Preface of the 10th edition of the Ph. Eur.
Dette avsnittet er ikke gjengitt, se Den europeiske farmakopé
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 37 member states (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, Ukraine, United Kingdom) and the European Union.
The preparation of the European 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, Azerbaijan, Belarus, Brazil, Canada, China, Georgia, Guinea, Israel, Kazakhstan, Republic of Korea, Madagascar, Malaysia, Republic of Moldova, Morocco, Russian Federation, Senegal, Singapore, South Africa, Syrian Arab Republic, Tunisia, United States of America, Taiwan Food and Drug Administration (TFDA) and the World Health Organisation (WHO).
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 interactions 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 interactions by facilitating regulatory partnerships and the exchange of information and working documents as well as participation in the scientific work of the Commission.
The 9th Edition of the European Pharmacopoeia contains nearly 3000 monographs and general texts. This would not have been possible without the contribution from and dedication of a network of more than 700 experts in pharmaceutical sciences from European Pharmacopoeia member states and observers to the Commission. Participation by experts and stakeholders in the European Pharmacopoeia's public standards-setting process is vital for the development of authoritative and relevant monographs.
To take account of an environment which has undergone dramatic changes over the past 50 years to become a truly globalised pharmaceutical world, the Commission has revised its working procedures to open up to the nomination of experts from non-European Pharmacopoeia member states and non-observer states. This decision, taken at the 153rd session of the Commission (November 2015), is part of a deliberate policy to further involve manufacturers and other stakeholders from outside Europe in the work of the European Pharmacopoeia. Experts from all around the world, whether they are from authorities, industry or academia, will be able to contribute to the elaboration of the European Pharmacopoeia.
The functions of the Commission established by Article 6 of the Convention as amended by the Protocol are:
"Subject to the provisions 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."
The European Directorate for the Quality of Medicines & HealthCare (EDQM) of the Council of Europe supports the Commission in the elaboration and revision of texts of European Pharmacopoeia texts by providing the Scientific Secretariat. In addition, it is responsible for the establishment, production, monitoring and distribution of reference standards needed when applying the monographs. The EDQM is also active in a number of other areas related to the protection of public health, for example in certifying the quality of active pharmaceutical ingredients from specific sources and in biological standardisation.
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.
Purpose of the European Pharmacopoeia
The purpose of the European Pharmacopoeia is to promote public health by the provision of recognised common standards for the quality of medicines and their components. Such standards are to be appropriate as a basis for the safe use of medicines by patients. In addition, their existence facilitates the free movement of medicinal products in Europe and beyond.
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 medicinal products and their individual components.
The European Pharmacopoeia is widely used internationally. As globalisation and expansion in international trade present a growing need to develop global quality standards for medicines, the Commission works closely with all users of the Pharmacopoeia worldwide.
Seat of the European Pharmacopoeia Commission
The seat of the European Pharmacopoeia Commission is situated in Strasbourg, the headquarters of the Council of Europe.
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 immediately.
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 include 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 for the Protection of Vertebrate Animals used for Experimental and Other Scientific Purposes (CETS No. 123), elaborated under the auspices of the Council of Europe, 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. In 2014, the Commission approved the new policy for hydrates (see Style guide available on the EDQM website). When monographs refer to a hydrated form, either well-defined or not, the corresponding degree of hydration (mono-, di-, tri-, n-hydrate or hydrate) is indicated in the title, the chemical formula and the chemical name. For non-hydrates, 'anhydrous' is no longer specified in the title unless otherwise justified.
For new monographs, the degree of hydration is indicated where applicable. For existing monographs, where this precision is not yet indicated, the addition of the degree of hydration will be considered during the next technical revision of the monograph (including publication in Pharmeuropa). A number of existing monographs (e.g. for certain inorganic substances, contain the word 'hydrated' in the title. These will be considered on a case-by-case basis. The Commission decided in November 2014 to delete the term 'anhydrous' from the titles of a certain number of monographs already published in the European Pharmacopoeia, as of the 9th Edition (9.0). Impacted monographs were published in Pharmeuropa for public enquiry.
Chiral substances. Monographs on chiral substances that describe a particular enantiomer have a test to confirm enantiomeric purity, usually by measurement of optical rotation. According to the current policy, a test for racemic character using optical rotation is 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 as of 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) implies 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.
Elemental impurities. Limits for residues of metal catalysts or metal reagents as defined in the respective guideline of the European Medicines Agency (EMA) have been reproduced in general chapter
5.20. Metal catalyst or metal reagent residues and are not legally binding for European Pharmacopoeia users as the chapter is not cross-referenced in a monograph. Reference to general chapter 2.4.8. Heavy metals has been removed from all individual monographs on substances for pharmaceutical use except those for veterinary use only.
Following the adoption of the ICH Q3D guideline by the CHMP (Committee for Medicinal Products for Human Use), the Commission has defined the strategy for implementation in the European Pharmacopoeia and aligned it with the implementation schedule as decided by the CHMP. One decision taken by the Commission was to revise general chapter
5.20 in order to reflect the principles of the ICH Q3D guideline. Details of the strategy for implementation in the European Pharmacopoeia are available on the EDQM website.
Homoeopathic preparations. A monograph on methods of preparation 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). All relevant monographs are grouped together in a separate section of the European Pharmacopoeia.
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.
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. Since 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.
Monographs on pharmaceutical preparations
Up to the 8th Edition, individual monographs on pharmaceutical preparations were not elaborated, with a few exceptions, e.g. 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.
The general monograph
Pharmaceutical preparations (2619) was introduced in the 7th Edition. This monograph is intended to be a reference source of standards in the European Pharmacopoeia on active substances, excipients and dosage forms, which are to be applied in the manufacture/preparation of pharmaceuticals; but not a guide on how to manufacture as there is specific guidance available covering methods of manufacture and associated controls.
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. However, in 2012, the Commission decided to revisit its policy and initiated a pilot phase on individual pharmaceutical preparation monographs to further investigate their feasibility and usefulness.The first monograph on a finished product containing a chemically defined active substance [Sitagliptin tablets (2927)] was adopted by the Commission in March 2015 and published in Supplement 8.7 of the European Pharmacopoeia. With the adoption of this monograph, the Commission decided to extend the scope of the European Pharmacopoeia to include individual pharmaceutical preparation monographs; since then a number of such products have been added to its work programme.
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 3 annual sessions. In general, whenever 2 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 format (online, together with a tablet version, and USB stick).
Archives. The European Pharmacopoeia Archives contain the 1st Edition to 8th 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. Since 2012, both journals are only available as free online publications and individual drafts and scientific papers are published on an ongoing basis.
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:
- its status (e.g. whether a revision is ongoing, together with a brief description, if deemed appropriate);
- chromatography columns used in monograph development;
- suppliers of reagents and equipment that may be difficult to find for some users;
- 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 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.
In an increasingly globalised world, the need for global quality standards has become ever more pressing. Standards are a vital instrument for marketing authorisation, market surveillance and the free movement and trade of medicines amongst regions and countries. Amongst other harmonisation initiatives, 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).
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. To help regulatory authorities and other users recognise the interchangeability of selected harmonised general chapters, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) has issued topic-specific annexes with information about a limited number of these texts in order to facilitate their implementation. More information is available from the ICH website (ich.org).
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 and local requirements is included in the relevant European Pharmacopoeia general chapters and monographs.