4.1 The International Pharmacopoeia Second supplement
An update was presented on The International Pharmacopoeia (Ph.Int.) activities and work plan. The Expert Committee noted that the work on the compilation of the Second supplement to the fourth edition was progressing and that it would be published as a replacement CD-ROM and an online version.
This publication would comprise new and revised texts adopted by the Expert Committee since 2007.
As per the work process, the fi nal version of the monographs adopted during the present meeting would be made available on the WHO Medicines web site once completed and would subsequently be compiled into a publication.
Collaboration with other pharmacopoeias
The Secretariat reported to the Expert Committee that an enhanced collaboration between The International Pharmacopoeia and The British Pharmacopoeia had commenced.
This collaboration between The Medicines and Healthcare products Regulatory Agency of the United Kingdom of Great Britain and Northern Ireland (MHRA), which hosts The British Pharmacopoeia and WHO, which hosts The International Pharmacopoeia, was aimed at developing
a closer cooperation and exchange in the fi eld of quality specifi cations for medicines, which would be based on common priorities as identifi ed by both pharmacopoeias in their respective work plans.
It was foreseen that by sharing their experience in the development of specifi cations for formulated products, this collaboration would be of mutual benefi t for these pharmacopoeias, notably in making more specifi cations available to users.
The Secretariat informed the Expert Committee that, in the context of this cooperation, work had been rapidly initiated with a pilot phase comprising three monographs for anti-infectives (amoxicillin oral suspension, metronidazole oral suspension, sulfamethoxazole and trimethoprim tablets) that could be developed and discussed at the meeting of the Expert Committee.
Noting that this collaboration was to be formalized by an agreement between the two organizations hosting the pharmacopoeias, the Expert Committee welcomed this initiative and the outcome of this pilot phase in adopting the presented texts (see section 4.3.4 of this report on specifi cations for anti-infectives).
4.2 Current work plan and future work programme
Based on the 2010 work plan, the Expert Committee discussed and reviewed:
— the current development status of the monographs; and
— new proposals for developing specifi cations for active substances and dosage forms, including those for paediatric use.
New proposals were made, taking into account:
• substances remaining in the current work plan;
— substances initially listed in the previously adopted work programmes that were then prioritized, based on the importance of the products for the treatment of WHO priority diseases (including HIV/AIDS, tuberculosis, malaria, programmes and diseases with high prevalence in developing countries);
• new additions from the updated sixteenth WHO Model List of Essential Medicines (March 2010) and the updated second WHO Model List of Essential Medicines for Children (March 2010);
• new additions from the expressions of interest within the WHO Prequalifi cation of Medicines Programme; and
• requests for medicines recommended in WHO’s specifi c disease programmes.
Categories covered in the work programme included medicines used in the treatment of HIV/AIDS, malaria, tuberculosis, as well as anti-infectives (anthelmintics, antibacterial, antiprotozoal, antifungal, antiviral
and antimycobacterial agents), medicines used in oral rehydration therapy and those used for the treatment of various conditions grouped under the generic term “other medicines” (other antivirals, analgesics, antipyretics, agents used for palliative care, anti-epileptics, large-volume parenterals, reproductive health products, vitamins, cytotoxic agents and insulins).
The Expert Committee noted with satisfaction that good progress had been made in the development of specifi cations for essential medicines, notably for antiretrovirals (ARVs) where, with the exception of one substance, all the pharmaceutical substances recommended in the Model List of Essential Medicines for the treatment of HIV/AIDS were now covered in The International Pharmacopoeia in at least one single- or fi xed-dose combination dosage form.
The Expert Committee members were informed that efforts were being made to make the work plan available on the web and through correspondence with manufacturers’ associations. The aim was to enhance collaboration and to obtain samples, which was often not an easy undertaking.
The Expert Committee reviewed and approved the proposed new work programme in principle, and agreed that the list be reconfi rmed with the WHO Prequalifi cation of Medicines Programme and the respective disease programmes as well as partner organizations, to ensure that prioritization for development of specifi cations would refl ect their needs.
4.3 Specifi cations for medicines, including children’s medicines
4.3.1 Medicines for HIV and related conditions
New monographs for the following ARVs were presented to the Expert Committee for discussion:
dosage forms
• didanosine capsules
• efavirenz tablets
• emtricitabine capsules
• emtricitabine and tenofovir tablets
• emtricitabine, tenofovir and efavirenz tablets.
The monographs were adopted, subject to inclusion of the agreed changes, based on the comments received during the normal consultative process, i.e. in line with the steps followed in the development of new monographs, and based on comments made during discussion.
4.3.2 Antimalarial medicines
New monographs for the following antimalarials were presented to the Expert Committee for discussion:
dosage forms
• mefl oquine tablets
• sulfadoxine and pyrimethamine tablets
The monographs were adopted, subject to inclusion of the agreed changes, based on the comments received during the normal consultative process, i.e. in line with the steps followed in the development of new monographs, and based on comments made during discussion.
While carrying out the work for the general revision on the artemisinin derivatives monographs (artemether, artemisinin, artemotil, artenimol, artesunate and their associated dosage forms), the opportunity was taken to develop in parallel a new specifi cation for the parenteral preparation of artesunate, which is particularly recommended in the treatment of severe malaria.
The following monograph could, therefore, be presented to the Expert Committee for discussion:
dosage form
• artesunate for injection.
The monograph was adopted, subject to inclusion of the agreed changes, based on the comments received during the normal consultative process, i.e. in line with the steps followed in the development of new monographs, and based on comments made during discussion.
4.3.3 Antituberculosis medicines
New monographs for the following antituberculosis active substances and dosage forms were presented to the Expert Committee for discussion:
active pharmaceutical ingredients (APIs)
• capreomycin sulfate
• ofl oxacin
• levofl oxacin
dosage forms
• capreomycin injection
• ofl oxacin tablets
• levofl oxacin tablets
The monographs were adopted, subject to inclusion of the agreed changes, based on the comments received during the normal consultative process, i.e. in line with the steps followed in the development of new monographs, and based on comments made during discussion.
The following monograph was presented to the Expert Committee in October 2009 for addition to The International Pharmacopoeia:
dosage form
• kanamycin injection
Although the monograph was adopted, recirculation was recommended by the Expert Committee requesting comments on the shifting of the determination of the conversion factor from international units (IU) to micrograms.
To avoid the use of an arbitrary conversion factor, a revised version of the text was proposed for discussion during the consultation on specifi cations for medicines and quality control issues held in May 2010, where it was agreed that the replacement of the current microbiological assay by a high-performance liquid chromatography (HPLC) method would be preferable as this would allow direct expression of the quantities of kanamycin in terms of mass.
It was recognized, however, that the application of HPLC to this substance would be subject to detection diffi culties owing to the poor absorbance properties of kanamycin in ultraviolet (UV). Possible HPLC methods and their suitability for inclusion in Ph.Int. were thus discussed and it was fi nally recommended that a UV detection method using derivatization be developed, rather than a method using more sophisticated detectors such as electrochemical ones that may not be widely available. While this HPLC method was still under investigation, it was agreed that, once ready, the revised monograph would be circulated for comment.
Meanwhile, and in order to make the monograph available to users, it was agreed that the text adopted in October 2009 be posted on the WHO Medicines web site with an appropriate Note from the Secretariat indicating that a forthcoming revision was envisaged for the assay.
The Expert Committee endorsed the recommendations made by the participants at the consultation.
4.3.4 Anti-infectives
New monographs for the active dosage forms of the following anti-infectives were presented to the Expert Committee for discussion:
• amoxicillin oral suspension10
• levamisole tablets
• metronidazole oral suspension10
• sulfamethoxazole and trimethoprim tablets10
10 These monographs were developed in the context of collaboration between The International Pharmacopoeia and The British Pharmacopoeia, on which these texts are based.
The monographs were adopted, subject to inclusion of the agreed changes, based on the comments received during the normal consultative process, i.e. in line with the steps followed in the development of new monographs, and based on comments made during discussion.
4.3.5 Other medicines
New monographs for the following dosage forms were presented to the Expert Committee for discussion:
• levonorgestrel tablets
• oseltamivir capsules
• sodium bicarbonate intravenous injection
The monographs were adopted, subject to inclusion of the agreed changes, based on the comments received during the normal consultative process, i.e. in line with the steps followed in the development of new monographs, and based on comments made during discussion.
4.4 Revision of texts of The International Pharmacopoeia
4.4.1 Antimalarials: artemisinin derivatives
Since 2008, extensive revision work had been initiated for the general revision of the artemisinin derivatives monographs of The International Pharmacopoeia.
Particular aspects that required revision were the method used for the Related substances test and the Assay; and the addition of potential impurities shown to be controlled by the requirements of the monographs.
Artesunate
Subsequent to the development of a new monograph for artesunate for injection, the monograph for artesunate, revised in 2009, needed further modifi cation to add specifi c requirements for the API intended to be used for parenteral preparations. A newly revised text was thus presented to the Expert Committee for discussion. The monograph was adopted, subject to inclusion of the agreed changes, based on the comments received during the public inquiry and those made during the discussion.
Other artemisinin derivatives
This general revision of artemisinin derivatives involved about 15 texts.
Monographs for artesunate and artesunate tablets had already been adopted in October 2009. Prioritization for revision had been proposed for the rest of this series in order to make the most useful monographs available to users in a timely manner.
In line with the WHO treatment guidelines for malaria, where the use of these antimalarials as a monotherapy was no longer prescribed, the Expert Committee agreed that while revising the monographs for the corresponding monocomponent dosage forms, priority would be assigned to the products that could be co-packaged.
The Expert Committee was pleased to note that work had progressed, notably for the API monographs on artenimol (dihydroartemisinin) and artemether. Further, it was acknowledged that the development of other specifi cations had been initiated for fi xed-dose combination medicines used in the combination therapy, such as that for artesunate and amodiaquine tablets or artenimol and piperaquine phosphate tablets.
4.4.2 Other medicines Oseltamivir phosphate
The monograph for oseltamivir phosphate was initially adopted in October 2008. A revision of this text was presented in October 2009 after receipt of several comments on the tests for Sulfated ash and Related substances, leading to the adoption of a revised text where only the correction proposed for the Related substances test was retained. To respond to the continuing diffi culties encountered by users when carrying out the test for sulfated ash, a revised version of this monograph was considered.
The Expert Committee adopted the newly revised text, which now harmonized the Ph.Int. text to the specifi cations for oseltamivir phosphate, also available in other pharmacopoeias (Ph.Eur and USP).
Heparins
A brief update was presented on the revision of the Heparins monographs decided upon in 2009, in order to include an electrophoresis method capable of detecting potential glycosaminoglycan impurities of heparin (dermatan sulfate, chondroitin sulfate and oversulfated chondroitin sulfate). The Expert Committee noted that the revision work had been initiated.
Retinol
Vitamin A supplementation therapy was supported by several initiatives of WHO and partner organizations. UNICEF had expressed interest in pharmacopoeial specifi cations for oral dosage forms containing retinol concentrate, oily form, to fi ght vitamin A defi ciency, xerophthalmia and nutritional blindness.
To satisfy these needs, draft versions of the monographs:
• retinol concentrate, oily form
• paediatric retinol capsules
• paediatric retinol oral solution
were prepared and preliminarily discussed during a tele-/videoconference on specifi cations for medicines and quality control laboratory issues in August 2010. The draft monographs were circulated and comments were collated. The revised monographs were presented at the 45th meeting of the Expert Committee.
The Committee adopted the monograph on retinol concentrate, oily form, subject to inclusion of the agreed changes, based on the comments received and those made during the discussion.
Paediatric vitamin A soft-gel capsules have a unique mode of delivery. They are furnished with a small nipple which can be cut off so that the liquid content can be easily squeezed into the mouth of a child. The Committee decided to subsume this dosage form under the monograph on vitamin A oral solution, considering the soft gelatin shell as a single-unit container and the liquid content as the actual dosage form. The Expert Committee recommended that the monograph on paediatric retinol oral solution be modifi ed so that its specifi cations can also be applied to these single-dose units. The capsule monograph was then to be withdrawn.
Paracetamol
Draft versions of the monographs:
• paracetamol oral solution; and
• paracetamol oral suspension
were prepared and preliminarily discussed during a tele-/videoconference on specifi cations for medicines and quality control laboratory issues in August 2010. The draft monographs were circulated and comments were collated. The revised monographs were presented at the 45th meeting of the Expert Committee. The Committee adopted the monographs, subject to inclusion of the agreed changes, based on the comments received and those made during the discussion.
4.5 Review of published general monographs for dosage forms and associated method texts
4.5.1 Pharmacopoeial Discussion Group: harmonized general texts
The Expert Committee members were updated on the discussions and recommendations of the informal consultation held in May 2010. Ph.Int.
general methods, as discussed during previous Expert Committee meetings, are suggested for revision, taking into account the texts harmonized by the PDG (European Pharmacopoeia, Japanese Pharmacopoeia and United States Pharmacopeia).
During their 42nd and 44th meetings, the Expert Committee endorsed the suggestion that “the relevant method texts of The International Pharmacopoeia should be reviewed alongside the fi nalized, harmonized PDG texts in order to identify any differences and to ascertain to what extent it might be appropriate to revise the texts of The International Pharmacopoeia. Any proposed changes would then be circulated in accordance with the usual WHO consultation process. Once the suggested actions had been identifi ed and agreed by the Expert Committee, the WHO Secretariat would contact the PDG, as appropriate, with regard to its decisions on the use of PDG harmonized texts”.
Following this recommendation, a formal request was formulated by the WHO Secretariat to the PDG, which resulted in authorization being given by all three pharmacopoeias of the PDG to use the sign-off text as a basis for publication in The International Pharmacopoeia and agreeing that the text needed to be converted into the style of The International Pharmacopoeia.
The Expert Committee agreed that individual PDG method texts might be included in the Ph.Int. as follows, either as:
• methods supporting the text requirements of the Ph.Int. monographs:
included within the Methods of analysis section either in place of an existing method or as a new method.
In the case of a method intended to replace an existing method, it might be possible to publish both for an interim period so that the “old” method can be used until the relevant monographs are revised; or
• methods provided as guidance with a specifi c reference made in the Ph.Int.
monographs: included within the Supplementary information section; or
• as general information to which no reference is made within the Ph.Int.
monographs: included within the Supplementary information section.
Revisions to existing Ph.Int. texts would be circulated in accordance with the usual WHO consultation process.
In the case of a new text to be included in the Method of analysis section of the Ph.Int., it was recommended to indicate the monographs (published and under elaboration) to which it was intended that the new texts should apply.
The PDG harmonized general methods reviewed and covered by this approach were the following:
• Residue on ignition/sulfated ash
• Test for extractable volume of parenteral preparations
• Test for particulate contamination: subvisible particles
• Microbial examination of non-sterile products: microbial enumeration tests
• Microbial examination of non-sterile products: tests for specifi ed microorganisms
• Microbial examination of non-sterile products: acceptance criteria for pharmaceutical preparations and substances for pharmaceutical use
• Disintegration test
• Uniformity of dosage units
• Dissolution test
• Sterility test
• Tablet friability
Harmonization of the tests was still under discussion at the PDG and would be considered at a later date.
The Expert Committee endorsed the proposals presented and the general approach outlined in the background paper. It advised that clear indications be added to the proposed revised texts when circulating them for comment to explain the approach followed for each harmonized method (e.g. revision, addition or for supplementary information).
The Expert Committee also recommended that once a harmonized PDG method was included in the Ph.Int. a mechanism would be needed to ensure that any further change implemented in the PDG texts be captured in the corresponding text published in Ph.Int.
4.5.2 Uniformity of content for single-dose preparations
The Expert Committee discussed the application of the test for uniformity of content as described in Method 5.1 of the Ph.Int. for fi xed-dose combinations (FDCs) in view of the increasing importance of these products.
The Expert Committee recommended that, in deciding whether a requirement should be included in monographs for FDC tablets or capsules, where none of the APIs are present in less than 5 mg, each case would be judged on its merits. During development of the monograph, account would be taken of the WHO FDC guidelines. A test for uniformity of content of one or more of the active ingredients would be specifi ed for application to the relevant tablet/capsule strength(s). Meanwhile, in accordance with the new approach adopted on the implementation of PDG harmonized texts in the Ph.Int., the general method text 5.1 would not be modifi ed. It was noted that, in the absence of a requirement for uniformity of content in a specifi c, individual tablet/capsule monograph,
The Expert Committee recommended that, in deciding whether a requirement should be included in monographs for FDC tablets or capsules, where none of the APIs are present in less than 5 mg, each case would be judged on its merits. During development of the monograph, account would be taken of the WHO FDC guidelines. A test for uniformity of content of one or more of the active ingredients would be specifi ed for application to the relevant tablet/capsule strength(s). Meanwhile, in accordance with the new approach adopted on the implementation of PDG harmonized texts in the Ph.Int., the general method text 5.1 would not be modifi ed. It was noted that, in the absence of a requirement for uniformity of content in a specifi c, individual tablet/capsule monograph,