Drying and ignition to constant mass

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 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 under 2.2.32. Loss on drying.

Water-bath

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.

Apparatus and procedures

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.
Unless otherwise prescribed, comparative tests are carried out 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.

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 quantity. 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 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 in a zero (for example, 10.0 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 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.

Interchangeable methods

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.

Conventional terms

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.

General monographs

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 Notices of the European Pharmacopoeia

General Notices of the European Pharmacopoeia
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 serial number in italics.
A 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 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 ingredients (medicinal substances), excipients (auxiliary substances), 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 important for 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.

Part III

Part III
Monographs and other texts of the European Pharmacopoeia that are incorporated in this edition of the British Pharmacopoeia are governed by the general notices of the European Pharmacopoeia; these are reproduced below.

Crude Drugs

Crude Drugs
The macroscopical characteristics of a crude drug include those features that can be seen by the unaided eye or by the use of a hand lens.
Vegetable drugs are required to be free from insects and other animal matter, and from animal excreta. Not more than traces of foreign organic matter may be present in powdered vegetable drugs. Microbial contamination should be minimal.
In determining the content of active principle, Acid-insoluble ash, Ash, Extractive soluble in ethanol, Loss on drying, Sulphated ash, Water, Water-soluble ash and Water-soluble extractive of vegetable drugs, the calculations are made with reference to the drug that has not been specially dried unless otherwise prescribed in the monograph.
In the assays for alkaloids in crude drugs and their preparations, definite quantities of solvents are specified. The quantities are given as being suitable for typical cases; they may, however, be varied where necessary to overcome the difficulties that may be encountered in special instances, provided that the effect of the prescribed directions is ensured.
When it is found necessary to dry a crude drug before it can be reduced to powder for the purpose of assay, a correction is made for the loss on drying and the alkaloidal content is calculated with reference to the undried drug.

Action and Use

Action and Use
The statements given under this heading in monographs are intended only as information on the principal pharmacological actions or the uses of the materials in medicine or pharmacy. It should not be assumed that the substance has no other action or use. The statements are not intended to be binding on prescribers or to limit their discretion.

Labelling

Labelling
The labelling requirements of the Pharmacopoeia are not comprehensive and laws governing the statements to be declared on labels of official articles should also be met. In the United Kingdom the provisions of regulations issued in accordance with the Medicines Act 1968, together with those of regulations for the labelling of hazardous materials, should be met.
Only those statements in monographs given under the heading Labelling that are necessary to demonstrate compliance or otherwise with the monograph are mandatory. Any other statements are included as recommendations.
Such matters as the exact form of wording to be used and whether a particular item of information should appear on the primary label and additionally, or alternatively, on the package or exceptionally in a leaflet are, in general, outside the scope of the Pharmacopoeia. When the term 'label' is used in Labelling statements of the Pharmacopoeia, decisions as to where the particular statement should appear should therefore be made in accordance with relevant legislation.
The label of every official article states (i) the name at the head of the monograph and (ii) a reference consisting of either figures or letters, or a combination of figures and letters, by which the history of the article may be traced.
The label of every official formulated preparation other than those of fixed strength also states the content of the active ingredient or ingredients expressed in the terms required by the monograph. Where the content of active ingredient is required to be expressed in terms other than the weight of the official medicinal substance used in making the formulation, this is specifically stated under the heading Labelling. Thus, where no specific requirement is included under the heading Labelling, it is implied that the content of active ingredient is expressed in terms of the weight of the official medicinal substance used in making the formulation. For example, for Ampicillin Injection, which contains Ampicillin Sodium but for which the content is expressed in terms of the equivalent amount of ampicillin, a specific requirement to this effect is included under the heading Labelling. For Amitriptyline Tablets which contain Amitriptyline Hydrochloride and for which the result of the assay is expressed in terms of amitriptyline hydrochloride no specific statement is included under the heading Labelling; these Tablets are thus labelled with the nominal weight of Amitriptyline Hydrochloride.
These requirements do not necessarily apply to the labelling of articles supplied in compliance with a prescription.

Storage

Storage
Statements under the side-heading Storage constitute non-mandatory advice. The substances and preparations described in the Pharmacopoeia are to be stored under conditions that prevent contamination and, as far as possible, deterioration. Unless otherwise stated in the monograph, the substances and preparations described in the Pharmacopoeia are kept in well-closed containers and stored at a temperature not exceeding 25°. Precautions that should be taken in relation to the effects of the atmosphere, moisture, heat and light are indicated, where appropriate, in the monographs. Further precautions may be necessary when some materials are stored in tropical climates or under other severe conditions. The expression ¢protected from moisture¢ means that the product is to be 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. The expression ¢protected from light¢ means that the product is to be 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. The expression ¢tamper-evident container ¢ means a closed container fitted with a device that reveals irreversibly whether the container has been opened.

TITLES

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.
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.
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

Assays and Tests

Assays and Tests
The assays and tests described are the official methods upon which the standards of the Pharmacopoeia depend. The analyst is not precluded from employing alternative methods, including methods of micro-analysis, in any assay or test if it is known that the method used will give a result of equivalent accuracy. Local reference materials may be used for routine analysis, provided that these are calibrated against the official reference materials. In the event of doubt or dispute, the methods of analysis, the reference materials and the reference spectra of the Pharmacopoeia are alone authoritative.
Where the solvent used for a solution is not named, the solvent is Purified Water.
Unless otherwise prescribed, the assays and tests are carried out at a temperature between 15 °C and 25 °C.
A temperature in a test for Loss on drying, where no temperature range is given, implies a range of ±2 °C about the stated value.
Visual comparative tests, unless otherwise prescribed, are carried out using identical tubes of colourless, transparent, neutral glass with a flat base. The volumes of liquid prescribed are for use with tubes 16 mm in internal diameter; tubes with a larger internal diameter may be used but the volume of liquid examined must be increased so that the depth of liquid in the tubes is not less than that obtained when the prescribed volume of liquid and tubes 16 mm in internal diameter are used. 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.
Where a direction is given that an analytical operation is to be carried out 'in subdued light', precautions should be taken to avoid exposure to direct sunlight or other strong light. Where a direction is given that an analytical operation is to be carried out 'protected from light', precautions should be taken to exclude actinic light by the use of low-actinic glassware, working in a dark room or similar procedures.
For preparations other than those of fixed strength, the quantity to be taken for an assay or test is usually expressed in terms of the active ingredient. This means that the quantity of the active ingredient expected to be present and the quantity of the preparation to be taken are calculated from the strength stated on the label.
In assays the approximate quantity to be taken for examination is indicated but the quantity actually used must not deviate by more than 10% from that stated. The quantity taken is accurately weighed or measured and the result of the assay is calculated from this exact quantity. Reagents are measured and the procedures are carried out with an accuracy commensurate with the degree of precision implied by the standard stated for the assay.
In tests the stated quantity to be taken for examination must be used unless any divergence can be taken into account in conducting the test and calculating the result. The quantity taken is accurately weighed or measured with the degree of precision implied by the standard or, where the standard is not stated numerically (for example, in tests for Clarity and colour of solution), with the degree of precision implied by the number of significant figures stated. Reagents are measured and the procedures are carried out with an accuracy commensurate with this degree of precision.
The limits stated in monographs are based on data obtained in normal analytical practice; they take account of normal analytical errors, of acceptable variations in manufacture 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 last figure is increased by 1 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.
In certain tests, the concentration of impurity is given in parentheses either as a percentage or in parts per million by weight (ppm). In chromatographic tests such concentrations are stated as a percentage irrespective of the limit. In other tests they are usually stated in ppm unless the limit exceeds 500 ppm. In those chromatographic tests in which a secondary spot or peak in a chromatogram obtained with a solution of the substance being examined is described as corresponding to a named impurity and is compared with a spot or peak in a chromatogram obtained with a reference solution of the same impurity, the percentage given in parentheses indicates the limit for that impurity. In those chromatographic tests in which a spot or peak in a chromatogram obtained with a solution of the substance being examined is described in terms other than as corresponding to a named impurity (commonly, for example, as any (other) secondary spot or peak) but is compared with a spot or peak in a chromatogram obtained with a reference solution of a named impurity, the percentage given in parentheses indicates an impurity limit expressed in terms of a nominal concentration of the named impurity. In chromatographic tests in which a comparison is made between spots or peaks in chromatograms obtained with solutions of different concentrations of the substance being examined, the percentage given in parentheses indicates an impurity limit expressed in terms of a nominal concentration of the medicinal substance itself. In some monographs, in particular those for certain formulated preparations, the impurity limit is expressed in terms of a nominal concentration of the active moiety rather than of the medicinal substance itself. Where necessary for clarification the terms in which the limit is expressed are stated within the monograph.
In all cases where an impurity limit is given in parentheses, the figures given are approximations for information only; conformity with the requirements is determined on the basis of compliance or otherwise with the stated test.
The use of a proprietary designation to identify a material used in an assay or test does not imply that another equally suitable material may not be used.
Biological Assays and Tests
Methods of assay described as Suggested methods are not obligatory, but when another method is used its precision must be not less than that required for the Suggested method.
For those antibiotics for which the monograph specifies a microbiological assay the potency requirement is expressed in the monograph in International Units (IU) per milligram. The material is not of pharmacopoeial quality if the upper fiducial limit of error is less than the stated potency. For such antibiotics the required precision of the assay is stated in the monograph in terms of the fiducial limits of error about the estimated potency.
For other substances and preparations for which the monograph specifies a biological assay, unless otherwise stated, the precision of the assay is such that the fiducial limits of error, expressed as a percentage of the estimated potency, are within a range not wider than that obtained by multiplying by a factor of 10 the square roots of the limits given in the monograph for the fiducial limits of error about the stated potency.
In all cases fiducial limits of error are based on a probability of 95% (P = 0.95).
Where the biological assay is being used to ascertain the purity of the material, the stated potency means the potency stated on the label in terms of International Units (IU) or other Units per gram, per milligram or per millilitre. When no such statement appears on the label, the stated potency means the fixed or minimum potency required in the monograph. This interpretation of stated potency applies in all cases except where the monograph specifically directs otherwise.
Where the biological assay is being used to determine the total activity in the container, the stated potency means the total number of International Units (IU) or other Units stated on the label or, if no such statement appears, the total activity calculated in accordance with the instructions in the monograph.
Wherever possible the primary standard used in an assay or test is the respective International Standard or Reference Preparation established by the World Health Organization for international use and the biological activity is expressed in International Units (IU).
In other cases, where Units are referred to in an assay or test, the Unit for a particular substance or preparation is, for the United Kingdom, the specific biological activity contained in such an amount of the respective primary standard as the appropriate international or national organisation indicates. The necessary information is provided with the primary standard.
Unless otherwise directed, animals used in an assay or a test are healthy animals, drawn from a uniform stock, that have not previously been treated with any material that will interfere with the assay or test. Unless otherwise stated, guinea-pigs weigh not less than 250 g or, when used in systemic toxicity tests, not less than 350 g. When used in skin tests they are white or light coloured. Unless otherwise stated, mice weigh not less than 17 g and not more than 22 g.
Certain of the biological assays and tests of the Pharmacopoeia are such that in the United Kingdom they may be carried out only in accordance with the Animals (Scientific Procedures) Act 1986. Instructions included in such assays and tests in the Pharmacopoeia, with respect to the handling of animals, are therefore confined to those concerned with the accuracy and reproducibility of the assay or test.

Identification

Identification
The tests described or referred to under the heading Identification are not necessarily sufficient to establish absolute proof of identity. They provide a means of verifying that the identity of the material being examined is in accordance with the label on the container.
Unless otherwise prescribed, identification tests are carried out at a temperature between 15 °C and 25 °C.
When tests for infrared absorption are applied to material extracted from formulated preparations, strict concordance with the specified reference spectrum may not always be possible, but nevertheless a close resemblance between the spectrum of the extracted material and the specified reference spectrum should be achieved.

Solubility

Solubility: Statements on solubility given under the heading Characteristics are intended as information on the approximate solubility at a temperature between 15°C and 25°C, unless otherwise stated, and are not to be considered as official requirements.
Statements given under headings such as Solubility in ethanol express exact requirements and constitute part of the standards for the substances under which they occur.
The following table indicates the meanings of the terms used in statements of approximate solubilities.
Descriptive term Approximate volume of solvent in millilitres per gram of solute
very soluble less than 1
freely soluble from 1 to 10
soluble from 10 to 30
sparingly soluble from 30 to 100
slightly soluble from 100 to 1000
very slightly soluble from 1000 to 10 000
practically insoluble more than 10 000 The term 'partly soluble' is used to describe a mixture of which only some of the components dissolve.

Characteristics

Characteristics
Statements given under the heading Characteristics are not to be interpreted in a strict sense and are not to be regarded as official requirements. Statements on taste are provided only in cases where this property is a guide to the acceptability of the material (for example, a material used primarily for flavouring). The status of statements on solubility is given in the general notice on Solubility.

Antimicrobial Preservatives

Antimicrobial Preservatives
When the term 'suitable antimicrobial preservative' is used it is implied that the preparation concerned will be effectively preserved according to the appropriate criteria applied and interpreted as described in the test for efficacy of antimicrobial preservation (Appendix XVI C). In certain monographs for formulated preparations defined by means of a full formula, a specific antimicrobial agent or agents may be prescribed; suitable alternatives may be substituted provided that their identity and concentration are stated on the label.

Colouring Agents

Colouring Agents
If in a monograph for a formulated preparation defined by means of a full formula a specific colouring agent or agents is prescribed, suitable alternatives approved in the country concerned may be substituted.

Excipients

Excipients Where an excipient for which there is a pharmacopoeial monograph is used in preparing an official preparation it shall comply with that monograph. Any substance added in preparing an official preparation shall be innocuous, shall have no adverse influence on the therapeutic efficacy of the active ingredients and shall not interfere with the assays and tests of the Pharmacopoeia. Particular care should be taken to ensure that such substances are free from harmful organisms.

Water

Water
The term water used without qualification in formulae for formulated preparations means either potable water freshly drawn direct from the public supply and suitable for drinking or freshly boiled and cooled Purified Water. The latter should be used if the public supply is from a local storage tank or if the potable water is unsuitable for a particular preparation.

Methods of Sterilisation

Methods of Sterilisation The methods of sterilisation used in preparing the sterile materials described in the Pharmacopoeia are given in Appendix XVIII. For aqueous preparations, steam sterilisation (heating in an autoclave) is the method of choice wherever it is known to be suitable. Any method of sterilisation must be validated with respect to both the assurance of sterility and the integrity of the product and to ensure that the final product complies with the requirements of the monograph.

Freshly and Recently Prepared

Freshly and Recently Prepared
The direction, given under the heading Extemporaneous Preparation, that a preparation must be freshly prepared indicates that it must be made not more than 24 hours before it is issued for use. The direction that a preparation should be recently prepared indicates that deterioration is likely if the preparation is stored for longer than about 4 weeks at 15° C to 25° C.

Manufacture of Formulated Preparations

Manufacture of Formulated Preparations
Attention is drawn to the need to observe adequate hygienic precautions in the preparation and dispensing of pharmaceutical formulations. The principles of good pharmaceutical manufacturing practice should be observed.
The Definition in certain monographs for pharmaceutical preparations is given in terms of the principal ingredients only. Any ingredient, other than those included in the Definition, must comply with the general notice on Excipients and the product must conform with the Pharmacopoeial requirements.
The Definition in other monographs for pharmaceutical preparations is presented as a full formula. No deviation from the stated formula is permitted except those allowed by the general notices on Colouring Agents and Antimicrobial Preservatives. Where additionally directions are given under the heading Extemporaneous Preparation these are intended for the extemporaneous preparation of relatively small quantities for short-term supply and use. When so prepared, no deviation from the stated directions is permitted. If, however, such a pharmaceutical preparation is manufactured on a larger scale with the intention that it may be stored, deviations from the stated directions are permitted provided that the final product meets the following criteria:
(1) compliance with all of the requirements stated in the monograph;
(2) retention of the essential characteristics of the preparation made strictly in accordance with the directions of the Pharmacopoeia.
Monographs for yet other pharmaceutical preparations include both a Definition in terms of the principal ingredients and, under the side-heading Extemporaneous Preparation, a full formula together with, in some cases, directions for their preparation. Such full formulae and directions are intended for the extemporaneous preparation of relatively small quantities for short-term supply and use. When so prepared, no deviation from the stated formula and directions is permitted. If, however, such a pharmaceutical preparation is manufactured on a larger scale with the intention that it may be stored, deviations from the formula and directions stated under the heading Extemporaneous Preparation are permitted provided that any ingredient, other than those included in the Definition, complies with the general notice on Excipients and that the final product meets the following criteria:
(1) accordance with the Definition stated in the monograph;
(2) compliance with all of the requirements stated in the monograph;
(3) retention of the essential characteristics of the preparation made strictly in accordance with the formula and directions of the Pharmacopoeia.
In the manufacture of any official preparation on a large scale with the intention that it should be stored, in addition to following any instruction under the heading Production, it is necessary to ascertain that the product is satisfactory with respect to its physical and chemical stability and its state of preservation over the claimed shelf-life. This applies irrespective of whether the formula of the Pharmacopoeia and any instructions given under the heading Extemporaneous Preparation are followed precisely or modified. Provided that the preparation has been shown to be stable in other respects, deterioration due to microbial contamination may be inhibited by the incorporation of a suitable antimicrobial preservative. In such circumstances the label states appropriate storage conditions, the date after which the product should not be used and the identity and concentration of the antimicrobial preservative.

Production

Production
Statements given under the heading Production draw attention to particular aspects of the manufacturing process but are not necessarily comprehensive. They constitute mandatory instructions to manufacturers. 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 product (bulk material or dosage form) either on selected batches or on each batch prior to release. These statements cannot necessarily be verified on a sample of the final product 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 or by testing appropriate samples.
The absence of a section on Production does not imply that attention to features such as those referred to above is not required. A substance, preparation or article described in a monograph of the Pharmacopoeia is to be manufactured in accordance with the principles of good manufacturing practice and in accordance with relevant international agreements and supranational and national regulations governing medicinal products.
Where in the section under the heading Production a monograph on a vaccine defines the characteristics of the vaccine strain to be used, any test methods given for confirming these characteristics are provided as examples of suitable methods. The use of these methods is not mandatory.
Additional statements concerning the production of formulated preparations are given in the general notice on Manufacture of Formulated Preparations.

Definition

Definition
Statements given under the heading Definition constitute an official definition of the substance, preparation or other article that is the subject of the monograph. They constitute instructions or requirements and are mandatory in nature.
Certain medicinal or pharmaceutical substances and other articles are defined by reference to a particular method of manufacture. A statement that a substance or article is prepared or obtained by a certain method constitutes part of the official definition and implies that other methods are not permitted. A statement that a substance may be prepared or obtained by a certain method, however, indicates that this is one possible method and does not imply that other methods are proscribed.
Additional statements concerning the definition of formulated preparations are given in the general notice on Manufacture of Formulated Preparations.

Chemical Formulae

Chemical Formulae
When the chemical composition of an official substance is known or generally accepted, the graphic and molecular formulae, the molecular weight and the Chemical Abstracts Service Registry Number are normally given at the beginning of the monograph for information. This information refers to the chemically pure substance and is not to be regarded as an indication of the purity of the official material. Elsewhere, in statements of standards of purity and strength and in descriptions of processes of assay, it is evident from the context that the formulae denote the chemically pure substances.
Where the absolute stereochemical configuration is specified, the International Union of Pure and Applied Chemistry (IUPAC) R/S and E/Z systems of designation have been used. If the substance is an enantiomer of unknown absolute stereochemistry the sign of the optical rotation, as determined in the solvent and under the conditions specified in the monograph, has been attached to the systematic name. An indication of sign of rotation has also been given where this is incorporated in a trivial name that appears on an IUPAC preferred list.
All amino acids, except glycine, have the L-configuration unless otherwise indicated. The three-letter and one-letter symbols used for amino acids in peptide and protein sequences are those recommended by the Joint Commission on Biochemical Nomenclature of the International Union of Pure and Applied Chemistry and the International Union of Biochemistry.
In the graphic formulae the following abbreviations are used:
Me –CH3 Bus–CH(CH3)CH2CH3
Et –CH2CH3 Bun–CH2CH2CH2CH3
Pri –CH(CH3)2 But–C(CH3)3
Prn –CH2CH2CH3 Ph–C6H5
Bui –CH2CH(CH3)2 Ac–COCH3

Titles

Titles
Subsidiary titles, where included, have the same significance as the main titles. An abbreviated title constructed in accordance with the directions given in Appendix XXI A has the same significance as the main title.
Titles that are derived by the suitable inversion of words of a main or subsidiary title, with the addition of a preposition if appropriate, are also official titles. Thus, the following are all official titles: Aspirin Tablets, Tablets of Aspirin; Ginger Tincture, Tincture of Ginger; Atropine Injection, Injection of Atropine.
A title of a formulated preparation that includes the full nonproprietary name of the active ingredient or ingredients, where this is not included in the title of the monograph, is also an official title. For example, the title Promethazine Hydrochloride Oral Solution has the same significance as Promethazine Oral Solution and the title Brompheniramine Maleate Tablets has the same significance as Brompheniramine Tablets.
Where the English title at the head of a monograph in the European Pharmacopoeia is different from that at the head of the text incorporated into the British Pharmacopoeia, an Approved Synonym has been declared in accordance with section 65(8) of the Medicines Act 1968. The titles and subsidiary titles, if any, are thus official titles. A cumulative list of such Approved Synonyms is provided in Appendix XXI B.
Where the names of pharmacopoeial substances, preparations and other materials occur in the text they are printed with capital initial letters and this indicates that materials of Pharmacopoeial quality must be used. Words in the text that name a reagent or other material, a physical characteristic or a process that is described or defined in an appendix are printed in italic type, for example, methanol , absorbance, gas chromatography, and these imply compliance with the requirements specified in the appropriate appendix.

Caution Statements

Caution Statements
A number of materials described in the monographs and some of the reagents specified for use in the assays and tests of the Pharmacopoeia may be injurious to health unless adequate precautions are taken. The principles of good laboratory practice and the provisions of any appropriate regulations such as those issued in the United Kingdom in accordance with the Health and Safety at Work etc. Act 1974 should be observed at all times in carrying out the assays and tests of the Pharmacopoeia.
Attention is drawn to particular hazards in certain monographs by means of an italicised statement; the absence of such a statement should not however be taken to mean that no hazard exists.

Indicators

Indicators
Indicators, the colours of which change over approximately the same range of pH, may be substituted for one another but in the event of doubt or dispute as to the equivalence of indicators for a particular purpose, the indicator specified in the text is alone authoritative.
The quantity of an indicator solution appropriate for use in acid-base titrations described in assays or tests is 0.1 ml unless otherwise stated in the text.
Any solvent required in an assay or test in which an indicator is specified is previously neutralised to the indicator, unless a blank test is prescribed.

Reagents

Reagents
The reagents required for the assays and tests of the Pharmacopoeia are defined in appendices. The descriptions set out in the appendices do not imply that the materials are suitable for use in medicine.

Water Bath

Water Bath The term 'water bath' means a bath of boiling water, unless water at some other temperature is indicated in the text. An alternative form of heating may be employed providing that the required temperature is approximately maintained but not exceeded.

Expression of Concentrations

Expression of Concentrations
The term 'per cent' or more usually the symbol '%' is used with one of four different meanings in the expression of concentrations according to circumstances. In order that the meaning to be attached to the expression in each instance is clear , the following notation is used:
Per cent w/w (% w/w) (percentage weight in weight) expresses the number of grams of solute in 100 g of product.
Per cent w/v (% w/v) (percentage weight in volume) expresses the number of grams of solute in 100 ml of product.
Per cent v/v (% v/v) (percentage volume in volume) expresses the number of millilitres of solute in 100 ml of product.
Per cent v/w (% v/w) (percentage volume in weight) expresses the number of millilitres of solute in 100 g of product.
Usually the strength of solutions of solids in liquids is expressed as percentage weight in volume, of liquids in liquids as percentage volume in volume and of gases in liquids as percentage weight in weight.
When the concentration of a solution is expressed as parts per million (p.p.m.), it means weight in weight, unless otherwise specified.
When the concentration of a solution is expressed as parts of dissolved substance in parts of the solution, it means parts by weight (g) of a solid in parts by volume (ml) of the final solution; or parts by volume (ml) of a liquid in parts by volume (ml) of the final solution; or parts by weight (g) of a gas in parts by weight (g) of the final solution.
When the concentration of a solution is expressed in molarity designated by the symbol M preceded by a number, it denotes the number of moles of the stated solute contained in sufficient Purified Water (unless otherwise stated) to produce 1 litre of solution.

Constant Weight

Constant Weight
The term 'constant weight', used in relation to the process of drying or the process of ignition, means that two consecutive weighings do not differ by more than 0.5 mg, the second weighing being made after an additional period of drying or ignition under the specified conditions appropriate to the nature and quantity of the residue (1 hour is usually suitable).

Atomic Weights

Atomic Weights
The atomic weights adopted are the values given in the Table of Relative Atomic Weights 1989 published by the International Union of Pure and Applied Chemistry. The values are based on the carbon-12 scale (Appendix XXII).

Weights and Measures

Weights and Measures
The metric system of weights and measures is employed; SI Units have generally been adopted. Metric measures are required to have been graduated at 20°C and all measurements involved in the analytical operations of the Pharmacopoeia are intended, unless otherwise stated, to be made at that temperature. Graduated glass apparatus used in analytical operations should comply with Class A requirements of the appropriate specification issued by the British Standards Institution.

Expression of Standards

Expression of Standards
Where the standard for the content of a substance described in a monograph is expressed in terms of the chemical formula for that substance an upper limit exceeding 100% may be stated. Such an upper limit applies to the result of the assay calculated in terms of the equivalent content of the specified chemical formula. For example, the statement 'contains not less than 99.0% and not more than 101.0% of C20H24N2O2,HCl' implies that the result of the assay is not less than 99.0% and not more than 101.0%, calculated in terms of the equivalent content of C20H24N2O2,HCl.
Where the result of an assay or test is required to be calculated with reference to the dried, anhydrous or ignited substance, the substance free from a specified solvent or to the peptide content, the determination of loss on drying, water content, loss on ignition, content of the specified solvent or peptide content is carried out by the method prescribed in the relevant test in the monograph.

Official Standards

Official Standards
The requirements stated in the monographs of the Pharmacopoeia apply to articles that are intended for medicinal use but not necessarily to articles that may be sold under the same name for other purposes. An article intended for medicinal use that is described by means of an official title must comply with the requirements of the relevant monograph. A formulated preparation must comply throughout its assigned shelf-life (period of validity). The subject of any other monograph must comply throughout its period of use.
A monograph is to be construed in accordance with any general monograph or notice or any appendix, note or other explanatory material that is contained in this edition and that is applicable to that monograph. All statements contained in the monographs, except where a specific general notice indicates otherwise and with the exceptions given below, constitute standards for the official articles. An article is not of pharmacopoeial quality unless it complies with all of the requirements stated. This does not imply that a manufacturer is obliged to perform all the tests in a monograph in order to assess compliance with the Pharmacopoeia before release of a product. The manufacturer may assure himself that a product is of pharmacopoeial quality by other means, for example, from data derived from validation studies of the manufacturing process, from in-process controls or from a combination of the two. Parametric release in appropriate circumstances is thus not precluded by the need to comply with the Pharmacopoeia. The general notice on Assays and Tests indicates that analytical methods other than those described in the Pharmacopoeia may be employed for routine purposes.
Requirements in monographs have been framed to provide appropriate limitation of potential impurities rather than to provide against all possible impurities. Material found to contain an impurity not detectable by means of the prescribed tests is not of pharmacopoeial quality if the nature or amount of the impurity found is incompatible with good pharmaceutical practice.
The status of any statement given under the headings Definition, Production, Characteristics, Storage, Labelling or Action and use is defined within the general notice relating to the relevant heading. In addition to any exceptions indicated by one of the general notices referred to above, the following parts of a monograph do not constitute standards: (a) a graphic or molecular formula given at the beginning of a monograph; (b) a molecular weight; (c) a Chemical Abstracts Service Registry Number; (d) any information given at the end of a monograph concerning impurities known to be limited by that monograph; (e) information in any annex to a monograph. Any statement containing the word 'should' constitutes non-mandatory advice or recommendation.
The expression 'unless otherwise justified and authorised' means that the requirement in question has to be met, unless a competent authority authorises a modification or exemption where justified in a particular case. 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 licensing authority or an official control laboratory. For a formulated preparation that is the subject of monograph in the British Pharmacopoeia any justified and authorised modification to, or exemption from, the requirements of the relevant general monograph of the European Pharmacopoeia is stated in the individual monograph. For example, the general monograph for Tablets requires that Uncoated Tablets, except for chewable tablets, disintegrate within 15 minutes; for Calcium Lactate Tablets a time of 30 minutes is permitted.
Many of the general monographs for formulated preparations include statements and requirements additional to those of the European Pharmacopoeia that are applicable to the individual monographs of the British Pharmacopoeia. Such statements and requirements apply to all monographs for that dosage form included in the Pharmacopoeia unless otherwise indicated in the individual monograph.
Where a monograph on a biological substance or preparation refers to a strain, a test, a method, a substance, etc., using the qualifications 'suitable' or 'appropriate' without further definition in the text, the choice of such strain, test, method, substance, etc., is made in accordance with any international agreements or national regulations affecting the subject concerned.

Part II

Part II
The following general notices apply to the statements made in the monographs of the British Pharmacopoeia other than those reproduced from the European Pharmacopoeia and to the statements made in the Appendices of the British Pharmacopoeia other than when a method, test or other matter described in an appendix is invoked in a monograph reproduced from the European Pharmacopoeia.

European Pharmacopoeia

European Pharmacopoeia
Monographs of the European Pharmacopoeia are reproduced in this edition of the British Pharmacopoeia by incorporation of the text published under the direction of the Council of Europe (Partial Agreement) in accordance with the Convention on the Elaboration of a European Pharmacopoeia (Treaty Series No. 32 (1974) CMND 5763) as amended by the Protocol to the Convention (Treaty Series No. MISC16 (1990) CMND 1133). They are included for the convenience of users of the British Pharmacopoeia. In cases of doubt or dispute reference should be made to the Council of Europe text.
Monographs of the European Pharmacopoeia are distinguished by a chaplet of stars against the title and by reference to the European Pharmacopoeia monograph number included immediately below the title in italics.The beginning and end of text from the European Pharmacopoeia are denoted by means of horizontal lines with the symbol 'Ph Eur' ranged left and right, respectively.
Inclusion of a triangle within the chaplet of stars denotes monographs that have been adopted by the European Pharmacopoeia Commission following their preparation according to a procedure of harmonisation agreed between the bodies responsible for the European Pharmacopoeia and those of Japan and the United States of America.
The general provisions of the European Pharmacopoeia relating to different types of dosage form are included in the appropriate general monograph in that section of the British Pharmacopoeia entitled Monographs: Formulated Preparations. These general provisions apply to all dosage forms of the type defined, whether an individual monograph is included in the British Pharmacopoeia or not.
Texts of the European Pharmacopoeia are governed by the General Notices of the European Pharmacopoeia. These are reproduced as Part III of these notices.

Contents of the General Notices

Contents of the General Notices
Part I
Italic introduction
European Pharmacopoeia
Part II
Italic introduction
Official Standards
Expression of Standards
Temperature
Weights and Measures
Atomic Weights
Constant Weight
Expression of Concentrations
Water Bath
Reagents
Indicators
Caution Statements
Titles
Chemical Formulae
Definition
Production
Manufacture of Formulated Preparations
Freshly and Recently Prepared
Methods of Sterilisation
Water
Excipients
Colouring Agents
Antimicrobial Preservatives
Characteristics
Solubility
Identification
Assays and Tests
Biological Assays and Tests
Storage
Labelling
Action and Use
Crude Drugs
Part III
Italic introduction
General Notices of the European Pharmacopoeia
1.1 General Statements
Conventional terms

1.2 Other Provisions Applying to General Chapters and Monographs
Quantities
Apparatus and procedures
Water-bath
Drying and ignition to constant mass
Reagents
Solvents
Expression of content
Temperature
1.3 General Chapters
Containers
1.4 Monographs
Titles
Relative atomic and molecular masses
Definition
Limits of content
Vegetable drugs
Production
Characters
Solubility
Identification
Tests and assays
Scope
Calculation
Limits
Indication of permitted limits of impurities
Vegetable drugs
Equivalents
Storage
Labelling
Warnings
Impurities
Critical physical properties
Reference substances, reference preparations and reference spectra
Chemical reference substances
Biological reference preparations
Reference spectra

Volume I

contributed to this important work.
Volume I
Published on the recommendation of the Medicines Commission pursuant to the Medicines Act 1968 and notified in draft to the European Commission in accordance with Directive 98/34/EEC.
The monographs of the Fourth Edition of the European Pharmacopoeia (2001), as amended by Supplements 4.1, 4.2, 4.3, 4.4 and 4.5 published by the Council of Europe in October 2001, January 2002, June 2002, November 2002 and February 2003 respectively are reproduced either in this edition of the British Pharmacopoeia or in the associated edition of the British Pharmacopoeia (Veterinary).
See General Notices
Effective date: 1 December 2003
see Notices
London: The Stationery Office
In respect of Great Britain:
THE DEPARTMENT OF HEALTH
In respect of Northern Ireland:
THE DEPARTMENT OF HEALTH, SOCIAL SERVICES AND PUBLIC SAFETY
© Crown Copyright 2003
Published by The Stationery Office under licence from the Controller of Her Majesty's Stationery Office for the Department of Health on behalf of the Health Ministers
Printed in the United Kingdom by The Stationery Office Limited under the authority and superintendence of the Controller of Her Majesty¢s Stationery Office and Queen's Printer of Acts of Parliament
This publication is a ¢value added¢ product and falls outside the scope of the Class licensing terms offered by HMSO. Applications to reproduce this material should be made to the Licensing Division HMSO, St Clements House, 2–16 Colegate, Norwich NR3 1BQ or by e-mailing: anne.battley@cabinet-office.x.gsi.gov.uk.
First Published 2003
ISBN 0 11 322595 4
117073 C37 09/03
British Pharmacopoeia Commission Office:
Market Towers
1 Nine Elms Lane
London SW8 5NQ
Telephone: +44 (0)20 7273 0561
Fax: +44 (0)20 7273 0566
E-mail: bpcom@mhra.gsi.gov.uk
Web site: www.pharmacopoeia.org.uk
Laboratory:
Government Buildings
Block 2, Honeypot Lane
Stanmore
Middlesex HA7 1AY
Telephone: +44 (0)20 7972 1040
Fax: +44 (0)20 8951 3069
E-mail: queries@bpclab.co.uk
Web site: www.bpclab.co.uk

Preface

Preface
The British Pharmacopoeia 2003 is published for the Health Ministers on the recommendation of the Medicines Commission in accordance with section 99(6) of the Medicines Act 1968.
The Medicines Commission believes that the British Pharmacopoeia contributes significantly to the overall control of the quality of medicinal products by providing an authoritative statement of the quality that a product is expected to meet at any time during its period of use. The Pharmacopoeial standards, which are publicly available and legally enforceable, are designed to complement and assist the licensing and inspection processes and are part of the system for safeguarding purchasers and users of medicinal products.
The Medicines Commission wishes to record its appreciation of the services of all those who have contributed to this important work.

Effective dates

Effective dates
New and revised monographs of national origin enter into force on 1 December 2003. Monographs of the European Pharmacopoeia have previously been published by the Council of Europe and have been brought into effect by means of Notices published in the Belfast, Edinburgh and London Gazettes.

Patents

Patents
In this Pharmacopoeia certain drugs and preparations have been included notwithstanding the existence of actual or potential patent rights. In so far as such substances are protected by Letters Patent their inclusion in this Pharmacopoeia neither conveys, nor implies, licence to manufacture.

Effective dates

Effective dates
New and revised monographs of national origin enter into force on 1 December 2003. Monographs of the European Pharmacopoeia have previously been published by the Council of Europe and have been brought into effect by means of Notices published in the Belfast, Edinburgh and London Gazettes.
Monographs of the European Pharmacopoeia are distinguished by a chaplet of stars against the title. The term European Pharmacopoeia, used without qualification, means the fourth edition of the European Pharmacopoeia comprising, unless otherwise stated, the main volume, published in 2001 as amended by any subsequent supplements and revisions.

Patents

Patents
In this Pharmacopoeia certain drugs and preparations have been included notwithstanding the existence of actual or potential patent rights. In so far as such substances are protected by Letters Patent their inclusion in this Pharmacopoeia neither conveys, nor implies, licence to manufacture.

Consultative Groups

Consultative Groups
L: Surgical materials
J M Midgley (Chairman), A Austin, G J Collyer, D J Harris, D Metcalfe, P Newlands, M Parkin, S Thomas
R: Radioactive materials
S R Hesslewood, D Lui, A M Millar, R D Pickett, A E Theobald, S Waters
Current members of staff of the Commission who have taken part in the production of this edition include:
Secretariat
M Vallender, F J Swanson, R Middleton, R A Pask-Hughes, P Holland
Laboratory
A Islam, D C Brougham, R L Turner, T Morarji, C M Shah, R Mannan, V Pathak, M Barrett, W Jeffries
Administrative
A C Chapman, B F Delahunty, T Garrett
Notices
Monographs of the European Pharmacopoeia are distinguished by a chaplet of stars against the title. The term European Pharmacopoeia, used without qualification, means the fourth edition of the European Pharmacopoeia comprising, unless otherwise stated, the main volume, published in 2001 as amended by any subsequent supplements and revisions.

Committees

Committees
A: Medicinal chemicals
N Randall (Chairman), G D Rees (Vice-Chairman), L Anderson, A L Barber, T G Beaumont, J C Berridge, A C Caws, A G Davidson, W J Lough, A J Woolfe
B: Medicinal chemicals
J M Midgley (Chairman), F Breslin, H B Davis, T D Duffy, B M Everett, A J Hutt, M A Lee, B Midcalf, S A Norton, M Turgoose
C: General Chemicals
J M Midgley (Chairman), J A Goldsmith (Vice-Chairman), S K Branch, A C Cartwright, B M Everett, C T Goddard, P Henrys, D J Malpas, C Mroz, I D Newton, J Seaton
D: Medicinal chemicals
J A Goldsmith (Chairman), J F Chissell (Vice-Chairman), W J Mossop, R A Packer, G F Phillips, W J Poling, W K L Pugh, G Skellern, A A Wagland, I R Williams
E: Antibiotics
G D Rees (Chairman), D H Calam (Vice-Chairman), J F Chissell, J Dolman, A M French, K J Leiper, W Mann, W F H McLean, C G Taylor, I R Williams
G: Crude drugs and galenicals
A C Moffat (Chairman), L A Anderson (Vice-Chairman), A G Davidson, K Helliwell, P J Houghton, B P Jackson, P Linley, W F H McLean, J D Phillipson, E Williamson
H: Biological materials
D H Calam (Chairman), N Randall (Vice-Chairman), K J Ayling, T W Barrowcliffe, A F Bristow, B Cuthbertson, T Forsey, P Sheppard, T J Snape, W J Tarbit, L Tsang
(Corresponding members S Poole, L W Whitehouse)
J: Immunological products
A M T Lee (Chairman), A H Andrews, M J Corbel, M A Dow, I G S Furminger, A M Pickett, A H Thomas, P W Wells
(Corresponding members E Griffiths, M L Kavanagh)
M: Microbiology
R J Pinney (Chairman), V Fenton-May (Vice-Chairman), B Alexander, R Baird, A L Davison, D P Hargreaves, W L Hooper, R Johnson, B R Matthews, W F H McLean, M P Summers
N: Nomenclature
M A Simmonds (Chairman), D H Calam (Vice-Chairman), J K Aronson, D Cousins, E W Godly, P W Golightly, H McNulty, D K Mehta, G P Moss, G F Phillips, R Thorpe
(Corresponding members R G Balocco Mattavelli, E M Cortés Montejano)
P: Pharmacy
A D Woolfson (Chairman), R Horder (Vice-Chairman), G Davison, G Eccleston, M C R Johnson, B R Matthews, S C Nichols, G Smith, M P Summers, J D Tovey, R Withington, P Wood

British Pharmacopoeia Commission

The British Pharmacopoeia Commission is appointed by the Health and Agriculture Ministers, that is to say in respect of England, Scotland and Wales the Secretary of State concerned with health in England and the Secretary of State concerned with the Environment, Food and Rural Affairs and in respect of Northern Ireland the Minister of Health, Social Services and Public Safety and the Minister of Agriculture and Rural Development, acting jointly, in exercise of their powers under section 4 of the Medicines Act 1968.
The duties of the British Pharmacopoeia Commission are as follows:
(a) the preparation under section 99(1) of the Act of any new edition of the British Pharmacopoeia;
(b) the preparation under section 99(1) of the Act, as given effect by section 102(1) thereof, of any amendments of the edition of the British Pharmacopoeia published in 1968 or any new edition of it;
(c) the preparation under section 100 of the Act (which provides for the preparation and publication of lists of names to be used as headings to monographs in the British Pharmacopoeia) of any list of names and the preparation under that section as given effect by section 102(3) of the Act of any amendments of any published list;
(d) the preparation under section 99(3)(b) of the Act of any compendium or any new edition thereof;
(e) the preparation under section 99(3)(b) of the Act, as given effect by section 102(1) thereof, of any amendments to any such compendium.
Members of the British Pharmacopoeia Commission are appointed by Ministers, having regard to recommendations made by the Medicines Commission. Appointments are usually for a (renewable) term of 4 years.
Membership of the British Pharmacopoeia Commission. The list below includes those members who served during the period 2002 to 2003.
Chairman
Professor Derek H Calam OBE MA DPhil CChem FRSC FRSA HonMRPharmS HonMBIRA
Visiting Professor of Pharmaceutical Sciences, University of Strathclyde; formerly European Co-ordinator, National Institute for Biological Standards and Control
Vice-Chairman
Professor John A Goldsmith BSc PhD CChem FRSC FIQA
Visiting Professor, University of Strathclyde; formerly a Director of Technical Operations, Roche
Dr Anthony H Andrews BVetMed PhD MRCVS
Veterinary Consultant
Professor Graham Buckton BPharm PhD DSc AKC FRPharmS CChem FRSC
Professor of Pharmaceutics; School of Pharmacy, University of London
Mrs Margaret A Dow MSc MRPharmS
Consultant in the regulation of biological and biotechnological products
Dr Thomas D Duffy BSc PhD FRPharmS CChem MRSC FIQA MRQA
Consultant in quality management systems, quality assurance and training in production, development and QC Laboratories; formerly Head of the Medicines Testing Laboratory
Mr V'Iain Fenton-May BPharm MI PharmM FRPharmS
Specialist Quality Controller to the Welsh Hospitals
Dr Rodney L Horder BPharm PhD MRPharmS
Vice President, Global Pharmaceutical R & D Quality Assurance, Abbott Laboratories
Dr Aileen M T Lee BVMS PhD MRCVS
Member of the Veterinary Medicines Directorate
Specialism: Regulation of Veterinary Immunological Products
Professor John M Midgley OBE BSc MSc PhD FRPharmS CChem FRSC
Emeritus Professor of Pharmaceutical and Medicinal Chemistry, University of Strathclyde
Professor Anthony C Moffat BPharm PhD DSc CChem FRSC FRPharmS FCPP
Chief Scientist, Royal Pharmaceutical Society of Great Britain; Royal Pharmaceutical Society Professor, School of Pharmacy, University of London
Professor John O'Grady MD FRCP FFPM FBIRA
Medical Director for Europe, Daiichi Pharmaceutical Company
Dr Norman Randall PhD CChem FRSC FIQA
Consultant in Quality Assurance; formerly a Director of Quality Assurance, Aventis
Dr Gareth D Rees BPharm PhD MRPharmS CChem MRSC FIQA
A Director of Quality Assurance, Wyeth Europa
Professor David Woolfson BSc PhD CChem FRSC MPSNI
Professor of Pharmaceutics, Queens University of Belfast
Secretary and Scientific Director
Dr Gerard Lee BPharm PhD FRPharmS MRSC CChem
Membership of Committees and Consultative GroupsThe Commission appointed the following Committees and Corresponding Consultative Groups to advise it in carrying out its duties. Membership has changed from time to time; the lists below include all who have served during the period 2002 to 2003.

MAIN STEAM SYSTEM

Diagram
- Main Steam System P&ID YJE M VVP FD221
1 FUNCTION
The main steam system provides routing of the NSSS steam from downstream the steam generator MSIVs located in the valve compartments to the main turbine and to the following components :
- MSRs 2nd-stage reheater (normal supply) (GSS),
- turbine bypass (GCT),
- turbine gland seal (CET),
- feedwater storage tank (steam backup) (ADG),
- steam transformer (STR) (if any) and,
- vacuum ejectors (CVI).
2 DESIGN BASES
The main steam pipes material and dimensions are calculated according to ASME Standard.
Design pressure : 100 bar abs Design temperature : 311 °C
3 DESCRIPTION
The main steam piping system comprises four main steam lines (one for each steam generator), pressure equalizing and auxiliary supply connecting pipes, drain pipes and drain tanks.
The main steam pipes are connected together for pressure equalizing and supply the steam turbine HP casing through the four main stop and control valve assemblies.
Pipe connections are provided on the main steam supply system for :
- heating steam supply to the 2nd-stage reheater of the MSRs (GSS),
- turbine bypass to the condenser (GCT),
^

Appendix 5.2.11 Main Steam System
- HP steam supply to the turbine gland seal system (CET), feedwater storage tank main steam backup (ADG),
- steam transformer (STR) (if any) and,
- condenser vacuum ejectors (CVI),
The following drains are recovered in drain tanks, as follows :
- from upstream each steam generator isolation valve to the turbine hall drain system or to the turbine condenser during hot shutdown, hot standby and pipe warmup.
- from the main steam supply pipes and the turbine bypass pipes via a drain tank to
the turbine condenser during pipe warmup and normal operation.
Startup drains are evacuated via the drain tank through an automatic drain valve.
During normal operation, the drains from the main steam pipes are continuously evacuated via the drain tank through a drain trap bypassing the drain valve.
Each main steam pipe is fitted with pressure taps, thermowells and sampling taps. Metal temperature transmitters allow the temperature increase rate to be monitored from the main control room during the pipe warmup phase.
Pressure measurement transmitters are also provided on the main steam supply for the turbine bypass.
4 EQUIPMENT LOCATION
The main steam pipes come in the axis of the steam turbine and cross the turbine hall wall at a level of approximately 13.900 m.
They spread out to the turbine into expansion loops and come up towards the main stop valves located on the turbine floor.
The drain tanks are located in the turbine hall at an elevation that allows proper drainage by gravity flow from the drain extraction points. Drain discharge valves and drain traps are located in the vicinity of the condenser HP flash compartment.
#- A

Appendix 5.2.11 Main Steam System

TABLE 21

MAIN STEAM SYSTEM DESIGN DATA



Main steam pipes within turbine plant
- number of pipes
- design pressure
- design temperature
- material
- outside diameter
- thickness
- mass flow, each
- main steam velocity in pipes
- moisture content at NI/CI interface

100 bar a
311 °C
A672B60CL22
813 mm
39 mm
652.4 kg/s
39 m/s
0,4 %



APPENDIX 5.2.12
TURBINE BYPASS SYSTEM






Appendix 5.2.12 Turbine Bypass System
Diagram
- Turbine Bypass System P&ID YJE M GCT FD411
1 FUNCTION
The turbine bypass system provides an artificial load for the NSSS during turbine transient operations which exceed normal NSSS capability by discharging HP steam directly to the turbine condenser.
It expands and desuperheats steam before its admission into the condensation zone of the condenser.
2 DESIGN BASES
The turbine bypass system is designed for a capacity of 60 % of the rated steam flow at the rated steam pressure. It allows turbine sudden load reduction from full load to house load, without actuation of the steam generator overpressure protection devices and opening of the pressurizer relief valves.
The six pressure reducing valves are capable, when combined, to handle the total bypass flow.
3 DESCRIPTION
The turbine bypass performs the following functions:
- allow turbine trip without incurring a reactor trip, or reactor trip without actuation of the main steam relief control valves or lifting of the steam generator safety valves,
- remove stored energy and residual heat from the reactor coolant system to bring coolant average temperature (TAVG) to no load temperature,
- maintain the reactor coolant temperature at the no load con-ditions, during hot shutdown,
- allow reactor coolant system controlled cooldown from hot shutdown conditions until startup of the residual heat removal system,
- at startup, allow heat up of the main steam pipes and turbine run up and loading up over the manual rod control range.
The turbine bypass system is composed of one steam manifold connected to the main steam piping system and six pressure reducing valves. These valves discharge steam into the condenser. Valve flow characteristics are linear. The valves are arranged in
#~

Appendix 5.2.12 Turbine Bypass System
parallel, so that when combined the required bypass flow is produced. All valves are interlocked and controlled to prevent operating modes which may have adverse consequences on plant safety and to protect the condenser against overpressure.
The steam is discharged into the condenser through expansion compartments integral with the condenser. These expansion compartments are supplied with desuperheating water taken at the condensate extraction pump discharge through on-off pneumatically-operated valves.
OPERATION
Detailed description of the turbine bypass control system is given by the nuclear island designer.
EQUIPMENT LOCATION
The turbine bypass manifold runs alongside the condenser at a level of approximately 9,600 m. The pressure reducing valves spread out from this manifold in front of the condenser wall.

\

4t~

Appendix 5.2.12 Turbine Bypass System

TABLE 23

TURBINE BYPASS SYSTEM DATA



TURBINE BYPASS TO THE CONDENSER
Bypass pipes (upstream bypass control valves)
- number
- design pressure
- design temperature
- material
- outside diameter
- thickness
- mass flow, max each

6 100 bar a
311°C
A106GrB
406.4 mm
26.19 mm
286 kg/s



Pressure reducing control valves
- number

EnSeal® Tissue Sealing Device Instruments, Generator and Footswitch

Product Codes:
NSEAL514H, NSEAL514RH, NSEAL525H, NSEAL525RH, NSEAL535H,
NSEAL535RH, NSEAL545H, NSEAL545RH, ETRIO314H, ETRIO325H, ETRIO335H,
ETRIO345H, NSEAL514E, NSEAL514RE, NSEAL525E, NSEAL525RE, NSEAL535E,
NSEAL535RE, NSEAL545E, NSEAL545RE, ETRIO314E, ETRIO325E, ETRIO335E,
ETRIO345E, RF60 and EEF
1. Description, Function, Intended Medical Usage
The EnSeal® Tissue Sealing System consists of disposable instruments and an
electrosurgical generator and footswitch. The EnSeal disposable devices are tubular
instruments with grasping jaws at the distal end, which are actuated by a handle at the
proximal end of the device. The distal end contains bipolar electrodes for sealing vessels,
and a mechanical cutting blade for transecting vessels and soft tissues. EnSeal device
jaws are unique in that they have a patented jaw design that allows for uniform
compression and temperature control. Devices are provided sterile and are intended for
single use only. An electrical cable connects the device to the electrosurgical
radiofrequency generator. The radiofrequency generator supplies power to the EnSeal
disposable instruments. The EnSeal devices with TAPtronic have a handswitch for power
activation which allows the user an alternative to footswitch power activation.
The EnSeal device jaws employ a unique bipolar technology which provides various
enhanced tissue sealing effects. The active electrode is contained within the jaw
mechanism, unexposed to surrounding tissues, with the jaw itself as the return path. The
jaws grasp, enclose, and compress the tissue while current is directed only to the tissue
captured within the jaws. Less heat is required to obtain a seal as the tissue volume is
minimized through compression, energy is focused on the captured, tissue, and the vessel
is reformed through compression into a secure seal. This technology also provides
temperature control to minimize undesirable thermal effects. As the tissue begins to
desiccate, the electrode maintains the conductive path and the current continues to flow at
the proper temperature required to achieve an effective seal. The cutting mechanism is in
the shape of an ―I‖-beam, referred to as the I-Blade™. The I-Blade provides additional
compression to the tissue in order to enhance seal-ability as the blade is advanced along
the length of the jaw.
EnSeal devices have a 360° rotatable shaft and are available in a 5mm shaft diameter, and
various shaft lengths (14cm, 25cm, 35cm, and 45cm), as well as a variety of tip
configurations which include a 5mm dia. Standard Tip (with 90° jaw corner and grasping
rat tooth), 5mm dia. Round Tip, and 3mm dia. TRIO (with curved jaw).
The EnSeal devices are powered by EnSeal generators RF60. The EnSeal® RF-60
Generator is 100V/240V is 50/60Hz input microprocessor controlled quasi-sinusoidal
waveform, 60W maximum output electrosurgical radiofrequency generator (RFG). The
EnSeal® RF60 Generator controls and monitors the RF energy transmission to the tissue
through the EnSeal® Tissue Sealing Device (EnSeal Device). An electrical cable
connects the EnSeal instrument to the radiofrequency generator.
There is an Erbe Generator call the VIO 300D. EnSeal devices that work with the Erbe
VIO have a unique cable (8 pin), and require a special adapter (provided by Erbe). These
Erbe functional devices are designated with special product codes ending in the letter
―E‖. Erbe generators are sold in Europe.
Lifetime or Shelf life of the product --No assigned shelf life, Lifetime is 3 years from the
date of manufacture
RF60 Generator Package Includes RF Generator, IFU, power cord, and footswitch

hydrophobia; rabies

Rabies
　　Definition
　　Rabies is a frequently fatal, acute viral infection which is transmitted to humans by infected animals (often dogs or bats) via a bite or by the exposure of broken skin to an infected animal's saliva.
　　Causes, incidence, and risk factors
　　Rabies is transmitted by infected saliva that enters the body through a bite wound or other open wound. The virus travels from the wound along nerve pathways to the brain, where it causes inflammation (irritation and swelling with presence of extra immune cells) that results in the symptoms of the disease.
　　The incubation period ranges from 10 days to 7 years, with the average being 3 to 7 weeks.
　　In the past, human cases in the U.S. usually resulted from a dog bite, but recently, more cases of human rabies have are linked to bats and there have not been any rabies cases caused by dog bites for a number of years.
　　Worldwide, dogs still pose a significant risk for transmitting rabies, however. Bats, skunks, raccoons, foxes, and other animals can also be sources of rabies virus. There are an estimated 15,000 cases of rabies worldwide each year.
　　Few cases occur in the US (only 3 reported in 1991 and 9 in 1994) because of extensive animal vaccination programs.
　　The United Kingdom has completely eradicated rabies, which is why Americans cannot bring pets or other animals to the UK without having them undergo a 6-month quarantine.Symptoms
　　* low-grade fever (102 degrees F or lower)
　　* pain at the site of the bite
　　* exaggerated sensation at the bite site
　　* swallowing difficulty (drinking produces spasms of the larynx) or swallowing difficulty with liquids only
　　* restlessness
　　* excitability
　　* muscle spasms
　　* convulsions
　　* numbness and tingling
　　* loss of muscle function
　　* loss of feeling in an area of the body
　　* drooling
　　* anxiety, stress, and tension
　　* positive Babinski's reflex
　　Signs and tests
　　If a person has a history of animal bite, the animal will be observed for signs of rabies. Immunofluorescence (fluorescent antibody test) or necropsy (after death) performed on the suspect animal may show that the animal has rabies.Treatment
　　Clean the wound well with soap and water and seek professional care after sustaining an animal bite. Try to gather as much information about the animal as possible. Contact local animal control authorities to confine suspect animals for observation and examination if rabies is suspected.
　　Thorough cleaning and removal of foreign objects (debridement) from the wound is needed. Animal bite wounds usually should not be sutured. A passive immunization by human rabies immune globulin as well as immunization with a vaccine may be given if there is any risk of rabies.
　　Expectations (prognosis)
　　If immunization is given within 2 days of the bite, rabies is usually prevented. To date, no one in the U.S. has yet developed rabies when given the vaccine promptly and appropriately.
　　Once the symptoms appear, few people survive the disease. Death from respiratory failure usually occurs within 7 days of symptom onset.
　　Complications
　　* allergic reaction to rabies vaccine (rare)
　　Calling your health care provider
　　Go to the emergency room or call the local emergency number (such as 911) if you are bitten by a wild or domestic animal and suspect rabies may develop.
　　Prevention
　　Prevention depends upon enforcement of the following public health policies:
　　* vaccination of dogs and cats every 2 years in areas of the United States where rabies exists in wild animals
　　* avoiding contact with animals not known to you
　　* vaccination of people in high-risk occupations or certain travelers
　　* quarantine regulations on importing dogs and other mammals in disease-free countries
　　Update Date: 7/16/2004
　　Updated by: Daniel Levy, M.D., Ph.D., Infectious Diseases, Greater Baltimore Medical Center, Baltimore, MD. Review provided by VeriMed Healthcare Network.

A clinical trial comparing pantoprazole and esomeprazole to explore the concept of achieving ‘complete remission’ in gastro-oesophageal reflux disease

SUMMARY
Background and Aim
The outcome of gastro-oesophageal reflux disease treatment is traditionally
assessed by measuring endoscopically confirmed healing and
symptom relief separately. Both terms together, indicating complete
remission, are intuitively a more realistic clinical endpoint but are
assessed less often.
Aim
To explore this concept, we formally compared the efficacy of the proton
pump inhibitors (PPIs) pantoprazole and esomeprazole using rates
of complete remission judged against rates of healing and symptom
relief separately.
Methods
Five hundred and eighty-two patients with erosive gastro-oesophageal
reflux disease were randomized to treatment for 4, 8, or 12 weeks with
either pantoprazole or esomeprazole 40 mg daily. Symptom relief was
assessed with the validated ReQuestTM-GI subscale.
Results
Approximately 75% of patients were free of symptoms or had no oesophageal
lesions after 4 weeks’ treatment, rising to about 93% and 96%,
respectively, at 12 weeks. Complete remission rates were, however,
lower at these time points; approximately 60% and about 90%, respectively.
Both PPIs had similar efficacy.
Conclusions
Endoscopically confirmed healing and symptom relief assessed separately
over-estimated the benefits of both drugs. In contrast, complete
remission indicates that patients may be treated inadequately when
given the standard 4- to 8-week treatment. We suggest that complete
remission is a more reliable and clinically relevant endpoint of treatment.
Aliment Pharmacol Ther 25, 1461–1469

Universal Method Facilitating the Amplification of Extremely GC-Rich DNA Fragments from Genomic DNA

Maochen Wei,†,‡ Jing Deng,†,‡ Kun Feng,†,‡ Boyang Yu,† and Yijun Chen*,†,‡,§
Laboratory of Chemical Biology and Jiangsu Provincial Key Laboratory of Molecular Targeted Antitumor Drug Research, China Pharmaceutical University, Nanjing, People’s Republic of China, and Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey

Polymerase chain reaction (PCR) is a basic technique with
wide applications in molecular biology. Despite the development
of different methods with various modifications,
the amplification of GC-rich DNA fragments is
frequently troublesome due to the formation of complex
secondary structure and poor denaturation. Given the fact
that GC-rich genes are closely related to transcriptional
regulation, transcriptional silencing, and disease progression,
we developed a PCR method combining a stepwise
procedure and a mixture of additives in the present work.
Our study demonstrated that the PCR method could
successfully amplify targeted DNA fragments up to 1.2
Kb with GC content as high as 83.5% from different
species. Compared to all currently available methods, our
work showed satisfactory, adaptable, fast and efficient
(SAFE) results on the amplification of GC-rich targets,
which provides a versatile and valuable tool for the
diagnosis of genetic disorders and for the study of functions
and regulations of various genes.
Most tumor-suppressor genes, housekeeping genes, and approximately
40% of tissue-specific genes in their promoter regions
contain high GC content,1 and 28% of genes in the human genome
are located in GC-rich regions.2 The GC-rich genes in these
regions are closely related to transcriptional regulation, transcriptional
silencing, and disease progression. Therefore, study of GCrich
regions is of great interest to biological and clinical investigations.
To study the function and regulation of various genes of
interest, amplification of related genes typically is an essential and
necessary step. Polymerase chain reaction (PCR) is a powerful
technique to amplify DNA fragments but needs specific adjustments
to amplify GC-rich DNA fragments (usually greater than
60%) due to complex secondary structures and poor denaturation
resulting in the formation of short and nonspecific DNA fragments
instead of the desired products.3-5
To amplify GC-rich templates, several approaches have been
attempted with different additives and PCR procedures. For
example, addition of chemical reagents, such as dimethylsulfoxide
(DMSO),6 glycerol,7 sulfoxide,8,9 betaine,10 and 7-deaza-dGTP11
and combinations of betaine and DMSO12-14 or DMSO, betaine,
and 7-deaza-dGTP,15 have shown promises to improve the amplification
of GC-rich templates to some extent. However, the
performance of these additives alone has been unsatisfactory
without further modification of the PCR procedures. On the other
hand, “Slowdown PCR”11 and “Two-Step PCR”16 exhibit superiority
in amplifying GC-rich sequences. Unfortunately, when dealing with
extremely GC-rich (greater than 80%) fragments, none of them
was able to provide adequate results. To the best of our
knowledge, the only successful example for amplifying target
DNA, which is located in the 5′ noncoding region of the Gas
subunit of heterotrimeric G protein (GNAS1) (GenBank Accession
No. M21139), with GC content of 83%, was a combination of
“Slowdown PCR” and 7-deaza-dGTP. However, this method did
not work on the amplification of the same gene longer than 250
bp.11 Thus, current PCR protocols have considerably limited the analyses of genotype and phenotype in the extremely GC-rich
regions, and there is a high demand for a new protocol to conquer
such a problem.

Cancer Risk Assessment

Restylane gel contains 1,4-butanediol diglycidyl ether (BDDE), a compound that
has been shown to be mutagenic in various assay systems and may have been
associated with tumor formation in mice following topical application in one study.
Consequently, it is prudent to assess the potential carcinogenic risk of BDDE in
patients who receive injections of Restylane gel. The excess cancer risk in
humans was determined using two approaches: 1) simple linear extrapolation of
the dose associated with 10-6 risk from the tumor incidence at the lowest dose of
BDDE that produced an increased tumor incidence in the mouse study, with
conversion of this dose to a human equivalent dose; and 2) use of doseresponse
models to estimate the 10% tumor incidence, with subsequent
application of uncertainty factors to estimate the dose associated with 10-6 risk in
humans. The human equivalent doses associated with 10-6 excess cancer risk
derived using either approach were then compared to the dose of BDDE
estimated to be received by patients treated with Restylane.