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British Pharmacopoeia (Veterinary) 2013

Prepared by the British Pharmacopoeia Commission, published in accordance with Section 99(6) of The Medicines Act 1968 and notified in draft to the European Commission in accordance with Directive 98/34/EEC.

The monographs of the Seventh Edition of the European Pharmacopoeia (2010), as amended by Supplements 7.1 to 7.5, published by the Council of Europe are reproduced either in this edition of the British Pharmacopoeia (yeterinary) or in the associated edition of the British Pharmacopoeia.

see General N atices

Effective date: 1 January 2013

see Natices

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 2012

Published by The Stationery Office on behalf of the Medicines and Healthcare products Regulatory Agency (MHRA) except that:

European Pharmacopoeia monographs are reproduced with the permission of the Council of Europe and are not Crown Copyright. These are identified in the publication by a chaplet of stars.

This publication is a 'value added' producto If you wish to re-use the Crown Copyright material from this publication, applications must be made in writing, clearly stating the material requested for re-use, and the purpose for which it is required. Applications should be sent to: British Pharmacopoeia Secretariat, MHRA, 5th Floor, 151 Buckingham Palace Road, London SWIW 9SZ.

First Published 2012

ISBN 978 011 3229 239

British Pharmacopoeia Commission Office: MHRA 151 Buckingham Palace Road London SWl W 9SZ Telephone: +44 (0)20 3080 6561 E-mail: bpcom@mhra.gsi.gov.uk Web site: http://www .mhra.gov. uk/pharmacopoeia

Laboratory: ' British Phrm'acopoeia Commission Laboratory Queen's Road Teddington Middlesex TWll OLY Telephone: +44 (0)20 8943 8960 Fax: +44 (0)20 8943 8962 E-mail: bpcrs@mhra.gsi.gov.uk Web site: http://www.mhra.gov.uk/pharmacopoeia

Contents

NOTICES

PREFACE

BRITISH PHARMACOPOEIA COMMISSION

EXPERT ADVISORY GROUPS, Pl\NELS OF EXPERTS AND WORKING PARTIES

CODE OF PRACTICE

MEMBERSHIP

BP Commission, EAGs, Panels and W orking Parties

STAFF

British Pharmacopoeia, BP Laboratory, Publisher

INTRODUCTION

Additions, Omissions, Technical Changes, Reference Substances

GENERAL NOTICES

MONOGRAPHS

Medicinal and Pharmaceutical Substances

Formulated Preparations: General Monographs

Formulated Preparations: Specific Monographs

Immunological Products

Surgical Materials

INFRARED REFERENCE SPECTRA

APPENDICES

INDEX

vi

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 Seventh Edition of the European Pharmacopoeia comprising, unless otherwise stated, the main volume, published in 2010, as amended by any subsequent supplements and revisions.

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 New and revised monographs of national origin enter into force on 1 January 2013. Monographs of the European Pharmacopoeia have previously been published by the Council of Europe and have been brought into effect by means of N otices published in the Belfast, Edinburgh and London Gazettes.

Preface

The British Pharmacopoeia (Veterinary) 2013, a companion volume to the British Pharmacopoeia 2013, is prepared by the British Pharmacopoeia Commission ap.d is published for Ministers in accordance with Section 99(6) of The Medicines Act 1968. The British Pharmacopoeia Commission believes that the British Pharmacopoeia (Veterinary) contribut~s significantly to the overall control of the quality of materials used in the practice of veterinary medicine, by providing an authoritative statement of the quality that a product, material or article 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 pro ces ses and are part of the system for safeguarding animal and human health.

The British Pharmacopoeia Commission wishes to record its appreciation of the services of all those who have contributed to the preparation of this work.

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viii

British Pharntacopoeia Contntission

The British Pharmacopoeia Commission is appointed, on behalf of the Secretary of State for Health, by the Appointments Commission, the body responsible for appointments to all of the Medicines Act 1968 Advisory Bodies.

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(6) of the Act, of any compendium, or any new edition thereof, containing information relating to substances and articles which are or may be used in the practice of veterinary medicine or veterinary surgery;

( e) to frame clear and unequivocal technical advice in order to discharge the Commission's responsibilities both for the British Pharmacopoeia, the British Pharmacopoeia (Veterinary) and British Approved N ames and as the national pharmacopoeial authority with respect to the European Pharmacopoeia.

Members of the British Pharmacopoeia Commission are appointed for a (renewable) term of 4 years and, under the requirements laid down by the Office of the Commissioner for Public Appointments, can serve for a maximum of 10 years.

Expert Advisory Groups, Panels of Experts and W orking Parties

Members of Expert Advisory Groups, Panels of Experts and W orking Parties are appointed by the British Pharmacopoeia Commission.

The duties of the members are as fol\ows:

(a) To collaborate in the preparati6n and revision of Monographs, Appendices and Supplementary Chapters for inclusion in the British Pharmacopoeia and British Pharmacopoeia (Veterinary).

(b) To collaborate in the preparation and revision of Monographs, Methods and General Chapters of the European Pharmacopoeia.

(c) To review reports from the British Pharmacopoeia Laboratory in terms of technical content and, where possible, provide independent experimental data to assist in decision making.

(d) To collaborate in the preparation and revision of the list of names to be used as titles for monographs of the British Pharmacopoeia and British Pharmacopoeia (Veterinary).

Members of Expert Advisory Groups, Panels of Experts and W orking Parties are usually appointed for a (renewable) term of 4 years.

IX

x

Code of Practice

Members of the British Pharmacopoeia Commission and its supporting Expert Advisory Groups, Panels of Experts and W orking Parties are required to comply with aCode of Practice on Declaration of Interests in the Pharmaceutical Industry.

British Pharmacopoeia Commission

Chairs and members of the British Pharmacopoeia Commission are required to make a full declaration of interests on appointment and annually thereafter. They must also inform the BP Secretariat promptly of any changes to these interests during the year. These interests are published in the Medicines Act 1968 Advisory Bodies Annual Reports which is available via the MHRA website (http://www.mhra.gov.uk). Relevant interests must be declared at meetings and are recorded in the Minutes.

Expert Advisory Groups, Panels ofExperts and Working Parties

Chairs and members are required to make a full declaration of interests on appointment and to update the Secretariat if these interests change during their term of office. A record is kept of those experts who have declared specific interests, but these are not published.

Relevant interests must be declared at meetings and are recorded in the Minutes.

Metnbership of the British Phartnacopoeia Cotntnission

The list below ,includes those members who served during the period 2011 to 2012" \

Chair Professor David Woolfson BSe PhD CChem FRSC FPSNI Professor of Pharmaceutics, Queens Univ~rsity of Belfast

Vice-Chair Mr V'Iain Fenton-May BPharm MIPharmM FRPharmS Former Specialist Quality Controller to the Welsh Hospitals

Professor Graham Buekton l BPharm PhD DSe AKC FRPharmS CChem FRSC Professor of Pharmaceuticsj School of Pharmacy, University of London Professor Donald Cairns BSe PhD MRPharmS CSei CChem FRSC Head: School of Pharmacy and Lije Sciences, Robert Gordon University, Aberdeen

Mr Barry Capon CBE MA DL (Lay representative) Non-executive Director, Norfolk and Waveney Mental Health NHS Foundation Trust

Dr Graham D Cook BPharm PhD MRPharmS Senior Director, Process Knowledge/Quality by Design, Pjizer Mr Andrew Coulson2 BVetMed MSe MRCVS Member of the Royal College of Veterinary Surgeonsj former Superintending Inspector, Science & Research Group, The Home Office Professor Alastair Davidson BSe PhD FRPharmS Visiting Professor of Pharmaceutical Sciences, University of Strathclyde Dr Thomas D Duffy BSe PhD FRPharmS CChem MRSC FCQI CQP MRQA Director, Lowden International (providz"ng consultancy and trainz"ng to pharmaceutical organisations)

Mr Christopher Goddard BSe DIS CSei EurChem CChem FRSC Quality Control Technical Manager, Recipharm Limited

Dr Keith Helliwell BPharm PhD MRPharmS Senior Technical Adviser, William Ransom & Son PLC

Dr Rodney L Horder BPharm PhD MRPharmS Former Divisional Vice President, European Quality and Regulatory Strategy, Abbott

Dr Gerard Lee2 BPharm PhD FRPharmS MRSC CChem Former Group Manager of the British Pharmacopoeia and Laboratory Services Section, MHRAj former Secretary & Scientific Director of the British Pharmacopoeia Commission

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xii

Dr Brian R Matthews BPharm PhD FRPharmS FTOPRA MRI Consultant on pharmaceutical and medical device regulatory affairs)' former Senior Director) BC Registration) Aleon Laboratories

Professor John Miller2 MSc PhD MRSC CChem Visiting Professor) Strathclyde Institute of Pharmacy and Biomedical Sciences)' former Head of the BDQM Laboratory Dr Ronald Torano2 BSc PhD MRSC CChem Pharmacopoeial Intelligence and Advisory Specialist) GlaxoSmithI

ABS: Antibiotics

HCM: Herbal and Complementary

Medicines

MC1: Medicinal Chemicals

MC2: Medicinal Chemicals

MC3: Medicinal Chemicals

NOM: Nomenclature

PCY: Pharmacy

ULM: Unlicensed Medicines

Metnbership of Exp~rt Advisory Groups, Panels of E,tperts and W orking Parties

The Commission appointed the following Expert Advisory Groups, Panel s of Experts and Working Parties to ad\7i~e it in carrying out its duties. Membership has changed from time to:' time; the lists below include all who have served during the period 2011 to 2012.

EXPERT ADVISORY GROUPS R L Horder (Chair), G Cook (Vice-Chair), P Ellis, V Jaitely, P Jones, A Livingstone, W Mann, J Miller, N Thomas, B White, 1 R Williams

E Williamson (Chair)) LA Anderson (Vice-Chair), P Bremner, T Chapman, A Charvill, K. Helliwell, P Hylands, C Leon, A C Moffat, M Pires, M Rowan, J Sumal, C Wright, K. Zhao (Corresponding members SS Handa, A Krauss) A G Davidson (Chair), D Cairns (Vice-Chair), M Ahmed, J C Berridge, M Broughton, A J Caws, P Fleming, W J Lough, D Malpas, G Marco

T D Duffy (Chair), C T Goddard (Vice-Chair), M Cole, S Jones, M A Lee, J Lim, J Miller, P Murray, M Turgoose (Corresponding members M Brits, B Sherwin) V Fenton-May (Chair), E Williamson (Vice-Chair), S Arkle, C T Goddard, P Hampshire, W K L Pugh, B Rackstraw, R Torano, M Tubby, 1 R Williams

J IZ Aronson (Chair), L Tsang (Vice-Chair), M Ahmed, G Cook, D Mehta, G P Moss, C Preston, R Thorpe (Corresponding members R G Balocco Mattavelli, E M Corts Montejano, A D McNaught, J Robertson) R L Horder (Chair), A D Woolfson (Vice-Chair), M Aulton, E Baker, N Broad, G Buckton, G Davison, G Eccleston, D Elder, R Lowe, J MacDonald, B R Matthews, J F McGuire, S C Nichols

V Fenton-May (Chair), T D Duffy (Vice-Chair), 1 Beaumont, S Branch, A Charvill, W Goddard, S Jones, M A Oldcorne, N J Precious, J Rothwell, M Santillo, J Smith

xiii

BIO: Biological and Biotechnological

Products

BLP: Blood Products

IGC: Inorganic and General Chemicals

MIC: Microbiology

RAD: Radioactive Materials

VET: Veterinary Medicines

VIP: Veterinary Immunological

Products

PANELS OF EXPERTS L Tsang (Chair), M A Dow (Vice-Chair), A F Bristow, D H Calam, J Cook, L Findlay, A Onadipe, B Patel, A M Pickett, C Ponsar, 1 Rees, D Sesardic, P Sheppard, W J Tarbit, J N A Tettey, AH Thomas, R Thorpe

K. Chidwick, A R Hubbard, S Jenkins, P Varley

C T Goddard (Chair), A C Cartwright, N Fox, P Henrys, D Malpas, C Mroz, D Riches

V Fenton-May (Chair), S Denyer, D P Hargreaves, B R Matthews, P Newby

J Ballinger, J Brain, D Graham, S R Hesslewood, G Inwards, P Maltby, A M Millar, R D Pickett, R Smith, S Waters

E Williamson (Chair), A Cairns, S Cockbill, D Evans, E Flahive, P Lees, B Ward

A M Brady, K. Redhead, J Salt, P W Wells

WORKING PARTIES CX: Excipients G Buckton (Chair), C Mroz (Vice-Chair), E Anno, R Cawthorne,

B R Matthews, M 1 Robertson, K. Slevin

IP: Inhaled Products S C Nichols (Chair), y Adjibade, M Dagli Alberi, J Lim, J Qiu, 1 Vaughan

XIV

Current British Pharrnacopoeia / Staff ~

Secretariat M Vallender (Editor-in-Chief) S Young (Head 01 Analytical Science) ,

\

M Barrett, H Corns, A Evans, J Francomb, A Gibb, P Holland, R A Pask-Hughes, J Pound, F J Swanson, R L Turner, M Whaley

Administrative M Cumberbatch, B F Delahunty, W Jeffries, D Myburgh, J Paine, N Salmon

ISO 9001 F527268

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Current British Phannacopoeia Laboratory Staff

!Z Powell (Laboratory Manager)

D Chan, V Devji, C Galdino, P Gallagher, J Gan, M Kimani, L Magee, R Mannan, A Panchal, !Z Patel, N Patel, E Sanderson, N Vadukal

ISO 9001 F527613

Current Staff of the Publisher of the British Phartnacopoeia

J Hook (Execupive Director) C Hackett (Project Manager) K Cole (Client Services Manager) P Allard, C Bailey, N Brownlow, T Horsnell, A Jackson, G Mannings, P Relfe, H Sinclair, 1 Webb, M Wood

1509001 F522428

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Introduction xix

Introduction

The British Pharmacopoeia (Veterinary) 2013 supersedes the British Pharmacopoeia (Veterinary) 2012. The British Pharmacopoeia (Veterinary) 2013 has been prepared by the British Pharmacopoeia Commission in accordance with the Medicines (British Pharmacopoeia Commission) Order 1970 (SI 1970 No. 1256) as amended (SI 1982 No. 1335). This empowers the British Pharmacopoeia Commissibn' to prepare a compendium under Section 99(3)(b) of the Medicines Actd 968 containing information relating to substances and articles which are or may be used in the practice of veterinary medicine or veterinary surgery. U nder the terms of the Medicines Act 1968 it is an offence to sell or supply a medicinal product in the United Kingdom that is the subject of a monograph in the Pharmacopoeia if that product doesnot comply with the standard s specified in the monograph.

This edition is published as a companion volume to the British Pharmacopoeia 2013 and thus contains only those monographs for substances and preparations used exclusively or predominantly in veterinary medicine within the U nited Kingdom, together with such additional texts as are necessary to support them. It therefore follows that any reference to a monograph, appendix or reagent not contained within this edition is to be construed as a reference to the said monograph, appendix or reagent contained within the British Pharmacopoeia 2013.

This edition, together with the British Pharmacopoeia 2013, contains all the monographs of the 7th Edition of the European Pharmacopoeia as amended by Supplements 7.1 to 7.5. U sers of the British Pharmacopoeia and British Pharmacopoeia (Veterinary) therefore benefit by finding within these two compendia all current pharmacopoeial standards for veterinary medicines used within the United Kingdom.

Effective Date The effective date for this edition is 1 }anuary 2013. Monographs omitted from this or earlier editions of the British Pharmacopoeia rema in effective in accordance with the Medicines Act 1968.

General Notices Part 11

The British Pharmacopoeia General N otices (Part II) have been amended as follows.

Crude Drugs; Traditional Herbal and Complementary Medicines

Monograph Title This General N otice has been amended 10 delete references to the acronyms THM and THMP.

xx Introduction

Labelling

The statement concerning Veterinary Medicines Regulations 2007 in this General Notice has been amended to refer to current Veterinary Medicines Regulations. The statement concerning best practice guidance has been amended to delete reference to "Veterinary Medicines Guidance Note 26: Marketing Authorisations - Legislative updates to SPCs and Product Literature" .

Part III

The British Pharmacopoeia General N otices (Part III) have been amended to harmonise with the changes published in Supplement 7.5 of the 7th edition of the European Pharmacopoeia.

Additions A list of monographs included for the first time in the British Pharmacopoeia (Veterinary) 2013 is given at the end of this Introduction. It includes 1 new monograph reproduced from the 7th Edition of the European Pharmacopoeia and 2 new national monographs for formulated preparations.

Revisions The requirement for Specific optical rotation has been amended in the monograph for Deltamethrin. The monograph for Cefalotin Sodium has been revised to refer to the use of British Pharmacopoeia Chemical Reference Substances.

Labelling Requirements

Following a review by the British Pharmacopoeia Commission's Panel of Experts on Veterinary Medicines and, in collaboration with the United l

European Pharmacopoeia

Phannacopoeial Requirements

Introduction xxi

All monographs of the 7th Edition of the European Pharmacopoeia, which are used in veterinary practice but not normally in human medicine in the United Kingdom, are reproduced in this edition of the British Pharmacopoeia (Veterinary). Each of these monographs is signified by a European chaplet of stars alongside its title. Additionally, reference to the European Pharmacopoeia monograph number is included immediately below the title in italics in the form 'Ph Eur monograph xxxx'. Where the title in the British Pharmacopoeia is different from that in the European Pharmacopoeia, an approved synonym has been created (see Appendix XXI B (Vet)) and the European Pharmacopoeia title is included before the monograph number. The entire Europeart Pharmacopoeia text is delineated by two horizontallines bearing the symbol 'Ph Eur'.

The European Pharmacopoeia texts have been reproduced in their entirety but, where deemed appropriate, additional statements of relevance to UK. usage have been added (e.g. action and use statement, a list of BP (Ve~) preparations). It should be noted, however, that in the event of doubt of interpretation in any text of the European Pharmacopoeia, the text published in English under the direction of the Council of Europe should be consulted.

Correspondence between the general methods of the European Pharmacopoeia and the appendices of the British Pharmacopoeia (Veterinary) is indicated in each appendix. A check list is also provided at the beginning of the appendices section. This provides a full listing of the European Pharmacopoeia method texts with their British Pharmacopoeia and British Pharmacopoeia (Veterinary) equivalents.

Pharmacopoeial requirements for articles used in veterinary medicine are established on the same basis as those used in human medicine. A proper understanding of the basis upon which these requirements are established is essential for their application and advice is provided within the General Notices of the British Pharmacopoeia (Veterinary) and the Supplementary Chapters to the British Pharmacopoeia. It should be noted that no requirement of the Pharmacopoeia can be taken in isolation. A valid interpretation of any particular requirement depends upon it being read in the context of (i) the monograph as a whole, (ii) the specified method of analysis, (iii) the relevant General Notices and (iv) where appropriate, the relevant general monograph(s). Where a preparation that is the subject of a monograph in the British Pharmacopoeia is supplied for use in veterinary medicine, the standards of the British Pharmacopoeia apply, unless otherwise justified and authorised. Attention is drawn to the Notice permitting the designation British Pharmacopoeia (Veterinary) [BP (Vet)] to be used in place of the designation British Pharmacopoeia [BP] where a preparation complying with the British Pharmacopoeia is supplied for use in veterinary medicine with the approval of the competent authority.

Code of Practice Members of the British Pharmacopoeia Commission and its supporting Expert Advisory Groups, Panels of Experts and W orking Parties are required to comply with aCode of Practice on Declaration of Interests in the pharmaceutical industry. Details of the Code are published on the website (www.mhra.gov.uk/pharmacopoeia).

xxii Introduction

Websites www. mhra.gov. uk/pharmacopoeia Information relating to the British Pharmacopoeia can be found on the website of the Medicines and Healthcare products Regulatory Agency. In the Pharmacopoeia section, draft new and revised monographs are available free to enable stakeholders to contribute to their development for a future edition.

Chromatograms for information to support new monographs published in the British Pharmacopoeia 2013 have been added to the Image Gallery to aid users of British Pharmacopoeia monographs. This service will increase year on year to allow users to examine chromatograms obtained during the practical evaluation of new monographs by the British Pharmacopoeia Commission Laboratory.

The subscription service identifying all changes to BP and BP (Vet) monographs has been discontinued at the present time but may be reinstated in the future.

http://www. pharmacopoeia. co. uk This website provides subscribers with access to the British Pharmacopoeia 2013 and British Pharmacopoeia (Veterinary) 2013 online and access to the current edition and Supplements of the British Approved Names publication. Concurrent access to the previous edition of the BP and the new edition is maintained for a short periodo This website is administered by the publisher of the British Pharmacopoeia.

Forward Look BP 2013 online updates will be published on the website, www.pharmacopoeia.co.uk, to enable users to keep up to date with monographs published in the European Pharmacopoeia. These updates will be integrated annually with the publication of the main edition of the British Pharmacopoeia and British Pharmacopoeia (V eterinary) . The British Pharmacopoeia Commission's Panel of Experts on Veterinary Medicines has identified a number of candidate new monographs. It is anticipated that there will be a gradual increase in the number of new monographs for formulated preparations for veterinary medicines in future editions of the British Pharmacopoeia (Veterinary).

Acknowledgements The British Pharmacopoeia Commission is greatly indebted to the members of its Expert Advisory .Groups and Panels of Experts, in particular, the Panel of Experts on Veterinary Medicines for their dedicated enthusiasm and assistance in the preparation of this edition.

Close co-operation has continued with many organisations at home and overseas. These include the Veterinary Medicines Directorate, the Medicines:'and Healthcare products Regulatory Agency, the National Institute for, Biological Standards and Control, the National Office of Animal Health, the Association of the British Pharmaceutical Industry, the European Pharmacopoeia Commission and the European Directorate for the Quality of Medicines & HealthCare, the Therapeutic Goods Administration (Australia), the ijealth Protection Branch of the Canadian Department of Health and Welfare, the United States Pharmacopeia, the Quality Assurance and Safety: Medicines Department of the World Health Organization (WHO) and the Health Sciences Authority of Singapore.

Introduction xxiii

The British Pharmacopoeia Commission wishes to thank the European Directorate for the Quality of Medicines & HealthCare for their support and assistance in the reproduction of the European Pharmacopoeia texts and monographs.

The British Pharmacopoeia Commission also acknowledges and appreciates the advice of the/ publishing team at The Stationery Office, in particular Mr Colin Hackett, in the production of this edition.

Additions The following monographs are new addi~ions to the British Pharmacopoeia (Veterinary) 2013. ' Medicinal and Pharmaceutical Substances Difloxacin Hydrochloride Trihydrate*

Formulated Preparations: Specific Monographs Meloxicam Injection Moxidectin Injection

Omissions The following monographs of the British Pharmacopoeia (Veterinary) 2012 are not included in the British Pharmacopoeia (Veterinary) 2013. Formulated Preparations: Specific Monographs Amitraz Dip Concentrate (Powder) Amitraz Pour-On Ampicillin Tablets Catechu Tincture Cefalonium Eye Ointment Cobalt Depot-Tablets Co-trimazine Oral Suspension Etamiphylline Veterinary Oral Powder Etorphine and Levomepromazine Injection Fenbendazole Veterinary Oral Powder Iron Dextran Injection (10 per cent) K.aolin Veterinary Oral Suspension Meclofenamic Acid Granules Methyltestosterone Tablets Metronidazole Sterile Solution Metronidazole Sterile Suspension Oxytetracycline Injection Oxytetracycline Intramammary Infusion (Lactating Cow) Piperazine Adipate Tablets Procaine Benzylpenicillin Intramammary Infusions Pyrethrum Dusting Powder Compound Pyrethrum Spray Sulfadimidine Tablets Sulfadoxine and Trimethoprim Tablets Sulfametoxypyridazine Inj ection Testosterone Phenylpropionate Injection Tylosin Tartrate and Sulfathiazole Sodium Veterinary Oral Powder Tylosin Tablets

* denotes a monograph of the European Pharmacopoeia.

xxiv Introduction

Technical Changes The following monograph in the British Pharmacopoeia (Veterinary) 2013 has been technically amended since the publication of the British Pharmacopoeia (Veterinary) 2012. This list does not include revised monographs of the European Pharmacopoeia. An indication of the nature of the change or the section of the monograph that has been changed is given in italic type in the right hand column.

Formulated Preparations: Specific Monographs Deltamethrin Specific optical rotation

Reference Substances A number of monographs of the British Pharmacopoeia (Veterinary) 2013 have been revised to refer to British Pharmacopoeia Chemical Reference Substances (BPCRS). The following reference standard has been revised. Cefalotin Sodium

General N otices 1

General Notices

2 General N otices

CONTENTS OF THE GENERAL NOTICES Partl ltalie introduction European Pharmacopoeia

Part II talie introduetion Official Standards Definition of Terms 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

Reference spectra Assays and Tests Biological Assays and Tests Reference Substances and Reference Preparations

Chemical Reference Substances Biological Reference Preparations

Storage Labelling Action and Use Antibiotics Intended for use in the Manufacture

of Intramammary Infusions Crude Drugs; Traditional Herbal and

Complementary Medicines Homoeopathic Medicines Part III talie introduction General N otices of the European Pharmacopoeia 1.1 General Statements

Quality Systems General Monographs Validaton of Pharmacopoeial Methods Conventional Terms Interchangeable Methods References to Regulatory Documents

1.2 Other Provsions.Applying to . Genetal Chapters. and Moriographs

Quanttis Apparatus andProcedures Water-bath

Expression of. Cantent Temperature

1.3 General Chapters Contamers

lA Monographs Titles Relative Atomic and Molecular Masses Chemical. Abstracts Service (CAS) Registry

Number Definition

Limits of content Herbal drugs

Production Choice ofVaccine Strain,Choiceof Vaccine Composition

Charactets Solubilty

Identificatian Sfpe First andsecondidentifications Powderedherbal drugs

Tests and Assays Scope Calculaton Lirnits Indicaton ofpermitted ltI:litlo:tJiml:lUI'tH!s Herbal drugs E quivalents Culture media

Storage Labelling Warnings Impurities Functionality-related Characteristicsof

Excipients Referellce Standa:rds

1.5. Abbreviations and Symbols 1.6Unitsof the International Systertl (SI)sed

in the Pharmacopoeia and Eqivalel1ce withother Units

European Phannacopoeia

General N otices 3

General N otices

Partl

The Brltish Pharmacopoeia (Veterinary) comprises the entire text withinthis publication. The word 'official'isusedin the Pharmacopoeia to signify 'ofthe Pharmacopoeia'. ltappliesto any title"substdnce,preparation, method or statement included inthegeneral notices,monographs andappendices ofthe PharmacopoeicThe .abbreviation for British Pharmacopoeia (Veterinary) is BP (VeV. MonographsoftheEuropean Pharmacopoeia are reproduced in this editill ofthe BritishPharroacopoeiaeveterinary)py incorporationof the text publishedunder thedirectionofthe COlIllCil of Europe (Partal Agreement) in accordancewithtbe Convention. ontbeElaborationofaEuropean Pharmacopoeia (TreatySe{'iesNo. 32 (1974)CMND 5763) as amended l1y the Protocol tothe Convention(Treaty Series No MISe 16(1990)CMND 1133). Theyare induqed fortheconvenience fusers of the British Pharinacopoeiaeveterinary). IncasesOf doubt or disputereferenceshould bemadeto . theCitudl . ofEuropetext. *****MonographsoftbeBuropeanPharrnacopoeiaare distinguished bya t***t ch~pletofstarsagait1st.the title andbyreferenceto .the.European

Pharmacopoeiamouographnumberindudedimmediatelybelow me title in.italics . Thebeginningandend .oftextfrom the . European Pharmacopoeiaaredenoted>bymeansofhorizontal1ines with the symbol 'Ph Bur' rangedleft and right, respectively.

The general provisions of theEuropean Pharmacopoeia relating to differenttypes ofdosage forro are induded. in the appropriategeneraI monograph in that section of either the British Pharmacopoeia or the BritishPharmacopoeia r:v eterinary) entitled Monographs; F ormulated Preparations. These general provisions apply to all veterinary dosage forms ofthe. type defined,.whemer.anitidividual monograph is induded in the British Pharmacopoeiaeveterinary) or. n()t.

Texts .ofilie13urop~~l1Phartnacopoeiaare. governed by the General Noticesofilie EuropeanPharmacopoeia.These are reproduced as Part JI! of theseritices.

4 General N otices

,PartII

The following genera/notices dpply to the statements made in the monographs of theBritish Pha:rmacopoeia (Veterinl1ry) other thanthosereproduced from the European Pharmacopoeia and to the statements made in the appendices of the British Pharmacopoeia (Veterinary) otherthan when a methodJ test or other matter described,' inan,' appendix is invokedin. a monograph reproduced from the European Pharmacopoeia.

Official Standards The requirements stated' in thelllonographs of thePharmacopoeia apply to artides that are intended for veterinary medicinal Use but not necessarily to anides that may be sold under the same name for other purposes. An artide intended for veterinary medicinal use that is described by means of an oflicial title must comply with the requirements of the relevant monograph. A formulated preparation must comply throughou! its assigned shelf-life '(period of validity). The subject of any other monograph must comply throughoutitsperiod of use.

A monograph isto be consttuedin accordancewithany general monograph ornotice, or any appendix, note 01' other explanatory material that is contain.ed in thiseciinol1and that isapplicabletorhat monQgrap~. Allstatementscontainedinthe monographs, except where aspecific general notice indicates otherwiseand withtheexceptions givell'below, constitute standards Jor the officialartides .An article ls not ofPharmacopoeialqllality unless it complies ,with aH,' ofthe reqllitementsstated.This ,do es, notimply that a ,manufacturerisobliged toperform allthe tests in amonographin order to assess compliance with the Pharmacopoeia, beforerelease ofa product. The 'mauufacturerrnay ass.ure himself that a product is' of Pharmacopoeialquality by other>means, for example, fr0111 data derived fromvalidation studiesofthemanufacturing process, from in-process controls 01' from a combillation of the two. Parametric release in appropriatecircutnstances isthus no! preduded by the need tocomply with thePharmacopoeia., The gelleral notice on Assays and Tests indicates that analytical methodsother thanthose described in the Pharmacopoeiamayhe e111ployed for' rounne purposes.

Requirements, in monographs have been framed to provide appropriate limitanonof potential impurities rather than to provide against' all possible i111purities. Material foundtocontainan impuritY notdetectable by tneans of the prescribed tests is not' of Pharmacopoeial quality if the nature or amount ofthe impurity found is incompatible with good phannaceutical practice.

The status of any statement given under the side-headings Definition, Production, Characteristics, Storage, LabeUing or Action' anduse ls defiried within the general notice relating to the relevant side-heading. In addition to any exceptions indicated ,by one of the general notices referred' to aboye, thefoUowing parts of a monograph do not constitute standards: Ca), a graphic, or molecular formula given at the beginning of a monograph; (b)a molecular weight; Ce) a Chemical Abstraets Service Registry Number;(d) any information given at the end of a monograph concerning impurities known to be limited by that monograph; , C e) information in any annex to a

General N otices 5

monograph. Any statement containing the word 'should' constitutes non-mandatory advice or recommendaton.

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, supranationalor intemational bodyor organisation vested with the authority formaking decisions conceming the issue in question. It may, for example, be a licensing authority oranofficial controllaboratory. For a formulated preparation that is the subject ofmonograph in theBritish Pharmacopoeia eVeterinary) anyjustified and authorised modification to, or exemption from, the requirements of the relevantgeneral monograph of the European Pharmacopoeia is stated in the individual monograph. F or example, the general monograph for Tablets requires that Uncoated Tablets, except for chewable tablets, disintegrate within 15 minutes; for Ampicillin Tablets a timeof 45. minutes ispermitted.

Additional statements and requirements applicable to theindividual monographs ofthe British Pharmacopoeia arealso inclridedin many of the general monographs of the British Pharmacopoeia for formulated preparations. Suchstatementsand requirements apply also to aH monographs for that dosage form includedin the British Pharmacopoeia (Veterinary). unless otherwise.indicated in either a general monograph oran individualmonographof theBritish Pharmacopoeia (Veterinary).

AnyadditioIls to ormodifications ofthe statements and requirements of the BritishPharmacopoeia that are generaIly applicable to the individual monographsof the British Pharmacopoeia (Veterinary) areprovided by means.of a supple1l1entary.text introduced by a .subsidiary heading together with an italicised statement . Thus . there is, for example, a supplemen tary text entitled 'Tablets of the British Pharmacopoeia (Veterinary)' that relates only to the specificmonographs for individual tablets that are contained in the. British Pharmacopoeia . (Veterinary).

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 ofsuch strain, test, method, substance, etc., is made in accordance with any international agreements or national regulations affecting the subject concerned.

Definition ofTerms Where the term 'about' is included in a monograph or test it should be taken to mean approximately (fairly correct or accurate; near to the actual value).

Where the term 'corresponds' is included in a monograph or test it shouldbe taken tornean similar or equivalent in character or quantity.

Where the term 'similar' isincludedin a monograph or test it shouldbe taken to mean alike thoughnot necessarily identical.

Further qualifiers (such as numerical acceptance criteria) for the above terms are. not includedin the BP (Vet). The acceptance criteria for any individual case are set based on the range of results obtained from known reference samples, the level of precision of the equipment or apparatus used and the .levelof accuracy required for the particular application. The user should determine the variability seen in his/he! own laboratory and set in ... house acceptance criteria that he/she judges to be appropriate based on the local operating conditions.

6 General N otices

Expression of Where the standard for the content of a substancedescribedin a Standards monograph is expressed in terms of the chemical formula forthat substance

an uppet limitexceeding 100% may bestated.Suchan upper limitapplies to the tesult of the assay calculatedin terms of the equivalent contentof the specified chernicalfotmula.assayortest isrequitedtobe calculated.

General N otices 7

When the concentration of a solution is expressed as parts per million (ppm), 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 Oy thesymbol M preceded. by a number, it denotes the number of moles of thestatedsolutecontainedin sufficient Purified Water (unless otherwise stated) to produce 1 litre of soludon.

The term 'water bath'means a bath of boiling water, unless water at sorne other temperature isindicated in the texto An alternative form of heating may. be employed providing that the required temperature is approximately maintained but notexceeded.

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. mate'rials aresuitable for use in medicine.

Indicators, the coloursof which change over approximately the same range ofpH,may be substituted forone another but in the event of doubt or dispute as to. the equivalenceof indicators for a particular purpose, the indicator specifiedjl1the text is alone authoritative.

Thequantity ofanindicatorsolution appropriate for use in acid-base titrations. described in assays or tests is 0.1 mL unless otherwise stated in the texto

An,y solventrequired in an assay or test in which an indicator is specified is previously neutralisedt theindicator, unless a blank test is prescribed. Anumber ofmatetialsdescribed inthe monographs and sorne of the reagentsspecified for use in the assays and tests of the Pharmacopoeia may beinjurious to healthunless adequate precautions are taken. The principIes of good laboratorypractice and the provisions of any appropriate regulationssuch 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.

Titles Subsidiary tides,where inc1uded, have the same significance as the main tides. An abbreviated title constructed in accordance with the directions givenihAppelldixXXI Ahasthe same significance as the main titie.

Titles thatate derivedby thesuitable inversion of words of amain or subsidiary title,withthe additionof a preposition if appropriate, are also officiaLtitles. Thus, the Iollowing are aH official tides: Acepromazine Tahlets, Tablets of Acepro111azine; Catechu Tincture, Tincture of Catechu; Levamis(}le Injection, Injectionof Levamisole.

A title ofa formulatedpreparation that includes the full nonproprietary nameofthe activeingredient or ingredients, where this is not included in the titleof the monograph, is also an official title. F or example, the title Acepro111azine Maleate. Injection has the same significance as Acepromazine

8 General Notices

Injectionand thetitleDiprenorphineHydrochloride Injection has the same significance asDiprenorphine Injectiol1s.

Where. theEnglish title atthehead of.amonograph inthe European Pharmacopoeia isdifferentfromthafat the headofthetextincorporated into the British Pharma.copoeia(Veterinary), an Approved Synonymhas been dec1ared in accordance with section65(8) of the Medicines Act 1968. The titles andsubsidirytit1es,if~ny,arethus .0fficial.titles.A cumulative lis! of such Approved Synonyms isprovidedin AppendixXXI B (Vet).

WherethenaIl1esoftb.amiacoP9eia~ substances, preprations and other .materials.occurinthetext.theyare printedwith capital initialletters and this indicates tllatmaterials ofPharmacopoeialqllality must be used. W ords in the text that name a reagent 01' othermaterial, a physical characteristic 01' a process that isdd;;cribed. ordefined inanappendix are printed in italic type, for example, methanol,absorbanfe, gas chromatography, . and these imply complince with the requirements specified in the appropriate appendix.

Chemical Formulae When the chemical composition of an official substance is known or generally accepted,the graphic andmolecular formulae, themolecular weight andthe Chemical Abstracts Service RegistryNumber are normalIy givenat the beginning ofthe monographforirforn:ultion. Thisinformationrefers to the chemically Ptlresubstanceandis119ttO be regardedas an indicationof the puri~ofthe . official .. material.Elsewl1ere,in.statement$.ofstandardsofpurity

andstren~fhand indescfipti~~80f processes ofa8say, it isevident from the contextthat. theformulae del1otedlec~emieallypure .substances.

Wheretheabsolute.stereoche~icalconfiguration is specified, .the International Unio~ofPureandAl'pliedChemistry (IUPAC}R/S and E/Z systems of designationhavebeetl used. If the substance. is an enantiomer of 1,lnlmQwn.ahsolll.te stereQ(;hel11istrythesign o the. opticalrotation, as determined in the solvent~ndunderthe conditions .specified in the monograph, has beenattacp.edtothe systematicname. An indication of signof rotation hasalso beengiven where this 18 iricorporated in a trivial nmethat appearson anIUPACpreferred listo

Allaminoadds; exceptglydne,havethe L-configuraton Unless otherwise indicated. The three;.letterandone.-Ietter symbols used for amino acids in peptide andprotirisequences arerhose recommended by the Joint Cornmission on BiochetnicalNomenclatttre ofthe International Unon of Pure. andAppliedChemistryandthe Intemational Union ofBiochemistry andMolecularBiology.

Inthe graphic fomiule the foUowing abbreviations are used:

Me Et Pri Prn Bui

-CH) -CH2 CH3 -"-CH(CH3h -.:CH2CH2CH3 .,..CH2CH(CH3)2

BuS -.:CH(CH3)CH2CH3 Blln -CH2CH2CH2CH3 But -C(CH3h Ph -C6Hs Ac -COCH3

Definition Statements given undel' theside-heading Definition constitute an official definition of thesuhstance, preparaton or. otherarticle that is the subject of the. monograph.Theyconstitute instrllctions 01' requirements and are mandatoryin nture.

Certainmedicinal 01' pharmaceutital substancesand othel' articles are defined byreference toaparticularmethod of manufacture. A statement that a substance or article is preparedor obtained bya certain method constitutes part of the official definition and implies that other methods are

Production

Manufacture of Formulated

Preparations

General N otices 9

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 F ormulated Preparations.

Statements given under the side-heading Production draw attenton to particular aspedts of the manufacturing process but are nor necessari1y comprehensive. Theyconstitute mandatory instructons to manufacturers~ They may relate, for example, to sourcematerials, to themanufacturing process itself and its validation and control, to in-process testing or to testingthat is to be carried out by the manufactureron the final product (bulk material or dosage form) either on selected batchesor on each batch prior to release. These statementscannotnecessarilybe verified ona sample of thefinal product byan independent analyst. The competent authority may establish that the instructionshave been followed, for example,by examination ofdata received froro the manufacturer, by inspection or by testng appropriate samples.

The absence of a section on Production does not imply that attention to features such as those referred to aboye is not required. A substance, preparation or artic1e describedin amonographofthe.Pharmacopoeiais to be rnanufactured in accordancewith the principIes of goodrnanufacturing practice and in accordance with relevant international agreements and supranational andnational regulations goveming medicinal products.

Where in the sectionunder the side-heading Producrion a monograph on a vaccine defines the characteristics of the vaccinestrain tobeused,anytest methods given for confirming these characteristicsare provided as examples of suitable methods. The use of these methods is not mandatory.

Additional statements concerning rhe production of formulated preparations are given in the general notice on Manufacture of Forroulated Preparatons.

Attenrion is drawn to the need to observe adequare hygienic precautions in the preparation and dispensing of pharmaceutical formulations. The principIes 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 ingredienr, other than those inc1uded in the Definirion, must comply with the general notce 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 srated formula is permitted except those allowed by the general norices on Colouring Agents and Antimicrobial Preservatives. Where additionally directions are given under the side':'headng Extemporaneous Preparaton these are intended for the extemporaneous prepararion 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 1hat ir may be stored, deviations from the stated directions are permitted provided that the final product meets the following criteria:

10 General N otices

FreshIy' and Recently Prepared

Methods of Sterilisation

Water

(1) compliancewith aIl oftherequirelllentsstated inth~ monograph; (2) tetentionoftheessential characteristicsofthe preparation madestriedy

in aCFordancewith.thedirections ofthePharmacopoeil. Monographsfor. yet other pharma

General N otices 11

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.

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

Antimicrobial When the term 'suitable antimicrobial preservative' is used it is impliedthat Preservatives the preparation concemed will be effectively.preserved according tothe

appropriate criteria applied and interpreted as described in the testfor efficacy of antimicrobial preservation (Appendix XVI C). In certain monographs for. formulated preparations defined by means of a full formula, a specific antimicrobialagent or. agents may be.prescribed; suitable alternatives lllay be substituted provided that their identity and

/ concentration are stated on the labe!'

Characteristics Statelllents given under the side-heading Characteristics are not to be interpreted in a strict sense and arenot to beregarded as offi ci al requirements. Statementson taste are providedonly in tases wherethis property is a guide to theacceptability of thematerial (for example; a material used primarily for flavouring). The status of statements on solubility is given in the general noticeon Solubility.

Solubility Statements on solubilitygiven under the side-heading Characteristics are intended as information on the approximatesolubilityat a temperature between 15 and 25, unless otherwisestated, andare notto be considered as official requirements.

Statements given under side-headings such as Solubility in. ethanol express exact requirements and constitute part of the standards for the substances under whichthey occur.

The following table indica te s the meanings of the terms used in statements of approximate solubilities.

Descriptive term

very soluble freely soluble soluble sparingly soluble slight1y soluble very slightly soluble practically insoluble

Approximate volume of solvent in millilitres per gram of solute less than 1 from 1 to 10 from 10 to 30 frOlll 30 to 100 frollllOO to 1000 from 1 OOOto 10,000 more than 10,000

The term 'partly soluble' isused todescribe a mixture of which only some of the components dissolve.

Identification The tests described or referred tounder the side-heading Identification are not necessarily sufficient to establish absolute proof of identity. They

12 General N otices

provide a means of verifying that the identity of the material being examined is in accordance with the label on the container.

Unlessotherwise prescribed, identification tests are carried out at a temperature between 15 and 25.

Reference spectra Whereamonograph refers to an infrared reference spectrum, this spectrum. is.provided in a separate section of the Pharmacopoeia. Asample spectrum isconsidered to be concordant with a referencespectrum. if the transmission minima (absorption maxima) of the principal bands intbe samplecorrespondinposition, relative.intensities and shapeto thoseofthereference. InstrUmentation software may be used to calculate concotdance with a previously. recorded reference spectrum.

When tests forinfrared absorption are applied to material extracted from formulated preparations, striet concordance with the specified reference spectrum may not always be possible, but neverthe1ess a close resemblance between the spectrum of the extracted material and the specified reference spectrum should be achieved.

Assays and Tests The assays and tests described are the official methods upon whieh the standards of the Pharmacopoeia dependo The analyst is not prec1uded from employing alternative methods, inc1uding methods of micro-analysis,in any assay or testif itis known that the method used will give a result of equivalent accura(2y~ Localreference materials may be used for routine analysis, provided that these are calibrated against the official reference materials~ In the eventof doubt or dispute, tbe methods of analysis, the reference materials andthereferencespectra of the Pharmacopoeia are alone authoritative.

Where the solvent used for a solution isuot named, the solvent is Purified.Water.

Unless otherwise prescribed, the assays and tests are carried out at a temperaturebetween 15 and 25.

A temperature.in a test for Loss on drying, where no temperature range is given, implies a range of 2 about the stated value.

Visual comparative tests, unless otherwise prescribed, are carried out using identical tubes of colourless, . transparent, neutral glass with a fIat base and an internal diameter of 16 mm; tubes with a larger internal diameter may be used but the volume of liquiq_examined must be increa.sed so tbat the depthof liquidin thetubeis not less than that obtained when tbe prescribed volume. of liquid and tubes 16 mm in internal diameter are. used. Equal vdlumes of the liquids to be compared are examined down tbe vertiealaxis of the tubes againstawhite 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', precautionsshould 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 exc1udeactinic light by the use of low-actnc glassware, workingin a dark roomor similar procedures.

For preparations other than those of fixed strength, the quantity to be taken for an assay or test is usualIy expressed in terms of the active ingrediente This means that the quantity of the active ingredient expected to be present and the quantity ofthe preparaton to be taken are calculated from the strength stated on the labe!'

General N atices 13

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 assayis calculated from this exact quantity. Reagents are measured and the procedures are carried out with an accuracy commensurate withthe degree of precision implied by the standard stated for the assay.

In tests the stated quantity tobe taken for examination must be used unless any divergence can be taken into account in conducting the test and calculating the resulto The quantity taken is accurate1y weighed ot measured with the degree of precision implied by the standard or, where the standard is not stated numericalIy (for example, in tests for Clarity and colour of solution), with the degree ofprecision implied by the number of significant figures stated. Reagents aremeasured 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 acceptabl variationsinmanufacture andof deterioration to an extent considered acceptable.No furthertolerancesareto be applied to the limits prescribed to determine whether the artic1e being examined complies with the requirements. of thelllonograph.

In determining compliance with a numericallimit, the caIculated resultof a test or assay is first rounded to the number of significant figures stated, unless otherwiseprescribed.The last flgureis increased by one when the pqrt rejected isequal to orexceeds onehalf-unit, whereas it is not modified when the partrejected is lessthan ahalf.:.unit.

In certain tests,. the.concentration of impurity is given in parentheses eitheras a percentageorinpartspermillionby weight(ppm). In chromatographic tests such cOrIcentrations are stated as a percentage irrespective of the limito In orher teststhey are usually stated in ppmunless the limit exceeds 500ppm.Inthose chromatographic tests in which a secondary spot orpeak in a chromatogramobtained with a solution of the substance being examined is described as corresponding to a named impurity and is compared withaspot orpeak in a chromatogram obtained with a reference solutionof 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 witha reference solution of a named impurity, the percentage given in parentheses indica tes 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 chromatogramsobtained with solutions. of different concentrations of the substancebeing 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 concentrationof 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.

14 General N otices

Biological Assays and Tests

In aH 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 do es not imply that another equaIly suitable material may not be used.

Methods of assay described as Suggested methods are not obligatory, but when another method is used its precision must be not les s than that required for the Suggested method.

For those antibiotics for which the monograph specifies a microbiological assay the potencyrequirement is expressed in the monograph in International Units (IU) or other Units per milligram. The material is not of pharmacopoeial quality if the upper fiduciallimit 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 fiduciallimits 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 ten the square roots of the limits given in the monograph for the fiduciallimits of error about the stated potency.

In aIl 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 labe1 in terms of International Unts (IV) or other Units per gram, per milligram or per millilitre. When no such statement appears on the labe1, the stated potencymeans the fixed or mnimum potency required in the monograph. This interpretation of stated potency applies in aH 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 Intemational Units (IU) ototherUnits stated on the label or, if no such statement appears, the total activity ca1culated in accordnce 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 W orld 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 therwise directed, animals used in an assay or a test are healthy animal s, 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

Reference SubstaIlces. and

RefereIlce

General N otices 15

light coloured. Unless otherwise stated, miee weigh not les s than 17 g and not more than 22 g.

Certain of the biological assays and tests of the Pharmacopoeia are sueh that in . the U nitedKingdom theymay be . earried out only in accordance withthe Animal s (Scientific Procedures). Act 1986. Instructions included in such assaysand tests in the PharmacQpoeia, with respect to the handling of animals, are therefor corif1ned to those concerned with the accuracy and reproducibility of theassayor test.

Certain IUonogtapl1s require theuseofa referencesubstanee, a referenee preparationorateferertcespectrum.1)eseare chosen with regard to their intendedllseasprescribedinthemon,pgraphsofthe Pharmacopoeia and are . notnecessarilystta~lein. Pthercircitmstances.

AnY informationn,eeessaryf()rproper}lse of the reference substanee 01' referel1cepreparationis give119rt thelabeLor inthe aeeompanying leafiet 01' broehure.Wl1erenpdryng cortgitions are .stated in the leafiet 01' on the label, the substance ist9be Llser~J:l~u!~tiQnsThe majority of the primary biologi~alt'~fere~Fe preparatipns .refFrred . to~rethe .appl'opriate Intyrl1ati()nalSt~l1~ardsangReferel1FFPreparati0:ns . established by the WorldHealthOrgarlisation.Becau~ethese referenqe material s are usualIy available only in limteg quantties, theEuropean>Pharmacopoeia has

establishedBiologicarR.~ference Preparations(indicated by the abbreviation BRP ol' EPBRP) whete appropriate. Where applieable, the poteney o the Biological Reference Preparations 18 expressed in lriternationalUnits.For someBiological Reference Preparations, where an

internationarstand~rd()rrefe~e~ee'prepflration cioes notexist, the poteney is expressegin European .Pharmg~opoeiaUnits.

8tat~?lle~tS.U11

16 General N otices

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 atll1osphere. A low moisture content may be maintained, if necessaty, by the use of a desiccant in the container provided that direct contact with the product is avoided.

Theexpression '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 containerendosed in an outer cover that provides such protection or stored in aplace from which all such light is exduded.

TheeXpression 'tamper-evident container' means a dosed container fitted witha device that revealsirreversibly whether thecontainer has been opened,whereas, the expression'tamper-proof container' mean s a dosed container inwhich access to the contents is prevented under normal conditions of use. The two terms are considered to be synonymous by the European Pharmacopoeia Commission~

Labelling The labelling requirements of the Pharmacopoeia are not comprehensive, and the provisions of regulations issued in accordance with the requirements of the territory in which the medicinal product is to be used should bemet.

Licensedmedicines intendedfor use within the United Kingdom must comply with the requirements of the current VeterinaryMedicines Regulations artd European Directive 2001/82/EG (as amended) in respectof theirlabellirtgand package leaflets, togetherwiththose regulations for the labelling ofhazardousmaterials.

Bestpractice guidanceon the labelling and packaging of veterinary medicinesfor use .in the United Kingdom advises thatcertain items .of illformation are deemed critical for the safe use ofthe medicine. Further informationa:ndguidance on the labellingof medicinal products can be foundinSupplementary Chapter 1 G.

Suchmatte:rs as the exact form of wordingto be .used and whether a pa.rticular item of information should appear on the primary label and additionalIy, oraltematively, on the package or exceptionalIyin a leafletare, in general, outside the scope of the Pharmacopoeia. When the term 'labe!' is used in Labelling . statements of the Pharmacopoeia, decisions as to where the particular.statement should appear should therefore be made in accordancewithrelevant legislaton.

The label of every official formulated preparation other than those of fixed strength als~ states the content of the active ingredient or ingredients expressed in the terms required by the monograph. Where the content of activeingredient is required to be expressed in terms other than theweight of theoffidal medicinal substance used in making the formulation, this is specifically stated under the heading Labelling. Unless otherwise stated in themonograph, the content of the active ingredient is expressed in terms of the official medicinal substance us~d in maldng the formulation.

Action and Use The statements given under this side-heading in monographs are intended only. as . information on the principal pharmacological actions or the uses of thematerials in veterinary 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.

Antibiotics Intended for Use in the

Manufacture of Intramammary

Infusions

Crude Drugs; Traditional Herbal

and. Complementary Medicines

General N otices 1 7

Where a monograph for an antibiotic in the British Pharmacopoeia 01' in the British Pharmacopoeia (Veterinary) contains specific requirements relating to sterility 01' toabnormal toxicity for material intended . for use in the manufacture of a parenteral dosage form,these requirements, together with any qualification, apply also to any material intended for use in the manufactureof an intl'amammaryinfusion.

Herbal and complementary meddnesare classed as medicines under Buropean Directive 2001/83/BC as amended. It is emphasised that, although requirements forthequaltyofthe material are provided in the monograph to assst the registraton schemcby theUK LicensingAttthority,the British Pharmacopoeia Commissionhas not assessed the sfety orefficacy ofthe material intraditional use.

Mongraph Ttle For tl'aditional hel'bal medicines,. themonograph title i8 a combination of thebinomial name togethel' with a description ofuse. Monographs Jol' the materialthat has not beenprocessed (the herbal drug) and the processedmaterial(the herbaldrug preparation) arepublished wherepossible .. To distinguishbetween the two, the \VOl'd'Processed' is included in the

18 General N otices

Homoeopathic Medicines

appropriate.

General N atices 19

Part III

Monographs and other texts oi the European Pharmacopoeiathat are incorporated in this edition oi the Brish Pharmacopoez'a are governed by the general notices Di the European Ph,armacopoeia; these are reproduced below.

20 General N otices

competent authority, altemativemethods 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 beachieved 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 thatare 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 somemonographs, 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 01' more of these characteristics may be given, also for.information.

Quality systems The quality standards represented by monographs are valid only where the artides in question are produced within the framework of a suitable quality system.

General monographs

Validation of pharmacopoeial

methods

Conventional terms

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.

Generalmonographsapplyto all substances and preparations within the scope of theDefinition sectioll ofthe general. monograph, except whera preamble .limits the application, for example to substances and preparatioIls that are the. subjectof a monbgraph of the Pharmacopoeia.

General monographs on dosage forms apply to allpreparations of the type defined. The requirements are not necessari1y comprehensive for>.a given specific preparationand requirements additional tothose prescribed in thegeneralmonograph may be imposed bythe competent authority.

General monographs and individual' monographs are complementary. If the provisions of a generalmonograph do not apply to a particularproduet, this is expressly stated in the individual monograph.

The test methods given in monographs and' general chapters have heen validated inaccordance with accepted scientific practice and current recommendationsonanalyticalvalidation.Unless otherwise stated' in the monograph or general chapter, validation of the test methodsbythe ana.lyst is not required.

The term 'competentauthority' means the national, supranatonalor international body or organisation vested with the authority for making decisions conceming 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, uIlless the competent authority authorises a modification or an, exemption where justified in a particular case.

Statements containing the word 'should' are informative oradvisory. In certain monographs or other texts, the terms 'suitable' and

'appropriate' are used to describe a reagent, micro-organism, test method etc.; if criteria for suitability are not described in the monograph, suitability is demonstrated to the satisfaction of the competent authority.

lnterchangeable l11.ethods

References to regulatol'Y documents

General N otices 21

Medicinal product Ca) Any substance or combination of substances presented as having properties for treating or preventing disease in human beings andlor animals; or (b) any substance or combination of substances that may be used in or administered to human beings and/or animals witha view. either to. restoring, correcting or modifying physiological functions by exerting a. pharmacological, immunological or metabolic action, or to making a medical diagnosis.

Herbal medicinalproduct Any medicinal product, exc1usively containing as active ingredients one or more herbal drugs or one ormore herbal drug preparations, or one or moresuch herbal drugs in combination with one or more 8uch. herbal drug preparations.

Active substance Any substance intended to be used in the manufacture ofa medicinal product and that, when so used, becomes an active ingredient of the medicinal producto 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 affectthe structureand functionof the body.

Excipient . (auxiliary substance). Anyconstituent of a medicinal product that is not an activesubstance. Adjuvants, stabilisers, antimicrobial preservatives, diluents, antioxidants, for example, are excipients.

Certain general chapters containastatement that the text in questionis harmonisedwiththecorres]?opding text of the Japanese Pharmacopoeia and/orthe United States.Pharmacopeia and that these. texts are interchangeable. This implies. that if a substance or preparation is found to comply with arequirePJ,ent using an interchangeable method from oneof these pharmacopoeiasitcomplies with the requirements of the European Pharmacopeia. Intheevent.ofdoubt or dispute, the textofthe.Eropean Pharmacopoeia is alone authoritative.

Monographs and

22 General Notices

fiask or a burette, as appropriate; otherwise, a graduated measuring cylinder ora graduated pipette may be llsed.Volumes stated in micro litres are m.easuredusinga11licropipetteormicrosyringe.

It. i8 reco~ised,however, that jn .certain cases the precision with which quantities. arestateddoesI1otcorre~pond to thenumber of significant figuresstatedinaspe9ifiednumerical1iIIiit. The weighings and measurements arethen carried out with asufficiently improved accuracy.

Voluluetricglasswarecomplies",irh Class A .requirements. ofthe appropriate Intemational.S.tan4ardissuedbythe International Organisation for Standal'disation.

Upless1:hetwiseprescribed:)anlyticalproceduresare carried out at a temperature between .15 Cand 25 oC.

Unless otherwiseprscrihed:)comparative tests are carried out using identical tubes of colourless, transparent, neutral glass with a fiat base; the volumesof liquidprescribed are for use with tubes having an internal diameter of 16 mm:) but tubes withalatger internal diameter may be used provided the volumeofliquid usedis adjusted (2.1.5). Equal volumes of the liquidstQ hecom.paredareexamined d()wn.the vertical axisof the tubes against a whitebac1

General N otices 23

The term 'ethanol' without qualification means anhydrous ethanol. The term 'alcohol'without qualification means ethanol (96 per cent). Other dilutions ofethanoLare indicated by the term 'ethanol' or 'alcohol' followed by a statement of the percentage by volume of ethanol (C2H 60) required.

In definingcontent, the expression'percent' is used according to circumstances with 1of2meanings:

per cent.rn/m (percentage,.mass in mass) expresses the number of gramsofsubstancein lOOgrams offinalproduct; pet c~Ilt VIV(petcentage, vollime in volume) expresses the number o mllilitres of Sllb stanc e in 1 OOmL of finalproduct.

Tneexpression 'partspermillion'(or ppm) refers to mass in mass, unless otherwise 8pedfit!d~

Wl1.ere atlatmlyticalproct!dure describes temperature without a figure, the general termslised havethefollowing meaning:

ina deep-freeze:below-15.o C; il1.arefrigyrator:2 QCto 8 oC; cold orcool;8Cto15?C; rQoil1tempera'tl.lte:15C t 25 oC. 1~3~ GENER.ttL .CHAPTERS l\t1terials1.l~edf

24 General N otices

ChemicalAbstracts Service (CAS)

Registry Number

Definition

Production

Potential Adulteration

CAS registry numbers are includedforinforl11ation in monographs, where applicable, to provideconvenient access to useful information for users. CASRegistryNul11ber@ is a Registered Trademark of the American Chemical Sodety.

Statementsunderthe headingDefip.itionconstitute an official definition of thesub&tance,.preparation . or other . artiele tliat is the subj ect of the monograph.

Limits ofcontent\VheJ;'eJi1J:lits>of contentare prescribed, they arethose cietermined bythemeth0d. describequnderAssay.

Herba.1 drugslnmonographspnherbal drugs, the definition indicates whether thesubjectof thel11onograph is,.for example, the whole drug or the drug in powdered form.Wherea monograph applies to the drug in severalstates, fo! examplbothtothewholedrug and the drug in powdered form, the definition states this.

Statements under the heading Production draw attention to particular aspects of themanufacturing processbut.are not necessari1y comprehensive. They constitutemandatory requirements formanufacturers, unless otherwise stated.They mayrelate, for example, to source materials; to the manufacturing process itself anciitsvalidationand. control; to in7process testing; orto testin~that i8.tO btcarried()ut by themanufacturer on the final article, .eitheron selected hatchesoron. eachbatch . prior to re1ease. Tliese .statefi1entscanp.ot necessarily beverified onasample. of thefinal article by an independent allalyst .. The.competent authority mayestablish that the instrtlcrlonshavebeen follo\iVed, forexample, by examination of datareceivedfromthemanufacturer, by inspection .of manufacture orby testingappropriatesamples.

The absenceof aPrdu

General Norices 25

products and finished products, where relevant). The absence of this section do es not imply that attention to features such as those referred to aboY i8 not required.

Characters The statements under the heading Charactersare not to be interpreted in. a strictsense and are not requirements.

Solubility In statements of solubility in the Characters section, the tenns used have the following significance, referred .. toa temperature between 15 oC and 25 o,C.

Descriptive tetm Approximate vohl1tie of solventin millilitres pef 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 slight1y soluble from 1000 to 10000

Practically insoluble more than 10000

The term 'partly soluble' lS used to describeamxture where onlysome of the components dissolve. The term 'miscible' is used to describe aliquid thatis miscible in all proportions with the stated solvento

Identification Scope The tests given in the Identification section are notdesigned t() giv~ afull confirmation of the chemical structure or compositin()f theproduc1:; they are intended to give conf1rmation,withanacceptable degree of assurance, that the article confonns to the descrptononthe labe!'

First and second identifications Certain monographs have subdivisions entitled 'First identification'and'Second identiction'.The test ot tests that constitutethe 'First identification'maybe used inall drcumstances. The test or tests that constitute the 'Second identification' may be used inphannacies provided it can be demonstrated that the substance or preparation is fully ttaceable t a batch certified lb. c011lply with all the other requirementsof the mon()graph.

Certain monographs give two or more sets of tests for the purpose of the first identification, which are equivalentand may be used independently. Qne 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 outthe identification and the prescribed tests. For example, one identificatiQn set cross':'refers to a test for enantiometicpurity whilethe other set gives a test for specific optical rotation: the intended purpose of the twO is the same, tha.t i8, verification that the correct enantiomer is. presento

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,thatan impurity that is not detectable by means of the prescribed tests is tolerated if common sehse and good pharmaceutical practice require that it be absent. See also below under Impurities.

26 General Notices

Storage

General N atices 27

The artides 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, induding the. type of container (seesection 1.3. General chapters )and litnits of temperature, they are stated in the monograph.

The following expressions are used inmonographsunder Storage with the meaning shown.

In an airtight container meansthat theproduct is stored in an airtight container (3.2)'. Care is to be taken when thecontaineris opened ina damp atmosphere. A low moisture content maybema.intained, if rtecessary, by the use of a desiccant in thecontainerprovidedthat direct contact wiID the product is avoided.

Protected from light means that theproductis stored either in a container made of a material that . absorbs actirtlc lightsuffici~ntly toprotect the contents from change induced by such light, or.irt a container endosed in an outer cover thar provides such protection, oris storedin a placefrom which a11 such light isexcluded.

Label1ing In general, labe11ing of medicines is subject to supranational and natiomtl regulation and to international agreements. The statements under the heading Labelling are not thereforecomprehensive. and, moreover,for the purposes of the Pharmacopoeia only thosestatements that ate necessaryto demonstrate compliance or nOll-compliance withthe monogniphare mandatory. Any other labe11ing statements. are included as recommendations. Wheri theterlll 'label' isusedin the Pharmacopoeia,the labelling statements may appearonthecontainer, thepackage, a leaflet accompanying the package, or a Certifica te ofanalysis accompanyingthe artide, as .decided by the competent authority.

Warnings Materialsdescribed in monographs arid reagents.specified forusein the Pharmacopoeia may be ibjuriollsto health urtlessadequate precautions are taken. The principles of gaod quality controllabaratory practiceand the provisions of any appropriatereglllations are tobe observedat a11 times. Attention is dtawn to.particular hazards in certain mon()graphs bymeansof a warning statement; absence ofsuch a statement is nottobe tal,ento mean that no hazard exists.

Impurities A list of a11 known and potential impurities that have been shown to be detected by the tests in a monograph may be given.See also chapter 5. JO . Control of impurities in substances for pharrnaceutical use. The impurities are designated by a letter or letters of the alphabet.Wherea lettet appears to be missing, the impurity designatedby this letter has been de1eted fromthe list during monograph development prior to publication orduringmonograph

Functionality-Related

Characteristics o Excipients

revision.

Monographs on excipients may have a sction on. functionality~related chatacteristics. The characteristics, any test methods for determination and any tolerances are notmandatoryrequirements; they maynevertheless be relevant for use of the excipient and are given for informaton (seealso secton 1.1. General statements).

28 General Notices

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, whicharealone authoritative in case of arbitration. These referencestandards are availablefrom the European Directorate for the Quality ofMedicines&HealthCare (EDQM) .. Information on the available referencesandardsarid a batch validitystatement can be obtained via the ED.QMwebsite.

General N atices 29

1.5. ABBREVIATIONS AND SYMBOLS

A Absorbance mp Melting point Al per cent

1 cm Specific absorbance n~O Refractive index Ar Relative atomic mass Ph. Eur. U. European Pharmacopoeia U nit

[a]~O Specific optcal rotation ppb Parts per billon (micrograms per kilogram) bp Boiling point ppm Parts per million (milligrams per kilogram) BRP Biological Reference Preparation R Substance or solution defined under CRS Chemical Reference Substance 4. Reagents

d20 Relative density Rp Retardation factor (see chapter 2.2.46) 20 A Wavelength Rst Used in chromatography to indicate the ratio

of the distance travelled by a substance tothe HRS Herbal reference standard distance travelled by a reference substance IU Intemational Unir RV Substance used as a primary standard in M Molarity volumetric analysis (chapter 4.2.1) M r Relative molecular mas s

Abbreviations used in the monographs on immunoglobulins, immunosera and vaccines

LDso The statistically determined quantity of a substance that, when administered by the specified route, may be expected tocause the death of 50 per cent of the test animals within a given period

MLD Mnimum lethal dos e L+/IO dos e The smaIlest quantity of a toxin that,in the

conditions of the test~ when mixed with 0.1 IU of antitoxin and administered by the specified route, causes the death of the test ani11lals within a given period

L+ dose The smallest quantity of a toxin that, in the conditions of the test, when mixed with 1 IU of antitoxin and administered by the specified route, causes the death of thetest animals within a given period

lr/l00dose The smallest quantity of a toxin that, in the conditions of the test, whe