WHO DRUG INFORMATION VOLUME 18 NUMBER 2 • 2004 PROPOSED INN LIST 91 INTERNATIONAL NONPROPRIETARY NAMES FOR PHARMACEUTICAL SUBSTANCES WORLD HEALTH ORGANIZATION • GENEVA WHO Drug Information Vol 18, No. 2, 2004 World Health Organization WHO Drug Information Contents Aspects of Quality Assurance Current Topics Stability testing for hot and humid climates 113 New oral rehydration solution adopted by WHO and UNICEF 138 A single oral rehydration solution for Safety and Efficacy Issues global use? 138 Efficacy of artesunate for emergency malaria Principles for fixed-dose combination treatment 117 drug products 140 Natural health products and drug interactions120 Mozambique issues compulsory license for Valdecoxib: severe cutaneous reactions 121 HIV antiretrovirals 141 Improved use of medicines 141 Rapid TB diagnostic test by 2005 142 International Nonproprietary Research bioethics training 142 Names An international role for nomenclature Consultation Document through INNs 123 The International Pharmacopoeia: monographs for antiretrovirals 143 Regulatory and Safety Action Didanosine 143 SSRIs: behavioural and emotional changes and risk of self-harm 127 ATC/DDD Classification Proposed rule on combination products 128 Final list 148 European Medicines Agency: new name Temporary list 150 and advisory role 128 Atypical antipsychotics warning 129 Tegaserod maleate: updated precautions 129 Recent Publications Rotavirus vaccine ready for licensing 129 and Sources of Information Tenofovir approved for HIV 130 Specifications for pharmaceutical Rosuvastatin: revised package insert 130 preparations 153 Sulphur hexafluoride: contraindicated WHO model formulary 153 in heart disease 131 Guidance on risk management 153 Oxandrolone and warfarin 131 Clinical trial fellowships 154 Oseltamivir: new preclinical findings 131 On-line course in medicines management 154 Muromonab: nervous system complications 132 Domperidone and unapproved use 132 Proposed International Safety of Medicines Nonproprietary Names: Combating counterfeit medicines 133 List 91 155 111 World Health Organization WHO Drug Information Vol 18, No. 2, 2004 WHO Drug Information is now available at: http://www.who.int/druginformation 112 WHO Drug Information Vol 18, No. 2, 2004 Aspects of Quality Assurance Stability testing for hot a view to establishing a common market for pharmaceutical products. Such a process would and humid climates include harmonization of requirements for stability testing. Regulators and experts from ASEAN In 1996, the WHO Expert Committee on Specifi- countries have met regularly with WHO and cations for Pharmaceutical Preparations adopted IFPMA experts to discuss whether the conditions the WHO Guidelines on Stability Testing (1). In outlined in current WHO and ICH (4) guidelines 2000, the International Conference on Harmoni- are appropriate for countries which have vast zation (ICH) Expert Working Group proposed a areas with climatic conditions that are above the modification to the WHO guidelines concerning average relative humidity (RH) and temperature long-term conditions for climatic zone IV (hot and used to characterize zone IV. None the less, the humid) from 30 ˚C and 70% relative humidity (RH) most recent of such meetings, held in Jakarta on to 30 ˚C and 60% relative humidity. After broad 12–13 January 2004, concluded that the condi- consultation, conditions for real-time stability tions described in WHO and ICH guidelines do studies for climatic zone IV were agreed as 30 ˚C not adequately address the climatic conditions (± 2 ˚C) and 65% (± 5%) RH (2). Where special prevalent in the majority of ASEAN countries and transportation and storage conditions did not has proposed that the conditions shown in Table 1 comply with these criteria, additional study data below should be adopted for stability studies in supporting these conditions might be needed (3). ASEAN countries. Arguments supporting this conclusion are set out as follows. The Association of South East Asian Nations (ASEAN) comprises Brunei Darussalam, Cambo- Average conditions dia, Indonesia, Lao PDR, Malaysia, Myanmar, versus more stressful conditions Philippines, Singapore, Thailand and Vietnam. Both WHO and ICH guidelines base their calcula- These countries are all situated in climatic zone tions on values of temperature and humidity that IV and ASEAN regulatory authorities are in the are the mean of the values calculated for 23 cities process of defining harmonized requirements for situated in Zone IV. These conditions are less marketing authorization for pharmaceuticals with stressful than those measured in half of the 23 Table 1 – Proposed conditions for stability testing in ASEAN countries TYPE CONDITIONS Products in primary containers 30 oC ± 2 oC/75% ± 5% RH permeable to water vapour Products in primary containers 30 oC ± 2 oC/RH not specified impermeable to water vapour Accelerated studies 40 oC ± 2 oC/75% ± 5% RH Stress studies Unnecessary if accelerated studies at above conditions are available Article contributed by Dr. Lucky S. Slamet, Deputy Director for Therapeutic Products, Narcotic, Psychotropic and Addictive Substance Control, National Agency of Drug and Food Control, Indonesia and Ms. Hjh Siti Mariam Hj Md. Jaafar, Principal Pharmaceutical Chemist, Department of Pharmaceutical Services, Ministry of Health, Brunei Darussalam. 113 Aspects of Quality Assurance WHO Drug Information Vol 18, No. 2, 2004 cities. It should be noted that climatic data of the amount of water in the air, or absolute humid- cities are not necessarily representative of ity (AH), is the most relevant factor to consider conditions of large areas of the countries sam- when setting conditions for stability testing. Based pled, which may experience higher humidity and/ on this assumption, AH values for ASEAN climatic or temperature extremes. In addition, as pointed conditions were calculated as follows: out in WHO guidelines (5), badly conditioned storage facilities may mitigate the lower extremes a) data on dew point and temperature were of temperature but not the higher ones. Finally, obtained from tables published by the World storage facilities are likely to be less protective in Meteorological Organization (WMO) and the developing countries, and especially outside of European Centre for Medium-Range Weather cities. Forecasts; On the basis of these considerations, as a matter b) from these data, calculations were performed of principle, testing should be biased towards to obtain: more stressful rather than less stressful condi- tions so as to provide a margin of error in favour partial vapour pressure, using Wexler’s of the patients and to increase the likelihood of equation: identifying substances or formulations that pose particular stability problems. (17.67 • T / (243.5 + T)) P = 6.112 • e Activation energy and mean D kinetic temperature (where T is the dew point obtained from Activation energy (Ea) is a determining factor in meteorological data). the calculation of mean kinetic temperature (MKT) as drawn from climatic data. WHO and ICH absolute humidity (or mix ratio), expressed guidelines refer to published data (6) which as mass of water per kilogram of dry air using indicate the average value of 19.8 kcal/mole (or the following equation: 82.8 kJ/mole) for Ea to be used for calculating MKT. These published data show that Ea for 38 0.018 • PD active ingredients and excipients (many no longer AH = –––––––––––– in use) ranged from 9 to 47 kcal/mole. 0.029 •(P - PD) where: Consequently, for many drugs, MKT is either overestimated or underestimated when the 0.018 = molar mass of water [ kg ] average of 19.8 kcal/mole is used. This in turn 0.029 = molar mass of dry air [ kg ] leads to underestimating or overestimating shelf- P = total atmospheric pressure [ mbar ] life values. Sample calculations have shown that PD = partial vapour pressure of water [ mbar ] shelf life values can be divided by four when Ea values are increased from 10 to 100 kcal/mole. It saturation vapour pressure (PS) from can be assumed that most degradation reactions Wexler’s equation at the corresponding have very low Ea and therefore long shelf-life measured temperature instead of dew point. values, but this needs to be demonstrated. What is relevant is that the use of an average value c) the relationship between RH, PS and PD is based on a limited sample of substances may be based on: inappropriate to help identify substances or RH = PD •100/ PS formulations that pose particular stability prob- lems. The data obtained are reproduced in Table 2 overleaf: Calculations based on climatic data from ASEAN counties The table shows that the ASEAN average AH is ASEAN average values for temperature and RH 0.0186 Kgwater/Kgdry air and that the pair tempera- are, respectively, 27.76 oC and 78.79% RH. Most ture/RH closest to that is 30 oC/70% RH. In line ASEAN member countries have average RH with the need for setting test conditions that better values that are above the mean RH of the 23 reflect extremes rather than mere average, and in cities used as a basis for the ICH Q1F guideline, order to provide a safety margin, the meeting which are 26.7 oC and 76% RH. ICH and WHO agreed that the pair 30 oC/75% RH be recom- guidelines assume that, at a given temperature, mended for long term stability studies. 114 WHO Drug Information Vol 18, No. 2, 2004 Aspects of Quality Assurance Table 2. Temperature/Relative Humidity Absolute Humidity Kgwater/Kgdry air 30 oC /60% RH 0.0161 25 oC /80% RH 0.0160 30 oC /65% RH 0.0174 30 oC /70% RH 0.0188 30 oC /75% RH 0.0202 40 oC /75% RH 0.0361 27.76 oC /78.79% RH 0.0186 (*) (*) ASEAN average It was also noted that the pair 40 oC/75% RH stressful than those required (e.g. 30 oC/65% used in accelerated studies represents a better RH). Factors to be taken into consideration stress than the 25 oC/80% RH proposed for stress include: testing in the ICH Q1F Guideline. On this basis, the meeting agreed to eliminate the requirement • complementary data provided to enable proper for stress testing if data on accelerated studies scientific evaluation; conducted at 40oC /75% RH are made available.