II Introduction (Ph. Eur. 7th Ed.)
The European Pharmacopeia is prepared under the auspices of the Council of Europe in accordance with the terms of the Convention on the elaboration of a European Pharmacopoeia (European Treaty Series No. 50) as amended by the Protocol to the Convention (European Treaty Series No. 134), signed by the Governments of Austria, Belgium, Bosnia and Herzegovina, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Montenegro, Netherlands, Norway, Poland, Portugal, Romania, Serbia, Slovak Republic, Slovenia, Spain, Sweden, Switzerland, “the former Yugoslav Republic of Macedonia”, Turkey, United Kingdom, and by the European Union.
The preparation of the Pharmacopoeia is the responsibility of the European Pharmacopoeia Commission (“the Commission”), appointed in accordance with Article 5 of the above-mentioned Convention. It is composed of delegations appointed by the Contracting Parties. Each delegation consists of not more than 3 members chosen for their competence in matters within the functions of the Commission.
Observers from non-Member States and international organisations are admitted to Sessions of the Commission in accordance with the Rules of Procedure. Observers are at present admitted from: Albania, Algeria, Argentina, Armenia, Australia, Belarus, Brazil, Canada, China, Georgia, Israel, Kazakhstan, Madagascar, Malaysia, Moldova, Morocco, Russian Federation, Senegal, Syria, Tunisia, Ukraine, United States of America and the World Health Organisation.
The Convention is open for signature by European countries and observer status can serve to familiarise European countries intending to become signatories with the working methods of the Commission. The Commission recognises that relations with countries outside Europe are essential in view of the globalisation of the supply chain for pharmaceuticals. Observer status for non-European countries helps to foster these relations by facilitating regulatory partnerships and the exchange of information and working documents.
The functions of the Commission established by Article 6 of the Convention as amended by the Protocol are:
Article 6
“Subject to the provision of Article 4 of the present Convention, the functions of the Commission shall be:
(a) to determine the general principles applicable to the elaboration of the European Pharmacopoeia;
(b) to decide upon methods of analysis for that purpose;
(c) to arrange for the preparation of and to adopt monographs to be included in the European Pharmacopoeia and;
(d) to recommend the fixing of the time limits within which its decisions of a technical character relating to the European
Pharmacopoeia shall be implemented within the territories of the Contracting Parties.”
In accordance with the terms of the Convention, the Contracting Parties undertake to take the necessary measures to ensure that the monographs of the European Pharmacopoeia shall become the official standards applicable within their respective territories.
The purpose of the European Pharmacopoeia is to promote public health by the provision of recognised common standards for use by healthcare professionals and others concerned with the quality of medicines. Such standards are to be appropriate as a basis for the safe use of medicines by patients. Their existence:
- facilitates the free movement of medicinal products in Europe;
- ensures the quality of medicinal products and their components imported into or exported from Europe.
European Pharmacopoeia monographs and other texts are designed to be appropriate to the needs of:
- regulatory authorities;
- those engaged in the quality control of medicinal products and their constituents;
- manufacturers of starting materials and medicinal products.
The European Pharmacopoeia is widely used internationally. It is the intention of the Commission to work closely with all users of the Pharmacopoeia in order to satisfy better their needs and facilitate their co-operation. To this end improved procedures are being developed for obtaining advice on priorities for elaborating new monographs and enhancing the quality of the European Pharmacopoeia.
The headquarters of the European Pharmacopoeia are situated in Strasbourg with a Scientific Secretariat, a Publications and Multimedia Department, a Laboratory and a Reference Standards Division, the latter two being charged, among other duties, with the establishment, production, monitoring and distribution of the reference standards needed for the monographs of the Pharmacopoeia. These entities are parts of the European Directorate for the Quality of Medicines & HealthCare (EDQM) of the Council of Europe, which, amongst others, also comprises the Department for Biological Standardisation, OMCL Network and HealthCare, and the Certification Division.
General rules for interpretation of the texts of the European Pharmacopoeia are given in the General Notices. The following information should also be noted.
The general principles applied in the elaboration of monographs of the European Pharmacopoeia are laid down in procedures and in technical guides available on the EDQM website. The principles applied are revised from time to time without complete retrospective application so that monographs already published may not always follow the latest recommendations, but wherever an issue with an impact on public health is identified, monographs are revised.
It is recognised that general chapters are used elsewhere than in the monographs of the Pharmacopoeia; in these circumstances users are recommended to consult the relevant Technical Guide, which gives extensive information on the application of many of the methods.
General and individual monographs. The standards of the European Pharmacopoeia are represented by general and individual monographs. The use of general monographs has developed in recent years to provide standards that best fulfil the aims stated above and meet the needs of users. From the 4th Edition, the scope of general monographs was extended, except where otherwise stated, to cover products where there is no individual monograph. It is now usually necessary to apply one or more general monographs along with any individual monograph. Where a substance is subject to the provisions of both a general monograph and an individual monograph, the two are complementary. An individual monograph may, exceptionally, include an exemption from one or more provisions of the general monograph.
Since it is not practically possible to include in each individual monograph a cross-reference to applicable or potentially applicable general monographs, cross-referencing has been discontinued except where it is necessary to avoid ambiguity. A list of general monographs is included in each new edition and supplement to aid users in identifying those that are needed for use with an individual monograph.
Use of animals. In accordance with the European Convention on the protection of animals used for experimental and other scientific purposes (1986), the Commission is committed to the reduction of animal usage wherever possible in pharmacopoeial testing, and encourages those associated with its work to seek alternative procedures. An animal test is included in a monograph only if it has clearly been demonstrated that it is necessary to achieve satisfactory control for pharmacopoeial purposes.
Hydrates. With the publication of the 4th Edition, the policy on monograph titles for hydrated forms changed. For all monographs published for the first time in the 4th Edition or subsequent editions, the degree of hydration, where applicable, is indicated in the monograph title. In previous editions, the policy was to indicate the degree of hydration only where several forms exist. If a monograph on both an anhydrous and a hydrated form of a given substance are published, then “anhydrous” will be included in the title of the relevant form. In order to avoid placing an unnecessary burden on manufacturers for relabelling, this policy will not be applied retrospectively to monographs published already, unless there is reason to believe that this is justified as a public health measure, notably for safety reasons where the substance contains a large proportion of water.
Chiral substances. Monographs on chiral substances that describe a particular enantiomer have a test to confirm enantiomeric purity, usually by measurement of optical rotation. Monographs that describe racemates are, in this respect, heterogeneous because of changes of policy during the 3rd Edition. Older monographs do not always have a test to show racemic character. During the course of the 3rd Edition, a test for racemic character was included in all new and revised monographs on racemates, using measurement of optical rotation. When it was shown that in many cases a test for optical rotation, even with narrow limits around zero rotation, was not necessarily sufficiently discriminating because of the low specific optical rotation of the enantiomers, the Commission modified the policy applied. A test for racemic character using optical rotation is now included only if there is information on the specific optical rotation of the enantiomers that indicates that such a test would be discriminating in terms of enantiomeric purity. If other techniques, such as circular dichroism, can serve the intended purpose, they will be prescribed instead of optical rotation.
Polymorphism. Where a substance shows polymorphism, this is usually stated under Characters. In general, no particular crystalline form is required in monographs; exceptionally, in a few monographs, the crystalline form required is specified, for example, via an infrared absorption spectrophotometric identification test where the spectrum is required to be recorded using the substance in the solid state without recrystallisation, the chemical reference substance provided being of the required crystalline form. However, for substances other than these exceptional cases, depending on the use of a given substance in a dosage form, it may be necessary for a manufacturer to ensure that a particular crystalline form is used. The information given under Characters is intended to alert users to the need to evaluate this aspect during the development of a dosage form. The general monograph Substances for pharmaceutical use (2034) and general chapter 5.9. Polymorphism should also be consulted.
Specificity of assays. For the elaboration of monographs on chemical active substances, the approach generally preferred by the Commission is to provide control of impurities (process-related impurities and degradation products) via a well-designed Tests section, with stability-indicating methods, rather than by the inclusion of an assay that is specific for the active moiety. It is therefore the full set of requirements of a monograph that is designed to ensure that the product is of suitable quality throughout its period of use.
Impurities. Following a review of policy on control of impurities, general chapter 5.10. Control of impurities in substances for pharmaceutical use was included in the 5th Edition. Together with the general monograph Substances for pharmaceutical use (2034), it describes the policy of controlling impurities in individual monographs and provides explanations on how the limits in the related substances test should be understood.
The current general policy of the Commission is to include quantitative tests for impurities in monographs. Most of the older monographs elaborated before the establishment of this policy have been revised to introduce quantitative methods. Where a monograph does not conform to the general policy, compliance with the general monograph Substances for pharmaceutical use (2034) will usually imply that the individual monograph requirements need to be supplemented accordingly.
Except where required for the application of the monograph, in which case the name is followed by “CRS”, impurities are not provided as reference standards nor can they be provided for experimental purposes.
Chromatographic columns. As an aid to users, information is made available via the website (see also Knowledge database, below) on chromatographic columns that have been found to be satisfactory during development of monographs and general methods. Information is also given on other equipment and reagents where this is considered useful. This information is given without warranty and does not imply that other columns, equipment or reagents than those specified are not suitable.
Residual solvents. The requirements for residual solvents are given in the general monograph Substances for pharmaceutical use (2034) and general chapter 5.4 Residual solvents. Thus all active substances and excipients are subject to relevant control of residual solvents, even where no test is specified in the individual monograph. The requirements have been aligned with the ICH guideline on this topic.
Medical devices. All editions of the Pharmacopoeia have contained monographs on articles that are regarded as medical devices. For Member States of the European Union, a unified framework for standardisation of medical devices is now provided by a Directive (93/42/EEC). Following an agreement between the various parties involved, the Commission has decided that the monographs on medical devices will be deleted once standards have been developed as foreseen by the Directive. Specifications included in the section on containers will be adapted to take account of future standards developed within the framework of the Directive. The monographs on surgical sutures remain in the Pharmacopoeia but they have been modified to conform to the requirements of the Directive and are now to be seen as standards of the type foreseen there. This adaptation of the monographs has involved the deletion of some monographs on specific types of sutures in favour of a more general approach.
Homoeopathic preparations. A monograph on methods of preparations of homoeopathic stocks and potentisation, general monographs on homoeopathic preparations, mother tinctures for homoeopathic preparations and herbal drugs for homoeopathic preparations, and individual monographs on raw materials and stocks for homoeopathic preparations are included in a separate section of the European Pharmacopoeia. It is understood that when the same substance is used in both homoeopathic and other preparations then the monograph in the main body of the European Pharmacopoeia applies.
Herbal drugs and herbal drug preparations (including traditional Chinese medicines). As of the 7th Edition, it has been decided to group all such relevant monographs together in a separate section in Volume 1.
Functionality-related characteristics. Following a policy decision of the Commission to highlight the need for attention to functionality-related characteristics of excipients and to foster harmonisation of methods for their evaluation, an informative section has been created in the monographs. The contents of this section do not constitute mandatory requirements but the characteristics may be relevant for a particular use of an excipient. The characteristics may be presented in different ways:
- citing the name only;
- citing the name and a suitable test method, preferably one included in the European Pharmacopoeia;
- citing the name, a suitable test method and typical values of tolerances on the stated value; these values or tolerances are used to define a suitable grade of an excipient for a particular use.
In all cases, the method and acceptance criteria are not mandatory requirements but are given for guidance. The decision to control a functionality-related characteristic of an excipient remains with the pharmaceutical manufacturer and is taken with knowledge of the formulation of the product in which it is to be used; the method of determination, acceptance criteria and tolerances are determined on a contractual basis by the user and the supplier of the excipient.
The Commission’s aim is to highlight the need for attention to functionality-related characteristics and to foster harmonisation of methods for their evaluation.
Editorial revision of monographs. Since the 3rd Edition, a new, improved editorial style has progressively been used during the elaboration and revision of monographs on chemicals. Furthermore, a large number of monographs on chemicals that were still published in the old style were converted to the new style for the 6th Edition to provide greater uniformity in editorial presentation. A new, improved editorial style was adopted for monographs on veterinary vaccines during the 5th Edition, and the same has been done for monographs on radiopharmaceutical preparations, materials for containers and containers for the 7th Edition. Conversion to the new style does not affect the technical content of the monographs, and consequently the changes are not tracked by the use of lines in the margin.
Patents. The description in the European Pharmacopoeia of articles subject to protection by patent does not confer or imply any right to the use of such patents by any person or persons other than the proprietors of the patents concerned.
Chemical Abstracts Service (CAS) registry number. In the 6th Edition, CAS registry numbers have been included for information in monographs, where applicable, to provide convenient access to useful information for users. Previously these numbers were given only for reagents, where they are of use in locating suppliers. CAS Registry Number® is a Registered Trademark of the American Chemical Society.
Protected species. Monographs, notably those on herbal drugs, may cover material obtained from protected species. Inclusion of these monographs is without prejudice to the provisions for protection of these species by national and international law.
According to the current policy of the Commission, monographs on pharmaceutical preparations are not elaborated, with the exception of those on immunosera for human use, immunosera for veterinary use, some biological preparations such as insulin preparations, radiopharmaceutical preparations, vaccines for human use and vaccines for veterinary use. This policy has been established since:
- the specifications for a given preparation are approved by the competent authority in light of data from pharmaceutical development work and stability studies; a unique specification for the dosage form of a given active substance would therefore be inappropriate in most instances;
- specifications for a pharmaceutical preparation depend on factors related to the particular formulation.
Harmonisation and standardisation for pharmaceutical preparations have so far been dealt with via the drafting of general dosage form monographs setting out elements common to all preparations within the scope of the monograph, and via the development of standard test methods used for testing of finished products. The inclusion of these general monographs and methods in the European Pharmacopoeia gives a common basis for competent authorities and manufacturers in the preparation and evaluation of applications for marketing authorisation.
Reference standards established for the assay of active substances and excipients may be suitable for use as assay standards for preparations when the conditions stated in general chapter 5.12. Reference standards are fulfilled.
The work programme (elaboration of new monographs or general chapters or revision of existing texts) is decided by the Commission at one of the three annual sessions. In general, whenever two Member States express a wish to elaborate a monograph, the Commission adds the item to the work programme. Changes to the work programme are published on the EDQM website and in Pharmeuropa. Information is also provided to industry associations registered with the Secretariat and to manufacturers’ liaison contacts. Interested parties are invited to contact the Secretariat for any items where they wish to be involved in the work.
A procedure for the certification of suitability of monographs of the Pharmacopoeia with respect to quality control of a product from a given source has been established (see Public Health Committee (Partial Agreement) Resolution AP-CSP (07) 1 or any subsequent revision, available from the EDQM and on its website) as an aid to the use of monographs in applications for marketing authorisation. The certification procedure also applies to herbal drugs, herbal drug preparations and transmissible spongiform encephalopathy (TSE) risk. Certificates of suitability are issued by the EDQM only for substances produced under a suitable quality system. Certificates are granted with respect to published monographs. Details of the operation of this scheme are available from the Secretariat and on the EDQM website. A daily updated list of certificates granted is available online on the EDQM website, including voided or suspended certificates.
The official version of the European Pharmacopoeia is available in English and in French, in the form of a book with 3 supplements per year, and in electronic form (online and USB stick). An electronic version in Spanish is available for the convenience of Spanish-speaking users.
Archives. The European Pharmacopoeia Archives contain the 1st Edition to 6th Edition in PDF format. They are available to all European Pharmacopoeia subscribers with an up-to-date subscription (paper, online or USB stick) and a registered EPID code.
Pharmeuropa, the European Pharmacopoeia Forum, is published 4 times per year as an aid for the elaboration of monographs and as a vehicle for information on pharmacopoeial and related matters. Pharmeuropa Bio & Scientific Notes, a publication indexed by bibliographic services, includes scientific papers related to the establishment of biological reference preparations and validation of biological methods within the Biological Standardisation Programme of the EDQM, and to various aspects of pharmaceutical analysis and other subjects relevant to the Pharmacopoeia.
Website. Information on activities and many other aspects of the European Pharmacopoeia is to be found on the EDQM website.
Knowledge database. The EDQM website provides access to a database containing information of various sorts related to monographs and intended to facilitate their proper use. Information is provided on:
- chromatography columns used in monograph development;
- suppliers of reagents and equipment that may be difficult to find for some users;
- the status of monographs (in development, adopted, published, under revision);
- revisions of the monographs on a historical basis, beginning from the 5th Edition;
- other useful information;
HelpDesk. Many technical and other enquiries are addressed to the EDQM by users. They should be submitted via the HelpDesk on the EDQM website. The EDQM will deal with enquiries that are related to the use of monographs of the European Pharmacopoeia. The HelpDesk has a section of Frequently Asked Questions that should be consulted by users before submission of an enquiry.
Implementation. The date on which monographs are to be implemented is fixed by a Resolution of the European Committee on Pharmaceuticals and Pharmaceutical Care (Partial Agreement) of the Council of Europe, following a recommendation by the Commission. This date is usually 1 year after adoption and about 6 months after publication. Where a monograph is to be implemented at a date earlier than the next publication date of the European Pharmacopoeia or a supplement, a Resolution of the European Committee on Pharmaceuticals and Pharmaceutical Care gives the full text to be implemented. The text is also published in Pharmeuropa for information and posted on the EDQM website as part of the Resolution.
Revision programme. Monographs and other texts of the European Pharmacopoeia are revised as necessary following a decision of the Commission. Revision proposals are published in Pharmeuropa. Proposals to revise monographs may be submitted by a delegation, by the Chair of the Commission or by the chair of a group of experts. Requests for revision from other parties should be submitted via the national pharmacopoeia authority of a Member State or, where this is not possible, to the EDQM, preferably via the HelpDesk. Proposals to revise monographs must be accompanied by sufficient data to justify the need for revision.
Certain tests in monographs, particularly biological assays, require statistical analysis of the results. The EDQM has developed a computer programme, CombiStats, that can be used for statistical analysis of results of biological dilution assays. Information on the programme, with conditions of access and use, is available on the EDQM website.
The European Pharmacopoeia is engaged in a process of harmonisation with the Japanese Pharmacopoeia and the United States Pharmacopeia, within an informal structure referred to as the Pharmacopoeial Discussion Group (PDG). The activities are developed in co-ordination with those of the International Conference on Harmonisation (ICH). Information on the status of harmonised texts is given in general chapter 5.8. Pharmacopoeial harmonisation and on the PDG page of the EDQM website.
Where harmonisation of general chapters is carried out, the aim is to arrive at interchangeable methods or requirements so that demonstration of compliance using a general chapter from one of the 3 pharmacopoeias implies that the same result would be obtained using the general chapter of either of the other pharmacopoeias. When a formal declaration of interchangeability has been recommended by ICH, it will be indicated in general chapter 5.8. Pharmacopoeial harmonisation.If residual differences remain in harmonised general chapters, information is given in this general chapter.
Where harmonisation of monographs is carried out, the aim is to arrive at identical requirements for all attributes of a product. Information on any non-harmonised attributes is included in general chapter 5.8. Pharmacopoeial harmonisation.
Sist gjennomgått: 12.01.2012
Første gang publisert: 12.01.2009