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Quality standards of the European Pharmacopoeia
Journal of Ethnopharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎
Contents lists available at ScienceDirect
Journal of Ethnopharmacology journal homepage: www.elsevier.com/locate/jep
Research Paper
Quality standards of the European Pharmacopoeia Anne-Sophie Bouin n, Michael Wierer European Directorate for the Quality of Medicines & Healthcare (EDQM), Council of Europe, 7 Allée Kastner, Cs 30026, F-67081 Strasbourg, France
art ic l e i nf o
a b s t r a c t
Article history: Received 25 March 2014 Received in revised form 21 May 2014 Accepted 8 July 2014
Ethnopharmacological relevance: The European Pharmacopoeia (Ph. Eur.) provides a legal and scientific reference for the quality control of medicines. It is legally binding in the 38 signatory parties of the Convention on the elaboration of a European Pharmacopoeia (37 member states and the European Union). Materials and methods: The requirements for a specific herbal drug are prescribed in the corresponding individual monograph and the relevant general monographs. Criteria for pesticides and heavy metals for example are defined in the general monograph on Herbal drugs. The Ph. Eur. also provides general methods including methods for determination of aflatoxins B1 and ochratoxin A. Screening methods for aristolochic acids are applied for herbal drugs that may be subject to adulteration or substitution with plant material containing aristolochic acids. Conclusion: The Ph. Eur. collaborate in many areas with the European Medicines Agency (EMA) to ensure close collaboration as regards the respective work programmes and approach. & 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Quality control Regulatory affairs European Pharmacopoeia Monographs Herbal drugs
1. European Directorate for the Quality of Medicines and HealthCare Founded in 1949, the Council of Europe (CoE) is the oldest panEuropean organisation, which today has 47 member states, representing 820 million European citizens. Its headquarters are located in Strasbourg, France. The CoE's main aim is to create a common democratic and legal area throughout the European continent, ensuring respect for its fundamental values: human rights, pluralist democracy and the rule of law. The European Directorate for the Quality of Medicines and HealthCare (EDQM), a directorate of the CoE, is based on the Convention on the elaboration of a European Pharmacopoeia, which was adopted in 1964 to harmonise quality standards for medicinal substances that in their original state or in the form of pharmaceutical preparations are of general interest and importance to the people of Europe. The EDQM's mission is to protect public health and to contribute to equal access to good quality medicines and healthcare – a basic human right for all of Europe's citizens. This is achieved by
Abbreviations: CoE, Council of Europe; EDQM, European Directorate for the Quality of Medicines and HealthCare; Ph. Eur., European Pharmacopoeia; EU, European Union; EMA, European Medicines Agency; HMPC, EMA's Committee on Herbal Medicinal Products; CRS, Chemical Reference Substance; HRS, Herbal Reference Standard n Corresponding author. Tel.: +33 3 90 21 46 23; fax: +33 3 88 41 27 71. E-mail address: [email protected] (A.-S. Bouin).
developing quality standards for medicines, supporting their implementation and monitoring their application. The European Pharmacopoeia (Ph. Eur.) provides a legal and scientific reference for the quality control of medicines. It is legally binding in the 38 signatory parties of the Convention: 37 member states and the European Union. In addition, the observers of the European Pharmacopeia Commission (currently 7 European and 17 non-European countries, as well as the WHO and the Taiwan Food and Drug Administration) can benefit from this European experience in work-sharing and harmonisation and have access to the scientific work on the quality control of medicines. The standards of the Ph. Eur. are recognised as a scientific benchmark world-wide. All medicines marketed in the signatory states of the Convention, together with their components, must comply with the quality standards of the Ph. Eur. Hence, companies must follow these standards when applying to a national competent authority or the European Medicines Agency (EMA) for a marketing authorisation and must include reference to the monographs in the quality part of their application dossiers. In addition to the work related to the Ph. Eur., the EDQM also develops guidance and standards in areas such as blood transfusion, organ, tissue and cell transplantation and consumer health issues. 1.1. Ph. Eur. Commission The Ph. Eur. Commission is the governing body of the Ph. Eur. Each Member State and Observer is entitled to send a delegation, which consists of up to three members appointed by the
http://dx.doi.org/10.1016/j.jep.2014.07.020 0378-8741/& 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Bouin, A.-S., Wierer, M., Quality standards of the European Pharmacopoeia. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.07.020i
A.-S. Bouin, M. Wierer / Journal of Ethnopharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎
2
respective country. Commission members normally hail from health ministries, health authorities, pharmacopoeias, universities or industry. The European Union (EU) delegation is comprised of a representative from both the Directorate General Health & Consumers and from the EMA. The Ph. Eur. Commission meets three times per year. It appoints the members of its permanent Groups of Experts and ad hoc Working Parties (currently numbering 20 and 50 separate entities, respectively) and co-ordinates their work. All texts are adopted by unanimous vote. The Secretariat of the Ph. Eur. Commission is provided by the European Pharmacopeia Department at the EDQM.
2. Monographs of the European Pharmacopoeia 2.1. Portfolio of monographs and general chapters for herbals About 12% of the Ph. Eur. texts are directly related to herbals. The Ph. Eur. contains general monographs on herbal drugs and herbal drug preparations (e.g. “Herbal teas”, “Extracts”, “Essential oils Ph. Eur., 2013), as well as an increasing number of monographs on specific herbals. In 2013, it included 187 monographs on herbal drugs (e.g. “Melissa leaf”, “Liquorice root” (Ph. Eur., 2013) – including 40 monographs on herbal drugs used in Traditional Chinese Medicine – and 85 monographs on herbal drug preparations (e.g. “Ginseng dry extract”, “Anise oil” (Ph. Eur., 2013). The Ph. Eur. also describes numerous general methods – of particular relevance to herbal drugs and herbal drug preparations are the 23 general methods published in sub-section “2.8 Methods for pharmacognosy” (Ph. Eur., 2013) (such as for “Ash insoluble in hydrochloric acid”, “Pesticide residues”, and “Sampling and sample preparation of herbal drugs”) and general method 2.4.27 on “Heavy metals in herbal drugs and fatty oils” (Ph. Eur., 2013). Finally, the general chapter on the “microbiological quality of herbal medicinal products for oral use and extracts used in their preparation” (5.1.8) (Ph. Eur., 2013) is of particular importance.
2.2.2.2. Identification. The Identification section typically includes details on the macroscopic botanical characters, the microscopic botanical characters and a thin-layer chromatography profile. The combination of these different methods allows an identification to be made without the use of expensive equipment. Identification can therefore also be carried out in community pharmacies for example. For most monographs, graphic illustrations of the diagnostic characters of the powdered herbal drugs are included in the monographs.
2.2.2.3. Tests. The Tests section may include many different tests such as foreign matter, loss on drying/water, heavy metals, total ash, ash insoluble in HCl, aflatoxin B1, ochratoxin, swelling index, bitterness value, extractable matter, etc. Some of these tests are prescribed directly in the corresponding specific monographs, whereas others are prescribed in a general monograph that is applied to all relevant monographs, unless stated otherwise in a specific monograph. For example, the following general limits for heavy metals are specified in the general monograph on herbal drugs: Lead – maximum 5.0 ppm, Mercury – maximum 0.1 ppm and Cadmium – maximum 1.0 ppm. These general limits apply to all herbal drugs, apart from a limited number of exceptions where specific limits are prescribed in the relevant monograph (for example, the monograph on “Kelp” (Ph. Eur., 2013). For certain contaminants of particular importance, general test methods have been established. For example:
Determination of aflatoxin B1 in herbal drugs (2.8.18) (Ph. Eur.,
2.2. Herbal drug monographs The monographs are prepared by the relevant Groups of Experts/Working Parties in accordance with the “Technical guide for the elaboration of monographs on herbal drugs and herbal drug preparations” (Technical guide for the elaboration of monographs on herbal drugs and herbal drug preparations). 2.2.1. Titles of herbal drug monographs Monograph titles are given both in Latin and English or French (depending on the language version of the Ph. Eur.). Many herbal drugs have a well-established name in English (or in French), and this is usually the one that is used in the title. Where there is no common name, the title is derived from the scientific name. In the case of herbal drugs used in traditional Chinese medicine for which a monograph is published in the Ph. Eur., the informative chapter 5.22 (Ph. Eur., 2013) provides a table for ease of reference that includes cross-references to the Chinese names in pinyin and in sinograms. 2.2.2. Typical sections of herbal drug monographs Monographs on herbal drugs are typically divided into the following sections: 2.2.2.1. Definition. The Definition gives the state of the drug (whole, fragmented, peeled, fresh, dried, etc.) and the complete scientific name of the plant (genus, species, subspecies, variety, author). Wherever possible, the minimum content of the quantified constituents determined by the method prescribed under the assay is specified.
2013). In this case, a very sensitive method that allows the quantification of aflatoxin B1 at levels lower than 2 ng/g has been established. It is based on an immunoaffinity clean-up procedure, followed by reversed-phase HPLC with fluorescence detection after post-column derivatisation. It aims at limiting aflatoxin B1, which is the most toxic and most prevalent of aflatoxins, but also effectively limits other aflatoxins since they are present in quantities not exceeding those of aflatoxin B1. The method has been shown to be satisfactory in terms of recovery, precision and limit of detection for devil's claw root, ginger and senna pods. Due to potential matrix effects, its suitability for other herbal drugs must be demonstrated by the manufacturer. Determination of ochratoxin A in herbal drugs (2.8.22) (Ph. Eur., 2013). Similarly to determination of aflatoxin, a method based on immunoaffinity extraction followed by HPLC has been established to limit ochratoxin A to a maximum of 20 ng/g in liquorice root and 80 ng/g in liquorice extract. It may be used for other herbal drugs but, again, due to matrix effects, the suitability for other herbal drugs must be demonstrated by the manufacturer or another validated method must be used. Test for aristolochic acids in herbal drugs (2.8.21) (Ph. Eur., 2013). In the past, adulteration or substitution of Stephania tetrandra with plant material containing aristolochic acid(s) has occurred and this has been identified as a serious threat to public health. Therefore, Health Authorities requested that a sensitive general method for detection of these acids to be elaborated. As a result, a tiered approach of screening and confirmatory testing involving several methods has been established. Methods A and B are intended to be cross-referenced in monographs on herbal drugs that are expected to be free from aristolochic acids according to chemotaxonomic knowledge, but that may be subject to adulteration or substitution with plant material containing aristolochic acids. Methods A (HPTLC) and B (HPLC) are used for the screening of herbal drugs and are usually complemented by macroscopic and/or microscopic tests to exclude plant material containing aristolochic acids. As an example, the monograph on “Clematis armandii stem”
Please cite this article as: Bouin, A.-S., Wierer, M., Quality standards of the European Pharmacopoeia. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.07.020i
A.-S. Bouin, M. Wierer / Journal of Ethnopharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎
(Ph. Eur., 2013) includes a cross-reference to Method A for aristolochic acids and a microscopic examination to exclude Aristolochia manshuriensis Kom and other species of Aristolochia. Method C (LC-MS) is not used in specific monographs for routine testing, but it is provided as a method to confirm the presence of aristolochic acid I at levels equal to or greater than 2 ppm. Thus, Method C is intended as a confirmatory test to be applied if chromatographic data suggests the presence of aristolochic acid I. It is important to note that these methods are not intended as assay methods for inclusion in monographs on drugs that produce aristolochic acids as secondary metabolites; for these, a more sensitive, validated method would be required. 2.2.2.4. Assay. Wherever possible, an Assay is included to determine the constituent with known therapeutic activity, an active marker or analytical markers. The determination of specific constituents by modern chromatographic methods such as LC or GC is preferred. In these cases, a corresponding reference standard (CRS or HRS) is established, which can be ordered from the EDQM. The choice of constituent should be scientifically-justified but also sustainability of the reference standard ensured. Modern instrumental methods are more specific, provide better reproducibility and generate more meaningful information in terms of stability compared to the colorimetric/spectrophotometric determinations that have traditionally been used in the past. Ph. Eur. groups of experts have to propose analytical methods that are appropriate for the intended purpose and take account of the current state of scientific knowledge. In this context, concerns have been raised that switching from an unspecific conventional assay method to a more selective LC method would lead to inconsistencies with existing authorised specifications and dosages that are based on
3
reference documents on the well-established or traditional use of herbal drugs and herbal drug preparations, notably the monographs of the EMA's Committee on Herbal Medicinal Products (HMPC). Content and dosage recommendations given in the HMPC monographs usually refer to established pharmacopoeial methods and many of these monographs still prescribe conventional assay methods. Once a modern, more selective method becomes the mandatory standard, different (typically lower) assay values are expected. Therefore, when a revision is envisaged that involves a change from a colorimetric method to a more specific and precise LC method, there is a need for a transition period. This transition period allows data to be collected that relates the content determined by the new method to the dosage as given in the reference documents (e.g. the respective HMPC monograph). This is the case, for example, for the monograph on “Standardised horse-chestnut dry extract” (Pharmeuropa, 2008).
3. Reference standards of the European Pharmacopoeia Pharmacopoeial monographs require the use of different reference materials as benchmarks for analytical testing. These reference materials can be classified according to their intended use, i.e. both qualitative (for the purpose of screening for adulterants or for peak identification and system suitability test in chromatography) and quantitative (assigned content). In the field of herbals, the Ph. Eur. establishes the following types of reference standards:
Chemical reference substances (CRS) of active or analytical markers. These are single compounds such as ferulic acid, rutoside trihydrate, astragaloside IV, baicalin, etc.
Fig. 1. Chromatogram obtained with kudzuvine root dry extract HRS, batch 1: it is used for peak assignment, verification of the peak to valley ratio between 3-methoxypuerarin and puerarin as system suitability test as well as for the calculation of puerarin content. The percentage content of kudzuvine root dry extract HRS, batch 1 is 8.98% puerarin.
Please cite this article as: Bouin, A.-S., Wierer, M., Quality standards of the European Pharmacopoeia. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.07.020i
A.-S. Bouin, M. Wierer / Journal of Ethnopharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎
4
Herbal extracts used as herbal reference standard (HRS). These
standards are a well-characterised sample of an extract that is used as an external standard when the active or analytical markers are not available in sufficient amounts or are unstable in isolated form. As an example, in the monograph on “Kudzuvine root” (Puerariae lobatae radix) (Ph. Eur., 2013), the assay prescribes the use of kudzuvine root dry extract HRS with an assigned content for puerarin (see Fig. 1). The following extracts have also been established as HRS: valerian dry extract HRS, ivy leaf dry extract HRS, etc. Herbal drugs also used as herbal reference standard (HRS). In some cases, powdered herbal drugs are established as HRS. As an example, the Equisetum palustre HRS is used in a TLC test for adulteration in the monograph on “Equisetum stem” (Ph. Eur., 2013). Another interesting example is Aristolochia HRS, which consists of powdered material from Aristolochia serpentaria. It has a known content of aristolochic acid I and is employed in the HPTLC screening test for aristolochic acids (general method 2.8.21, Method A (Ph. Eur., 2013)).
4. Interactions between the EDQM and regulators Since 1975, the EU pharmaceutical legislation makes direct reference to the Ph. Eur. Today, it also refers to other activities under the EDQM's responsibility, such as the procedure for certification of suitability to the monographs of the European Pharmacopoeia and co-ordination of the European network of Official Medicines Control Laboratories. While the Council of Europe is distinct from the European Union and its institutions, the two organisations collaborate in many areas. The EMA's quality-related working parties regularly interact with the Ph. Eur. Commission and its scientific groups during the development and revision of standards. The EMA participates as an observer in meetings of scientific groups related
to the Ph. Eur. For example, in the area of herbals, members of the EMA's HMPC participate at meetings of the Ph. Eur. Commission's Groups of Experts 13A and 13 B and the TCM Working Party. Likewise, the EDQM participates in meetings of the quality-related working parties and committees of the EMA. The EMA's Management Board has, inter alia, granted the EDQM observer status at the HMPC. The EDQM participates as an observer at EMA meetings so that it can be aware of upcoming guidelines and marketing authorisation applications. In addition, EDQM staff members, as well as the Chairs of the Ph. Eur. Commission's herbal-related Groups of Experts, also participate in the meetings of the HMPC Quality Drafting Group. These exchanges ensure close collaboration as regards the respective work programmes and approach of the EMA and Ph. Eur. Commission expert groups.
5. Conclusions In summary, the Ph. Eur. provides legally binding standards for a vast array of health-related products, including for herbal drugs and herbal drug preparations. It has to address public health issues, to regularly update analytical methods to ensure alignment with the current state of scientific knowledge and to establish and supply appropriate reference materials. Finally, particular attention is given to maintaining a close relationship with manufacturers, regulatory authorities, the HMPC and other EMA committees and working parties. References Ph.Eur 8th Edition. Strasbourg, France: Council of Europe; 20 (vol 1); 2013. Pharmeuropa Vol.20, N13, July 2008 [available from 〈http://pharmeuropa.edqm. eu〉]. Technical guide for the elaboration of monographs on herbal drugs and herbal drug preparations [available from 〈http://www.edqm.eu/en/technical-guides-589. html〉].
Please cite this article as: Bouin, A.-S., Wierer, M., Quality standards of the European Pharmacopoeia. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.07.020i
Contents lists available at ScienceDirect
Journal of Ethnopharmacology journal homepage: www.elsevier.com/locate/jep
Research Paper
Quality standards of the European Pharmacopoeia Anne-Sophie Bouin n, Michael Wierer European Directorate for the Quality of Medicines & Healthcare (EDQM), Council of Europe, 7 Allée Kastner, Cs 30026, F-67081 Strasbourg, France
art ic l e i nf o
a b s t r a c t
Article history: Received 25 March 2014 Received in revised form 21 May 2014 Accepted 8 July 2014
Ethnopharmacological relevance: The European Pharmacopoeia (Ph. Eur.) provides a legal and scientific reference for the quality control of medicines. It is legally binding in the 38 signatory parties of the Convention on the elaboration of a European Pharmacopoeia (37 member states and the European Union). Materials and methods: The requirements for a specific herbal drug are prescribed in the corresponding individual monograph and the relevant general monographs. Criteria for pesticides and heavy metals for example are defined in the general monograph on Herbal drugs. The Ph. Eur. also provides general methods including methods for determination of aflatoxins B1 and ochratoxin A. Screening methods for aristolochic acids are applied for herbal drugs that may be subject to adulteration or substitution with plant material containing aristolochic acids. Conclusion: The Ph. Eur. collaborate in many areas with the European Medicines Agency (EMA) to ensure close collaboration as regards the respective work programmes and approach. & 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Quality control Regulatory affairs European Pharmacopoeia Monographs Herbal drugs
1. European Directorate for the Quality of Medicines and HealthCare Founded in 1949, the Council of Europe (CoE) is the oldest panEuropean organisation, which today has 47 member states, representing 820 million European citizens. Its headquarters are located in Strasbourg, France. The CoE's main aim is to create a common democratic and legal area throughout the European continent, ensuring respect for its fundamental values: human rights, pluralist democracy and the rule of law. The European Directorate for the Quality of Medicines and HealthCare (EDQM), a directorate of the CoE, is based on the Convention on the elaboration of a European Pharmacopoeia, which was adopted in 1964 to harmonise quality standards for medicinal substances that in their original state or in the form of pharmaceutical preparations are of general interest and importance to the people of Europe. The EDQM's mission is to protect public health and to contribute to equal access to good quality medicines and healthcare – a basic human right for all of Europe's citizens. This is achieved by
Abbreviations: CoE, Council of Europe; EDQM, European Directorate for the Quality of Medicines and HealthCare; Ph. Eur., European Pharmacopoeia; EU, European Union; EMA, European Medicines Agency; HMPC, EMA's Committee on Herbal Medicinal Products; CRS, Chemical Reference Substance; HRS, Herbal Reference Standard n Corresponding author. Tel.: +33 3 90 21 46 23; fax: +33 3 88 41 27 71. E-mail address: [email protected] (A.-S. Bouin).
developing quality standards for medicines, supporting their implementation and monitoring their application. The European Pharmacopoeia (Ph. Eur.) provides a legal and scientific reference for the quality control of medicines. It is legally binding in the 38 signatory parties of the Convention: 37 member states and the European Union. In addition, the observers of the European Pharmacopeia Commission (currently 7 European and 17 non-European countries, as well as the WHO and the Taiwan Food and Drug Administration) can benefit from this European experience in work-sharing and harmonisation and have access to the scientific work on the quality control of medicines. The standards of the Ph. Eur. are recognised as a scientific benchmark world-wide. All medicines marketed in the signatory states of the Convention, together with their components, must comply with the quality standards of the Ph. Eur. Hence, companies must follow these standards when applying to a national competent authority or the European Medicines Agency (EMA) for a marketing authorisation and must include reference to the monographs in the quality part of their application dossiers. In addition to the work related to the Ph. Eur., the EDQM also develops guidance and standards in areas such as blood transfusion, organ, tissue and cell transplantation and consumer health issues. 1.1. Ph. Eur. Commission The Ph. Eur. Commission is the governing body of the Ph. Eur. Each Member State and Observer is entitled to send a delegation, which consists of up to three members appointed by the
http://dx.doi.org/10.1016/j.jep.2014.07.020 0378-8741/& 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Bouin, A.-S., Wierer, M., Quality standards of the European Pharmacopoeia. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.07.020i
A.-S. Bouin, M. Wierer / Journal of Ethnopharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎
2
respective country. Commission members normally hail from health ministries, health authorities, pharmacopoeias, universities or industry. The European Union (EU) delegation is comprised of a representative from both the Directorate General Health & Consumers and from the EMA. The Ph. Eur. Commission meets three times per year. It appoints the members of its permanent Groups of Experts and ad hoc Working Parties (currently numbering 20 and 50 separate entities, respectively) and co-ordinates their work. All texts are adopted by unanimous vote. The Secretariat of the Ph. Eur. Commission is provided by the European Pharmacopeia Department at the EDQM.
2. Monographs of the European Pharmacopoeia 2.1. Portfolio of monographs and general chapters for herbals About 12% of the Ph. Eur. texts are directly related to herbals. The Ph. Eur. contains general monographs on herbal drugs and herbal drug preparations (e.g. “Herbal teas”, “Extracts”, “Essential oils Ph. Eur., 2013), as well as an increasing number of monographs on specific herbals. In 2013, it included 187 monographs on herbal drugs (e.g. “Melissa leaf”, “Liquorice root” (Ph. Eur., 2013) – including 40 monographs on herbal drugs used in Traditional Chinese Medicine – and 85 monographs on herbal drug preparations (e.g. “Ginseng dry extract”, “Anise oil” (Ph. Eur., 2013). The Ph. Eur. also describes numerous general methods – of particular relevance to herbal drugs and herbal drug preparations are the 23 general methods published in sub-section “2.8 Methods for pharmacognosy” (Ph. Eur., 2013) (such as for “Ash insoluble in hydrochloric acid”, “Pesticide residues”, and “Sampling and sample preparation of herbal drugs”) and general method 2.4.27 on “Heavy metals in herbal drugs and fatty oils” (Ph. Eur., 2013). Finally, the general chapter on the “microbiological quality of herbal medicinal products for oral use and extracts used in their preparation” (5.1.8) (Ph. Eur., 2013) is of particular importance.
2.2.2.2. Identification. The Identification section typically includes details on the macroscopic botanical characters, the microscopic botanical characters and a thin-layer chromatography profile. The combination of these different methods allows an identification to be made without the use of expensive equipment. Identification can therefore also be carried out in community pharmacies for example. For most monographs, graphic illustrations of the diagnostic characters of the powdered herbal drugs are included in the monographs.
2.2.2.3. Tests. The Tests section may include many different tests such as foreign matter, loss on drying/water, heavy metals, total ash, ash insoluble in HCl, aflatoxin B1, ochratoxin, swelling index, bitterness value, extractable matter, etc. Some of these tests are prescribed directly in the corresponding specific monographs, whereas others are prescribed in a general monograph that is applied to all relevant monographs, unless stated otherwise in a specific monograph. For example, the following general limits for heavy metals are specified in the general monograph on herbal drugs: Lead – maximum 5.0 ppm, Mercury – maximum 0.1 ppm and Cadmium – maximum 1.0 ppm. These general limits apply to all herbal drugs, apart from a limited number of exceptions where specific limits are prescribed in the relevant monograph (for example, the monograph on “Kelp” (Ph. Eur., 2013). For certain contaminants of particular importance, general test methods have been established. For example:
Determination of aflatoxin B1 in herbal drugs (2.8.18) (Ph. Eur.,
2.2. Herbal drug monographs The monographs are prepared by the relevant Groups of Experts/Working Parties in accordance with the “Technical guide for the elaboration of monographs on herbal drugs and herbal drug preparations” (Technical guide for the elaboration of monographs on herbal drugs and herbal drug preparations). 2.2.1. Titles of herbal drug monographs Monograph titles are given both in Latin and English or French (depending on the language version of the Ph. Eur.). Many herbal drugs have a well-established name in English (or in French), and this is usually the one that is used in the title. Where there is no common name, the title is derived from the scientific name. In the case of herbal drugs used in traditional Chinese medicine for which a monograph is published in the Ph. Eur., the informative chapter 5.22 (Ph. Eur., 2013) provides a table for ease of reference that includes cross-references to the Chinese names in pinyin and in sinograms. 2.2.2. Typical sections of herbal drug monographs Monographs on herbal drugs are typically divided into the following sections: 2.2.2.1. Definition. The Definition gives the state of the drug (whole, fragmented, peeled, fresh, dried, etc.) and the complete scientific name of the plant (genus, species, subspecies, variety, author). Wherever possible, the minimum content of the quantified constituents determined by the method prescribed under the assay is specified.
2013). In this case, a very sensitive method that allows the quantification of aflatoxin B1 at levels lower than 2 ng/g has been established. It is based on an immunoaffinity clean-up procedure, followed by reversed-phase HPLC with fluorescence detection after post-column derivatisation. It aims at limiting aflatoxin B1, which is the most toxic and most prevalent of aflatoxins, but also effectively limits other aflatoxins since they are present in quantities not exceeding those of aflatoxin B1. The method has been shown to be satisfactory in terms of recovery, precision and limit of detection for devil's claw root, ginger and senna pods. Due to potential matrix effects, its suitability for other herbal drugs must be demonstrated by the manufacturer. Determination of ochratoxin A in herbal drugs (2.8.22) (Ph. Eur., 2013). Similarly to determination of aflatoxin, a method based on immunoaffinity extraction followed by HPLC has been established to limit ochratoxin A to a maximum of 20 ng/g in liquorice root and 80 ng/g in liquorice extract. It may be used for other herbal drugs but, again, due to matrix effects, the suitability for other herbal drugs must be demonstrated by the manufacturer or another validated method must be used. Test for aristolochic acids in herbal drugs (2.8.21) (Ph. Eur., 2013). In the past, adulteration or substitution of Stephania tetrandra with plant material containing aristolochic acid(s) has occurred and this has been identified as a serious threat to public health. Therefore, Health Authorities requested that a sensitive general method for detection of these acids to be elaborated. As a result, a tiered approach of screening and confirmatory testing involving several methods has been established. Methods A and B are intended to be cross-referenced in monographs on herbal drugs that are expected to be free from aristolochic acids according to chemotaxonomic knowledge, but that may be subject to adulteration or substitution with plant material containing aristolochic acids. Methods A (HPTLC) and B (HPLC) are used for the screening of herbal drugs and are usually complemented by macroscopic and/or microscopic tests to exclude plant material containing aristolochic acids. As an example, the monograph on “Clematis armandii stem”
Please cite this article as: Bouin, A.-S., Wierer, M., Quality standards of the European Pharmacopoeia. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.07.020i
A.-S. Bouin, M. Wierer / Journal of Ethnopharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎
(Ph. Eur., 2013) includes a cross-reference to Method A for aristolochic acids and a microscopic examination to exclude Aristolochia manshuriensis Kom and other species of Aristolochia. Method C (LC-MS) is not used in specific monographs for routine testing, but it is provided as a method to confirm the presence of aristolochic acid I at levels equal to or greater than 2 ppm. Thus, Method C is intended as a confirmatory test to be applied if chromatographic data suggests the presence of aristolochic acid I. It is important to note that these methods are not intended as assay methods for inclusion in monographs on drugs that produce aristolochic acids as secondary metabolites; for these, a more sensitive, validated method would be required. 2.2.2.4. Assay. Wherever possible, an Assay is included to determine the constituent with known therapeutic activity, an active marker or analytical markers. The determination of specific constituents by modern chromatographic methods such as LC or GC is preferred. In these cases, a corresponding reference standard (CRS or HRS) is established, which can be ordered from the EDQM. The choice of constituent should be scientifically-justified but also sustainability of the reference standard ensured. Modern instrumental methods are more specific, provide better reproducibility and generate more meaningful information in terms of stability compared to the colorimetric/spectrophotometric determinations that have traditionally been used in the past. Ph. Eur. groups of experts have to propose analytical methods that are appropriate for the intended purpose and take account of the current state of scientific knowledge. In this context, concerns have been raised that switching from an unspecific conventional assay method to a more selective LC method would lead to inconsistencies with existing authorised specifications and dosages that are based on
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reference documents on the well-established or traditional use of herbal drugs and herbal drug preparations, notably the monographs of the EMA's Committee on Herbal Medicinal Products (HMPC). Content and dosage recommendations given in the HMPC monographs usually refer to established pharmacopoeial methods and many of these monographs still prescribe conventional assay methods. Once a modern, more selective method becomes the mandatory standard, different (typically lower) assay values are expected. Therefore, when a revision is envisaged that involves a change from a colorimetric method to a more specific and precise LC method, there is a need for a transition period. This transition period allows data to be collected that relates the content determined by the new method to the dosage as given in the reference documents (e.g. the respective HMPC monograph). This is the case, for example, for the monograph on “Standardised horse-chestnut dry extract” (Pharmeuropa, 2008).
3. Reference standards of the European Pharmacopoeia Pharmacopoeial monographs require the use of different reference materials as benchmarks for analytical testing. These reference materials can be classified according to their intended use, i.e. both qualitative (for the purpose of screening for adulterants or for peak identification and system suitability test in chromatography) and quantitative (assigned content). In the field of herbals, the Ph. Eur. establishes the following types of reference standards:
Chemical reference substances (CRS) of active or analytical markers. These are single compounds such as ferulic acid, rutoside trihydrate, astragaloside IV, baicalin, etc.
Fig. 1. Chromatogram obtained with kudzuvine root dry extract HRS, batch 1: it is used for peak assignment, verification of the peak to valley ratio between 3-methoxypuerarin and puerarin as system suitability test as well as for the calculation of puerarin content. The percentage content of kudzuvine root dry extract HRS, batch 1 is 8.98% puerarin.
Please cite this article as: Bouin, A.-S., Wierer, M., Quality standards of the European Pharmacopoeia. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.07.020i
A.-S. Bouin, M. Wierer / Journal of Ethnopharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎
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Herbal extracts used as herbal reference standard (HRS). These
standards are a well-characterised sample of an extract that is used as an external standard when the active or analytical markers are not available in sufficient amounts or are unstable in isolated form. As an example, in the monograph on “Kudzuvine root” (Puerariae lobatae radix) (Ph. Eur., 2013), the assay prescribes the use of kudzuvine root dry extract HRS with an assigned content for puerarin (see Fig. 1). The following extracts have also been established as HRS: valerian dry extract HRS, ivy leaf dry extract HRS, etc. Herbal drugs also used as herbal reference standard (HRS). In some cases, powdered herbal drugs are established as HRS. As an example, the Equisetum palustre HRS is used in a TLC test for adulteration in the monograph on “Equisetum stem” (Ph. Eur., 2013). Another interesting example is Aristolochia HRS, which consists of powdered material from Aristolochia serpentaria. It has a known content of aristolochic acid I and is employed in the HPTLC screening test for aristolochic acids (general method 2.8.21, Method A (Ph. Eur., 2013)).
4. Interactions between the EDQM and regulators Since 1975, the EU pharmaceutical legislation makes direct reference to the Ph. Eur. Today, it also refers to other activities under the EDQM's responsibility, such as the procedure for certification of suitability to the monographs of the European Pharmacopoeia and co-ordination of the European network of Official Medicines Control Laboratories. While the Council of Europe is distinct from the European Union and its institutions, the two organisations collaborate in many areas. The EMA's quality-related working parties regularly interact with the Ph. Eur. Commission and its scientific groups during the development and revision of standards. The EMA participates as an observer in meetings of scientific groups related
to the Ph. Eur. For example, in the area of herbals, members of the EMA's HMPC participate at meetings of the Ph. Eur. Commission's Groups of Experts 13A and 13 B and the TCM Working Party. Likewise, the EDQM participates in meetings of the quality-related working parties and committees of the EMA. The EMA's Management Board has, inter alia, granted the EDQM observer status at the HMPC. The EDQM participates as an observer at EMA meetings so that it can be aware of upcoming guidelines and marketing authorisation applications. In addition, EDQM staff members, as well as the Chairs of the Ph. Eur. Commission's herbal-related Groups of Experts, also participate in the meetings of the HMPC Quality Drafting Group. These exchanges ensure close collaboration as regards the respective work programmes and approach of the EMA and Ph. Eur. Commission expert groups.
5. Conclusions In summary, the Ph. Eur. provides legally binding standards for a vast array of health-related products, including for herbal drugs and herbal drug preparations. It has to address public health issues, to regularly update analytical methods to ensure alignment with the current state of scientific knowledge and to establish and supply appropriate reference materials. Finally, particular attention is given to maintaining a close relationship with manufacturers, regulatory authorities, the HMPC and other EMA committees and working parties. References Ph.Eur 8th Edition. Strasbourg, France: Council of Europe; 20 (vol 1); 2013. Pharmeuropa Vol.20, N13, July 2008 [available from 〈http://pharmeuropa.edqm. eu〉]. Technical guide for the elaboration of monographs on herbal drugs and herbal drug preparations [available from 〈http://www.edqm.eu/en/technical-guides-589. html〉].
Please cite this article as: Bouin, A.-S., Wierer, M., Quality standards of the European Pharmacopoeia. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.07.020i