和通用章节的理解与执行提供了统一的框架和解释。它并非简单的序言,而是具有强制性法律效力的核心内容。
深刻理解并严格遵守通用凡例的规定,是所有药品研发、生产、质量控制及注册申报人员确保产品合规性的前提。任何对各论标准的解读,都必须首先回归到凡例的基本原则上来。
Source: European Pharmacopoeia (Ph. Eur.) - Chapter 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 in italics.
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 assigned to any given article and the time from which that 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 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 process and from in-process controls. Parametric release in circumstances deemed appropriate by the competent authority is thus not precluded by the need to 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, the requirements apply to all grades of the material. In some monographs, particularly those on excipients, a list of functionality-related characteristics that are relevant to the use of the substance may be appended to the monograph for information. Test methods for determination of one or more of these characteristics may be given, also for information.
Quality systems. The quality standards represented by 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 normally given in individual monographs.
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 of the type defined. The requirements are not necessarily 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. The test methods given in monographs and general chapters have been validated 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’ 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.
Medicinal product. (a) Any substance or combination of substances presented as having properties for treating or preventing 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. Any substance intended to be used in 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 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 product that is not an active substance. Adjuvants, stabilisers, antimicrobial preservatives, diluents, antioxidants, for example, are excipients.
Interchangeable methods. Certain general chapters contain a statement that the text in question is harmonised with the corresponding text of the Japanese Pharmacopoeia 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. Monographs and 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 of 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 of the substance to be taken for the test is approximate. The quantity actually used is accurately weighed or measured and the result is calculated from this exact quantity.
Clarity and opalescence of liquids. To compare the clarity of liquids, unless otherwise prescribed, use matched, flat-bottomed tubes of colourless, transparent, neutral glass with a nominal internal diameter of 16 mm. A defined volume of the liquid to be examined is placed in a tube and the liquid used for comparison is placed in another tube. The volumes of the liquids to be compared are adjusted. 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 temperature is near to but not higher than 100 °C or the indicated temperature.
Drying and ignition to constant mass. The terms ‘dried to constant mass’ and ‘ignited to constant mass’ mean that 2 consecutive weighings do not differ by more than 0.5 mg, the 2nd weighing following an additional period of drying or of ignition respectively appropriate to the nature and quantity of the residue.
Where drying is prescribed using one of the expressions ‘in a desiccator’ or ‘in vacuo’, it is carried out using the conditions described in chapter 2.2.32. 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 chapter 4. It is assumed that 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, 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 for the preparation of reagents, water complying with the requirements of the monograph Purified water (0008) is used, except that for many purposes the requirements for bacterial endotoxins (Purified water in bulk) and microbial 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 (C2H6O) required.
Expression of content. In defining content, the expression ‘per cent’ is used according to circumstances with one of 3 meanings:
– per cent m/m (percentage, mass in mass) expresses the number of grams of substance in 100 g of final product;
– per cent V/V (percentage, volume in volume) expresses the number of millilitres of substance in 100 mL of final product;
– per cent m/V (percentage, mass in volume) expresses the number of grams 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:
– deep-freeze: below −15 °C;
– refrigerator: 2 °C to 8 °C;
– cold or cool: 8 °C to 15 °C;
– room temperature: 15 °C to 25 °C.
1.3 GENERAL CHAPTERS
Containers. Materials used for containers are described in general chapter 3.1. 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 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 chapter 3.2 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 chapter 3.2. Containers. The general monographs for pharmaceutical 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.
RELATIVE ATOMIC AND MOLECULAR MASSES
The relative atomic mass (Ar) or the relative molecular mass (Mr) 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.
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 the subject of the monograph.
Limits of content. Where limits of content are prescribed, they are those determined by the method described under Assay.
Herbal drugs. In monographs on herbal 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.
PRODUCTION
Statements under the heading Production draw attention to particular aspects of the manufacturing process but are 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. users to help detect adulterated materials (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
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 Characters section, the terms used have the following significance, referred to a temperature between 15 °C and 25 °C.
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 designed to give a full confirmation of the chemical structure 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. Certain monographs 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 and may be used independently. One or more of these sets 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. Monographs on herbal drugs may 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 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 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 significant figures). The last figure of the result 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 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 or rejection is determined on the basis of compliance or 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 of the Pharmacopoeia only the figures shown are to be used in 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, particularly those of biological origin, are of variable quality, 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;
– buffering substances;
– 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 container means that the product is stored in an 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 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 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 decided 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 of any appropriate regulations are to be observed at all 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 chapter 5.10. 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.
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 chapter 5.12. Reference standards.
The European 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
(Content of abbreviations and symbols follows here)
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. 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 Pharmacopoeia are shown in Table 1.6-2.
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
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.
The Celsius temperature is expressed in degrees Celsius (symbol °C). The unit ‘degree Celsius’ is equal to the unit ‘kelvin’.
The practical expressions of concentrations used in the Pharmacopoeia are defined in the General Notices.
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.
In the Pharmacopoeia, conditions of centrifugation are defined by reference to the acceleration due to gravity (g): g = 9.806 65 m·s⁻².
Certain quantities without dimensions are used in the Pharmacopoeia: relative density (2.2.5), absorbance (2.2.25), specific absorbance (2.2.25) and refractive index (2.2.6).
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.
译文:
欧洲药典 - 第1章:通用凡例
1.1 通则概述
本通用凡例适用于欧洲药典的所有各论及其他正文。
欧洲药典的法定文本以英文和法文发布。欧洲药典公约的签署国可将药典内容翻译成其他语言。当出现疑问或争议时,仅以英文和法文版本为唯一权威依据。
在欧洲药典正文中,未加限定的药典一词系指欧洲药典。官方缩写 Ph. Eur. 可用于指代欧洲药典。
凡使用某各论的标题或副标题,即意味着该品种符合相关各论的要求。在药典正文中引用各论时,以斜体形式标示各论的标题和编号。
制剂在其整个有效期内必须符合规定;对于已开启或取用过的包装,主管当局可规定一个不同的使用期限和/或质量标准。其他各论收载的任何品种必须在其整个使用期间符合规定。任何特定品种的有效期及其起始计算时间,由主管当局根据稳定性研究的试验结果决定。
除非在通用凡例或各论中另有规定,各论中的陈述均构成强制性要求。当各论引用通用章节时,该通用章节即成为强制性要求,除非引用方式表明其目的并非强制执行,而仅为引用信息。
各论中收载的活性物质、辅料、药物制剂及其他品种,均可用于人用和兽用(除非明确限定于其中一种用途)。一个品种除非符合其各论中规定的所有要求,否则不能视为符合药典质量。这并不意味着,制造商在产品放行前为评估其是否符合药典,必须执行各论中的所有检验项目。制造商可通过其他方式获得产品符合药典质量的保证,例如,来自生产工艺验证和过程控制的数据。因此,在主管当局认为适当的情况下,参数放行(Parametric Release)并不因需要符合药典而被排除。
所述的检查和含量测定方法是建立药典标准的法定方法。经主管当局同意,可使用替代分析方法用于控制目的,前提是所用方法能明确判定,如果采用法定方法,结果是否能符合各论标准。若出现疑问或争议,仅以药典的分析方法为唯一权威依据。
某些药典各论收载的物料,可能存在适用于不同用途的不同级别。除非各论中另有规定,否则其要求适用于该物料的所有级别。在某些各论中,特别是辅料各论,可能会附有一份与该物质用途相关的功能性特性列表,仅供参考。为测定这些特性中的一项或多项而设的检验方法也可能一并给出,同样仅供参考。
质量体系。 各论所代表的质量标准,仅在相关品种是在一个适宜的质量体系框架下生产时方为有效。
通用各论。 凡已收载于单行各论的物质和制剂,也必须符合相关的、适用的通用各论。单行各论中通常不给出与适用通用各论的交叉引用。
通用各论适用于其定义部分范围内的所有物质和制剂,除非其前言部分限定了适用范围,例如,限定于药典各论已收载的物质和制剂。
剂型通用各论适用于所定义类型的所有制剂。对于某一特定制剂,这些要求不一定是全面的,主管当局可能会在通用各论规定之外施加额外要求。
通用各论和单行各论是互补的。若通用各论的规定不适用于某一特定产品,这会在其单行各论中明确说明。
药典方法的验证。 各论和通用章节中给出的检验方法,均已根据公认的科学实践和现行分析方法验证的建议进行了验证。除非在各论或通用章节中另有规定,否则分析人员无需对这些检验方法进行验证。
药典方法的实施。 在实施一个药典方法时,使用者必须根据相关各论、通用章节和质量体系的要求,评估是否需要在实际使用条件下以及在何种程度上证明该方法的适用性。
惯用术语。 主管当局(competent authority)一词系指被授予权力就相关问题做出决定的国家、超国家或国际性的机构或组织。例如,它可以是国家药典机构、药品许可当局或官方药品检定实验室。
除非经论证并获得批准(unless otherwise justified and authorised)这一表述意为,相关要求必须被满足,除非主管当局在特定情况下基于合理的论证,批准了修改或豁免。
凡包含应(should)一词的表述,均为信息或建议性质。
在某些各论或其他正文中,使用适宜的(suitable)和适当的(appropriate)等术语来描述试剂、微生物、检验方法等;若各论中未描述其适用性标准,则其适用性需通过论证以获得主管当局的认可。
药品(Medicinal product)。 (a) 任何以治疗或预防人类和/或动物疾病为特性进行介绍的物质或物质组合;或 (b) 任何可用于或施用于人类和/或动物,旨在通过发挥药理、免疫或代谢作用以恢复、纠正或改变生理功能,或用于医疗诊断的物质或物质组合。
草药产品(Herbal medicinal product)。 任何仅含有一种或多种草药、或一种或多种草药制剂、或一种或多种此类草药与一种或多种此类草药制剂的组合作为活性成分的药品。
活性物质(Active substance)。 任何旨在用于药品生产,并在使用后成为该药品活性成分的物质。此类物质旨在提供药理活性,或在诊断、治愈、缓解、治疗或预防疾病中提供其他直接作用,或影响机体结构和功能。
辅料(Excipient/auxiliary substance)。 药品中除活性物质外的任何组分。例如,佐剂、稳定剂、抗菌防腐剂、稀释剂、抗氧化剂等均为辅料。
可互换方法(Interchangeable methods)。 某些通用章节声明其内容与日本药局方(JP)和/或美国药典(USP)的相应内容已协调一致,且这些文本是可互换的。这意味着,若一物质或制剂被发现使用这些药典中的可互换方法能够符合要求,则其也符合欧洲药典的要求。若出现疑问或争议,仅以欧洲药典的文本为唯一权威依据。
对法规文件的引用。 各论和通用章节中可能含有对药品监管机构发布文件的引用,例如欧盟的指令和指南。这些引用为药典使用者提供信息。包含此类引用并不改变被引用文件的地位,它们本身可能是强制性的或指导性的。
1.2 适用于通用章节和各论的其他规定
取样量。 在有数值限度的检查和含量测定中,试验所用物质的取样量是约数。实际使用的量应精密称定或量取,并根据此精确量计算结果。
液体的澄清度与乳光。 比较液体的澄清度时,除非另有规定,应使用内径标示为16 mm的配套平底、无色、透明、中性玻璃管。将规定体积的供试液置于一管中,将用于比较的液体置于另一管中。应调节待比较液体的体积。在白色背景下,或必要时在黑色背景下,沿试管垂直轴向下观察等体积的液体。检查应在漫射光下进行。
在任何需使用指示剂的检查或测定中,所用的溶剂在使用前均需用该指示剂中和,除非规定了空白试验。
水浴。 水浴一词系指沸水浴,除非指明了其他温度。其他加热方式也可替代,前提是温度接近但不得高于100°C或指定温度。
干燥或炽灼至恒重。 干燥至恒重和炽灼至恒重系指连续两次称量之差不超过0.5 mg,第二次称量是在根据残渣性质和数量进行了额外一段适宜时间的干燥或炽灼之后进行。
当规定使用置干燥器中或真空等表述进行干燥时,应在第2.2.32章《干燥失重》所述的条件下进行。
试剂。 药典所述分析程序的正确执行及结果的可靠性,部分取决于所用试剂的质量。试剂在通用章节第4章中描述。除非另有规定,均假定使用分析纯级别的试剂;对于某些试剂,其规格中包含了确定其适用性的检验。
溶剂。 当未指明溶剂名称时,溶液一词意指水溶液。
当在药典所述的分析程序中或在试剂配制中规定或暗示使用水时,应使用符合《纯化水(0008)》各论要求的水,但对于许多用途,细菌内毒素(大包装纯化水)和微生物污染(瓶装纯化水)的要求是不相关的。蒸馏水一词指通过蒸馏法制备的纯化水。
乙醇一词若无限定,系指无水乙醇。酒精一词若无限定,系指乙醇(96%)。乙醇的其他稀释液,用乙醇或酒精后跟所需乙醇(C₂H₆O)的体积百分数来表示。
含量表示法。 在定义含量时,百分之(per cent)一词根据情况有以下三种含义之一:
– % m/m (质量/质量百分比) 表示100 g最终产品中所含物质的克数;
– % V/V (体积/体积百分比) 表示100 mL最终产品中所含物质的毫升数;
– % m/V (质量/体积百分比) 表示100 mL最终产品中所含物质的克数。
百万分率(ppm)一词,除非另有说明,均指质量与质量之比。
温度。 当分析程序中描述温度而未给出具体数值时,所用通用术语含义如下:
– **深冷 (deep-freeze):**低于 -15 °C;
– 冷藏 (refrigerator): 2 °C 至 8 °C;
– 冷处或凉处 (cold or cool): 8 °C 至 15 °C;
– 室温 (room temperature): 15 °C 至 25 °C。
1.3 通用章节
容器。 用于容器的材料在通用章节3.1中描述。用于材料的通用名称,特别是塑料材料,每个名称都涵盖了一系列产品,这些产品不仅在主要成分的性质上不同,在所用添加剂上也有差异。材料的检验方法和限度取决于其配方,因此仅适用于其配方已包含在规格前言中的材料。使用不同配方的材料,以及适用于它们的检验方法和限度,需经主管当局同意。
通用章节3.2中对容器的规格是为所述类别的容器的通用应用而制定的,但考虑到现有容器种类繁多且可能有新的发展,发布一项规格并不排除在有正当理由的情况下,经主管当局同意,使用符合其他规格的容器。
在药典各论中,可能会引用第3.2章《容器》中提供的容器定义和规格。剂型通用各论可能会在定义/生产标题下要求使用某些类型的容器。其他一些各论可能会在贮藏标题下指明推荐使用的容器类型。
1.4 各论
标题
各论标题在相应版本中为英文和法文,并有拉丁文副标题。
相对原子质量和相对分子质量
相对原子质量(Ar)或相对分子质量(Mr)酌情在每篇各论的开头标示。相对原子质量、相对分子质量以及分子式和结构式,不构成本各论所述物质的分析标准。
化学文摘社(CAS)注册号
在适用的情况下,各论中包含CAS注册号以供参考,为使用者获取有用信息提供便利。CAS Registry Number® 是美国化学会的注册商标。
定义
定义标题下的陈述构成了对该各论主题物质、制剂或其他品种的官方定义。
含量限度。 凡规定了含量限度,均指用含量测定项下所述方法测定的结果。
草药。 在草药各论中,定义部分会指明该各论的主题是,例如,原药材还是粉末状药材。若一个各论适用于药材的多种状态,例如同时适用于原药材和粉末状药材,定义中会予以说明。
生产
生产标题下的陈述提醒注意生产过程的特定方面,但不一定是全面的。除非另有说明,它们构成对生产商的强制性要求。这些要求可能涉及,例如,来源物料;生产过程本身及其验证和控制;过程检验;或由生产商在产品放行前对最终品种进行的检验(对选定批次或每批进行)。这些陈述不一定能由独立分析人员通过对最终品种的样品进行检验来核实。主管当局可通过例如审查生产商提交的数据、现场检查或检验适当的样品,来确认这些要求已得到遵守。
没有生产部分并不意味着不需要关注上述特性。
疫苗株的选择,疫苗组分的选择。 各论的生产部分可能定义疫苗株或疫苗组分的特性。除非另有说明,为验证这些特性而给出的检验方法是作为适宜方法的示例提供参考。经主管当局批准,可使用其他检验方法,而无需与各论中所示方法进行比对验证。
潜在掺杂
鉴于欺诈活动和掺杂案例日益增多,可能会向欧洲药典使用者提供信息,以帮助检测掺杂物料(即活性物质、辅料、中间产品、散装产品和成品)。
为此,在那些已发生过事件或存在故意污染风险的物质的各论中,本节可能包含一种检测潜在掺杂物的方法和相关限度,并提醒生产和采购的所有阶段都需遵守适宜的质量体系。生产商或使用者(例如,中间产品、散装产品和成品的生产商,如适用)的检测频率取决于风险评估,并考虑到对整个供应链的了解程度和国家要求。
本节构成了对从生产商到使用者(例如,中间产品、散装产品和成品的生产商,如适用)整个供应链的要求。没有本节并不意味着不需要关注上述特性。
性状
性状标题下的陈述不应作严格解释,也非强制性要求。
溶解度。 在性状部分的溶解度陈述中,所用术语在15°C至25°C温度下具有以下含义。
部分溶解一词用于描述一种混合物,其中只有部分组分溶解。混溶一词用于描述一种液体,它能与所述溶剂以任何比例混溶。
鉴别
范围。 鉴别部分给出的试验并非旨在完全确认产品的化学结构或组成;其目的是在可接受的保证程度上,确认该品种与标签上的描述相符。
第一鉴别和第二鉴别。 某些各论有题为第一鉴别和第二鉴别的子部分。第一鉴别所包含的一项或多项试验可在所有情况下使用。第二鉴别所包含的一项或多项试验可在药房使用,前提是能够证明该物质或制剂可完全追溯至一个已证明符合该各论所有其他要求的批次。
某些各论为第一鉴别提供了两套或多套试验,它们是等效的,可以独立使用。其中一套或多套通常包含对该各论检查部分规定的某项试验的交叉引用。这可用于简化分析人员进行鉴别和规定检查的工作。例如,一套鉴别试验交叉引用了对映体纯度检查,而另一套则给出了比旋度试验:两者的目的相同,即验证存在的是正确的对映异构体。
粉末状草药。 草药各论可能包含粉末状药材的示意图。这些图是对相关鉴别试验中描述的补充。
检查与含量测定
范围。 这些要求并非为涵盖所有可能的杂质而设。例如,不能因为某杂质无法通过规定试验检出,就假定它是可容忍的,如果常识和良好的药学实践要求它不存在的话。另见下文杂质部分。
计算。 当要求相对于干燥品、无水物或某些其他指定基准计算试验或测定结果时,干燥失重、水分含量或其他性质的测定应按照该各论相关试验中规定的方法进行。干燥品或无水物等字样出现在结果后的括号内。
当对残留溶剂进行定量测定,而未进行干燥失重试验时,在计算物质的含量、比旋度和比吸光度时,应考虑残留溶剂的含量。在具体各论中不再另行说明。
限度。 所规定的限度基于在正常分析实践中获得的数据;它们考虑了正常的分析误差、可接受的生产和配制偏差以及在可接受范围内的降解。在判断被检品种是否符合各论要求时,不得对规定的限度再施加任何公差。
在判断是否符合一个数值限度时,除非另有规定,试验或测定的计算结果首先应修约至规定的有效数字位数。无论限度值是以百分比还是绝对值表示,均被视为有效至显示的最后一位数字(例如140表示有3位有效数字)。当被舍弃的部分等于或大于半个单位时,结果的末位数字加一;当被舍弃的部分小于半个单位时,则不作改动。
杂质允许限度的标示。 有关物质的接受标准在各论中以峰面积比较(比较法)或数值的形式表示。对于比较法,括号中可能会标示出所允许的杂质的大约含量或杂质总和,仅供参考。接受与否取决于是否符合规定的试验。如果未规定使用指定杂质的对照品,此含量可以各论中规定的用于制备对照溶液的物质的标示浓度表示,除非另有说明。
草药。 对于草药,除非各论中另有规定,其硫酸灰分、总灰分、水溶性浸出物、醇溶性浸出物、水分含量、挥发油含量和有效成分含量,均以未经特殊干燥的药材计算。
当量。 凡给出当量,仅为药典目的,在应用各论要求时仅能使用所示的数值。
培养基。 各论和通用章节中描述的培养基已被证实能满足其预期用途。然而,培养基的组分,特别是生物来源的组分,质量各异,为达到最佳性能,可能需要调整某些成分的浓度,特别是:
– 蛋白胨和肉或酵母提取物,就其营养特性而言;
– 缓冲物质;
– 胆盐、胆汁提取物、脱氧胆酸盐和色素,取决于其选择性;
– 抗生素,就其活性而言。
贮藏
贮藏标题下给出的信息和建议不构成药典要求,但主管当局可规定必须满足的特定贮藏条件。
药典中描述的品种应以防止污染和尽可能防止变质的方式贮藏。当推荐特殊贮藏条件时,包括容器类型(见1.3节通用章节)和温度限度,会在各论中说明。
以下表述在各论的贮藏项下使用,其含义如下:
密闭容器(In an airtight container) 指产品贮存在一个密闭容器中(3.2)。在潮湿环境中开启容器时应小心。如有必要,可通过在容器中使用干燥剂来维持低水分含量,前提是避免与产品直接接触。
避光(Protected from light) 指产品贮存在一个由能充分吸收光化光以保护内容物免受此类光线引起变化的材料制成的容器中,或贮存在一个提供此类保护的外罩内的容器中,或贮存在一个完全排除所有此类光线的地方。
标签
总的来说,药品标签受超国家和国家法规以及国际协议的约束。因此,标签标题下的陈述并非详尽无遗,并且,为药典目的,只有那些为证明符合或不符合各论所必需的陈述才是强制性的。任何其他标签陈述均作为建议包含在内。当药典中使用标签一词时,标签内容可根据主管当局的决定,出现在容器、包装、随附包装的说明书或随附品种的检验报告单上。
警示
各论中描述的物料和药典中指定使用的试剂,如不采取足够的预防措施,可能对健康有害。应始终遵守良好质量控制实验室规范的原则和任何相关法规的规定。在某些各论中通过警示声明提请注意特定的危险;没有此类声明不应被视为不存在危险。
杂质
各论中可能会列出所有已知的和潜在的、且已被证明能被各论中试验检测出的杂质列表。另见第5.10章《药用物质中杂质的控制》。杂质用一个或多个字母标示。当某个字母似乎缺失时,表示该字母所指定的杂质已在各论制定发表前或修订期间从列表中删除。
辅料的功能相关特性
辅料各论可能有一个关于功能相关特性的章节。这些特性、任何用于测定的检验方法和任何允差,均非强制性要求;但它们可能与该辅料的使用相关,因此作为信息提供(另见1.1节通则概述)。
对照品
某些各论要求使用对照品(化学对照品、草药对照品、生物对照品、对照图谱)。另见第5.12章《对照品》。
欧洲药典委员会建立官方对照品,这些对照品在仲裁时是唯一具有权威性的。这些对照品可从欧洲药品质量管理局(EDQM)获得。有关可用对照品的信息和批次有效期声明,可通过EDQM网站获取。
1.5 缩写与符号
(缩写与符号内容在此后列出)
1.6 药典中使用的国际单位制(SI)单位及其与其他单位的换算关系
国际单位制(SI)
国际单位制包括三类单位,即基本单位、导出单位和辅助单位。基本单位及其定义在表1.6-1中列出。
导出单位可通过基本单位根据连接相应物理量的代数关系组合而成。其中一些导出单位有专门的名称和符号。药典中使用的SI单位在表1.6-2中显示。
国际单位制之外一些重要且广泛使用的单位在表1.6-3中显示。
表1.6-4中显示的词头用于构成SI单位的十进倍数和约数的名称和符号。
备注
在药典中,使用摄氏温度(符号 t)。其定义由以下方程给出:t = T − T₀,其中 T₀ = 273.15 K。摄氏温度以摄氏度(符号 °C)表示。摄氏度单位等于开尔文单位。
药典中使用的浓度的实用表示法在通用凡例中定义。
弧度是圆的两条半径之间的平面角,这两条半径在圆周上截取一段等于半径长度的弧。
在药典中,离心条件通过参照重力加速度(g)来定义:g = 9.806 65 m·s⁻²。
药典中使用某些无量纲的量:相对密度(2.2.5)、吸光度(2.2.25)、比吸光度(2.2.25)和折光率(2.2.6)。
微卡他(microkatal)定义为在规定条件下,每秒转化(例如水解)1微摩尔底物的酶活性。