WHO Drug Information Vol. 25, No. 3, 2011

WHO Drug Information

Contents

Quality Assurance Highlights Addiction to benzodiazepines and Recovery of solvents in API codeine: safer use 248 manufacturing 221 Nimesulide-containing medicines: Chewable tablets: time to reassess restricted use 249 a ‘neglected’ dosage form? 223 Pharmacopoeial Discussion Group: Regulatory Action and News update 228 Artemisinin-based malaria treatment Specifications for pharmaceutical approved 250 preparations 229 Pandemrix®: restriction in use 250 Indacaterol: approved for chronic WHO Prequalification of obstructive pulmonary disease 250 Medicines Programme Rivaroxaban approved to reduce Ensuring quality medicines: risk of blood clots 251 a decade of prequalification 231 Consultation Documents Regulatory Support The International Pharmacopoeia Paediatric medicines regulatory 3.3 Microbial purity of pharma- network 240 ceutical preparations 252 3.3.1. Microbiological examina- Safety and Efficacy Issues tion of non-sterile products: Dexrazoxane: contraindicated microbial enumeration tests 255 in children and adolescents 242 3.3.2 Microbial examination of Pioglitazone: risk of bladder cancer 243 non sterile products: tests for Proton pump inhibitors: hypomag- specified microorganisms 265 nesemia, hypocalcemia and 5.3 Disintegration test for tablets hypokalemia 243 and capsules 277 Floseal® hemostatic matrix: 5.6 Extractable volume of paren- misinterpretation of recurrent teral preparations 279 malignant disease 244 5.7 Tests for particulate con- Antipsychotic drugs update: tamination 280 newborns 245 2.3 Sulfated ash 287 Rituximab: fatal infusion-related Pyrantel embonate chewable reactions 245 tablets 288 Tamoxifen: CYP2D6 interactions Pyrantel embonate oral sus- and variable clinical response 246 pension 291 Thalidomide: risk of arterial and venous thromboembolism 247 International Nonproprietary Use of 2011 seasonal influenza Names vaccines in children 247 Recommended List No. 66 295

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WHO Drug Information & digital library are available online at: http://www.who.int/druginformation

220 WHO Drug Information Vol. 25, No. 3, 2011

Quality Assurance Highlights

Recovery of solvents in API manufacturing

The practice of recovering and using solvents in the pharmaceutical industry has implications for the quality of active pharmaceutical ingredients (APIs) in finished pharmaceutical products. Various recovery processes and installations are cur- rently being utilized. This article attempts to present the latest developments and collective provisions related to the topic and has been compiled based on expe- rience gained as part of activities related to the WHO Prequalification of Medicines Programme. Importantly, it presents typical questions that should be addressed when an API manufacturing site is being inspected. Of particular relevance is the reproducibility of the given recovery process and, by implication, the quality of the recovered solvent. Such considerations are crucial to the quality of the final product. Comments on this article are welcome and should be forwarded to [email protected].

Solvent recovery is a routine practice may become the solvent during a reac- in the pharmaceutical industry when it tion. This change of solvent may cause is technically and economically viable changes in the spectrum of impurities for the particular waste stream. Organic present in the final product. On the other solvents are ubiquitous in the reaction hand, intermediate and product isolation and separation steps of pharmaceutical via crystallization can be affected by the processes. The replacement of organic composition and even the impurity profile solvents appears to be difficult owing to of the solvent. the strong influence on the outcome of the reaction and /or quality of the separa- The following section drawn from the tion (e.g., crystallization). The use of mul- WHO good manufacturing practices for tiple solvents and reagents for different active pharmaceutical ingredients, which purposes within a process frequently is equivalent to ICHQ7, discusses specific leads to the formation of solvent mixtures. issues associated with solvent recovery in a pharmaceutical manufacturing setting It is hard and often impossible to recover (1). Recommendations have been made solvent in pure form from such a waste for inspection of API manufacturing facil- stream consisting of multiple solvents ties when dealing with solvent recovery. and reagents used in the reaction and The relevant provisions to recovery of separation process. Therefore, the use solvents in WHO good manufacturing of recovered solvents and the pooling of practices for active pharmaceutical ingre- solvents must be appropriately qualified dients are: to assure product quality and avoid cross contamination during active pharmaceuti- 14.40 Recovery (e.g., from mother liquor cal ingredient (API) production. or filtrates) of reactants, intermediates, or the API is considered acceptable The use of recovered solvents can gene- provided that approved procedures exist rate problems from a product purity stand for the recovery and that the recovered point. For example, a recovered solvent materials meet specifications suitable for can be of an azeotropic composition that their intended use.

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14.41 Solvents can be recovered and re- Solvents, as stated in the current guide- used in the same processes or in different line, can be recovered and re-used processes, provided that the recovery within the same process or in different procedures are controlled and monitored processes, provided that recovery to ensure that solvents meet appropriate procedures are strictly controlled and standards before re-use or co-mingling monitored to ensure that solvents meet with other approved materials. appropriate standards (critical process parameters) before re-use or co-mingling 14.42 Fresh and recovered solvents and with other approved materials. It is highly reagents can be combined if adequate recommended that recovered solvents be testing has shown their suitability for all used in the same process or in the same manufacturing processes in which they step of the aforementioned process to may be used. minimize potential cross-contamination.

14.43 The use of recovered solvents, Fresh and recovered solvents can be mother liquors and other recovered mate- combined if adequate testing has shown rials should be adequately documented. their suitability for all manufacturing pro- cesses. The ratio of fresh vs recovered According to the provisions, a recovery solvents should be defined in each step. process is allowed only when an esta- The use of recovered solvents should be blished procedure for a specific operation adequately documented in the process and an appropriate approval for such a including the date of recovery (sto- process is in place. The procedure should rage time) and history of the recovered detail the designated recovery system solvents. The recovered solvents should (e.g., type of distillation apparatus, reco- be avoided as media for the final purifica- very process flowsheets). Specifications tion of the API. However, use is permitted for a given recovered solvent should be if the recovered solvent meets predefined established and be met for the release. specifications in composition and purity and there is no additional risk of impact For the purpose of comparison, the on the purity of the API and its crystal specifications of both fresh and recovered form. Clarification or amendment may be solvents should include tests and para- requested in the next Expert Committee meters to take account of accumulation discussion for revision of the WHO gui- of impurities. Impurities and composition deline regarding impurity originating from of the recovered solvents for re-use other/different processes. should be determined and documented In evaluating solvents recovered during in the form of a certificate of analysis the API manufacturing process, ICH Q9 (COA) for recovered solvents. Analysis risk assessment may be employed. The of the impurity profile of the recovered specifications of recovered solvents, solvents is of utmost importance to avoid including the ratio of fresh vs recovered cross-contamination and accumulation of solvent, should be established for each impurities in the process. Knowledge of individual API production and controlled the composition of the solvents recovered before use. Risk assessment of the use from a multi-component solvent process of recovered solvents for final purification is crucial for strengthening reliability of of APIs should be conducted and docu- the process to ensure the quality of the mented. Use of the recovered solvent product (yield, crystal forms, etc.). Both should be avoided when assessment impurity profile and composition of the indicates that the risk is relatively high. recovered solvents intended for re-use in the process should br defined as critical When a recovered solvent with high process parameters. unknown impurities is used, the manufac-

222 WHO Drug Information Vol. 25, No. 3, 2011 Quality Assurance Highlights turer needs to show suitability in re-using standard operating procedures) estab- recovered solvent and demonstrate how lished and do they meet the COA when the risk of “carry over” will be avoided. It recovered solvents are used? is highly recommended to characterize all impurities before use for the purpose • Is there any process in place to improve of risk mitigation. The impurities from the quality of the recovered solvents? recovered solvents, and their implications • Do the recovered solvents come from for stability of the API, should be moni- the current API process or from a differ- tored as well. ent API process? In the event that they The following typical questions should be come from different processes, what addressed when an API manufacturing are the tests and acceptance criteria site is being inspected: proposed by the API manufacturer to control the carry over of impurities from • Are there any recovered solvents in- these other processes? volved in API manufacturing? • In what step is the recovered solvent • If no recovered solvents are being used used? in the process, a statement to this effect should be made by the applicant. • Is the use of recovered solvents docu- mented in the batch manufacturing • Is the use of recovered solvents in the record? process declared? • Is the yield and purity profile of the • What are the recovery methods (distilla- product affected and whether it is tion, column fractionation, etc.) and are proved by validation? batches pooled? • Is there any additional impurity gener- • Is there an approved procedure/stan- ated by the use of recovered solvents dard operating procedure (SOP) for and verified by batch analysis? recovered solvents in place? References • Is there a recovered process flowchart including source and destination? 1. WHO good manufacturing practices for active pharmaceutical ingredients at • Is the facility and apparatus for recov- http://www.who.int/medicines ered solvents qualified? 2. International Conference on Harmoniza- • Are specifications (composition and im- tion. ICH Guidelines: Q3 Impurities, Q7 Good purity profile, specification sheets and Manufacturing Practice, Q9 Quality Risk Management at http://www.ich.org/

Chewable tablets: time to reassess a ‘neglected’ dosage form? A survey recently conducted in six WHO coordinated by the WHO/NTD Secretariat Member States was aimed at identifying and financially supported by USAID, in possible quality problems in medicines collaboration with the medicines regula- for neglected tropical diseases (NTD). tory authorities of countries where these The medicines concerned were solid products are especially relevant — three oral forms of albendazole, azithromycin, in south-east Asia and three in west mebendazole, diethylcarbamazine, iver- Africa. Testing was conducted at the mectin, and praziquantel. The survey was National Institute for Drug Quality Control

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(NIDQC), Hanoi, Viet Nam and the Labo- To our knowledge, helminthic infections in ratoire National de Contrôle des Médica- humans have not been shown to deve- ments, Rabat, Morocco. Both testing sites lop resistance. However, it is known that have been prequalified by WHO. resistance to anthelminthics has deve- loped in animals (2, 3) and it has been Testing results show that 41 samples suggested that known widespread resis- out of 72 in the South-East Asian part tance in veterinary practice “threatens the of the survey did not conform to the success of treatment in humans” (4–6). requirements of the 32nd release of the In that event, low potency and/or poor United States Pharmacopoea (USP32). availability would be aggravating factors. In all the 41 cases of non-conformity, the samples failed the USP32 dissolution Current pharmacopoeial references to test. In one case (albendazole 400 mg), chewable tablets are listed in Table 1. the sample also failed content of active ingredient and uniformity of dosage units. No explicit mention of chewable tablets Particularly striking is the case of meben- was found in the text for disintegration dazole: among 22 samples collected time or dissolution rate in the Chinese in two countries, not a single sample (Ch.Ph), Indian (Ph.Ind) or Interna- conformed with monograph requirements. tional Pharmacopoeia (Ph.Int). The In the west-African part of the survey, 10 British Pharmacopoeia (BP) 2008 expli- samples out of 56 failed testing and all of citly states that a dissolution rate test is these failed the USP32 dissolution test. “inappropriate“ for chewable tablets; this In four cases the samples also failed to statement was not found in the 2011 BP conform with the disintegration test. In but no alternative test was found. The one case, impurities exceeded the mono- USP 2010, and both the 2008 and 2010 graph limit. editions of the BP, exclude chewable tablets from the requirement to comply In the majority of the cases of non-confor- with a disintegration test. However, the mity, the product was in chewable tablet USP requires compliance with a dissolu- form. tion test whereas the BP does not. The assumption appears to be that all patients The fact that such a high proportion of (including children and the elderly) will samples did not meet dissolution rate chew a tablet if it is labelled as chewable, requirements is a cause of concern and which is improbable. It should be assu- raises questions about the efficacy of med that some patients will swallow NTD medicines marketed in the countries tablets that are labelled ‘chewable’ with- that have participated in the survey. Non- out chewing them or after chewing them conformity occurred most frequently in incompletely. samples of albendazole and mebenda- zole. It has been shown that albendazole The aforementioned survey of NTD medi- preparations that fail dissolution testing cines found that some albendazole and achieve lower egg reduction rates than mebendazole tablets were described as preparations that meet dissolution requi- chewable but prescribing information was rements (1). In addition, in the absence of inconsistent as to whether patients were any alternative, it is difficult to challenge instructed to chew before swallowing. For dissolution testing as the best indica- example the same manufacturer used tor we have for availability of the active the words chew before swallowing or can drug for absorption by patient or parasite be chewed in different countries for the tissue or as an indicator of batch to batch same product. This raises a number of consistency. questions:

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Table 1. Pharmacopoeial references to chewable tablets

Pharmacopiea Definition British Phar- BP2008: From the general monograph for tablets: “Chewable tablets are prepared to macopoeia ensure that they are easily crushed by chewing”.“Chewable tablets are not required to (BP) / Euro- comply with the test [for disintegration]”. Supplementary chapter SC I E. Dissolution pean Pharma- Testing of Solid Oral Dosage Forms makes it clear that a dissolution test is considered copoiea (Ph. inappropriate for chewable tablets (“…where the nature or intended use of the prepa- EU) ration renders a dissolution test inappropriate (for example, liquid-containing capsules, dispersible, effervescent, chewable or soluble tablets”). BP 2011: All the above statements are no longer present in the BP 2011. Chinese Phar- From the general monograph for tablets: “Chewable tablets are intended to be chewed macopoeia or sucked to disintegrate and then swallowed to effect in gastrointestinal tract, or be (Ch.Ph) absorbed by the gastrointestinal tract for systemic action”. “The hardness of chewable (2005) tablets should be suitable”. No explicit mention of chewable tablets was found in the text for disintegration time or dissolution rate. India Pharma- From the general monograph for tablets: “Tablets for use in the mouth are usually copoeia uncoated tablets formulated to be chewed or to effect a slow release and local action of (Ph.Ind) the active ingredient (lozenges) or the release and absorption of the active ingredient (2007) under the tongue (sublingual tablets)”. No explicit mention of chewable tablets was found in the text for disintegration time or dissolution rate. International From the general monograph for tablets: “Tablets for use in the mouth and chewable Pharma- tablets are usually uncoated. They are formulated to effect a slow release and local copoeia action of the active ingredient(s) (for example, compressed lozenges) or the release Ph.Int and absorption of the active ingredient(s) under the tongue (sublingual tablets) or in (2008) other parts of the mouth (buccal) for systemic action”. The same monograph exempts chewable tablets from compliance with a disintegration test. The Ph.Int requires a dis- solution test only when a requirement is specified in the individual monograph. No explicit mention of chewable tablets was found in the sections of the Ph.Int entitled Disintegration test for tablets and capsules and Dissolution test for solid oral dosage forms. United States From the general chapter on pharmaceutical dosage forms: “Chewable tablets are Pharmaco- formulated and manufactured so that they may be chewed, producing a pleasant poea, USP 32 tasting residue in the oral cavity that is easily swallowed and does not leave a bitter or (2010) unpleasant aftertaste. These tablets have been used in tablet formulations for children, especially multivitamin formulations, and for the administration of antacids and selected antibiotics. Chewable tablets are prepared by compression, usually utilizing mannitol, sorbitol, or sucrose as binders and fillers, and containing colors and flavors to enhance their appearance and taste”. “Disintegration is an essential attribute of tablets intended for administration by mouth, except for those intended to be chewed before being swallowed and for some types of extended-release tablets. A disintegration test is provided [see cross reference] and limits on the times in which disintegration is to take place, appropriate for the types of tablets concerned, are given in the individual monographs”. From <1088> In vitro and in vivo evaluation of dosage forms: “The state of science is such that conduct of in vivo testing is necessary in the development and evaluation of dosage forms. Also, no product, including suspensions and chewable tablets, should be developed without dissolution or drug release characterization where a solid phase exists. This chapter sets forth, for products intended for human use, guidelines for characterizing a drug that include: (1) developing in vitro test methods for immediate- release and modified-release dosage forms, (2) designing in vivo protocols, and (3) demonstrating and assessing in vitro-in vivo correlations for modified-release dosage forms”.

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1. What is meant by the word chewable? phase exists”. It goes on to outline the Patients are generally unaware of defini- development of in vitro test methods tions included in compendia. Chambers and design of in vivo study protocols. English dictionary (7) defines the suffix Consistent with the USP, the Food and -able to mean “capable of being”. Thus, Drug Administration (FDA) Bioavailability the simple English meaning of chewable and Bioequivalence Studies for Orally is capable of being chewed and not Administered Drug Products — Gene- must be chewed. The USP definition is ral Considerations (2003), page 17 (8), consistent with this interpretation, using states: “We recommend that rapidly the words “may be chewed”. By way of dissolving drug products, such as buccal comparison, if a liquid is labelled inflam- and sublingual dosage forms (and chew- mable that is not to suggest that the able tablets), be tested for in vitro dissolu- user should set it on fire. The BP, Ch.Ph, tion and in vivo BA and/or BE. We recom- Ph.Ind and Ph.Int do not state explicitly mend that chewable tablets (as a whole) whether chewable tablets may alternati- be subject to in vitro dissolution testing vely be swallowed whole, but exemption because they might be swallowed by a from compliance with a disintegration patient without proper chewing. In gen- test, as in the BP and Ph.Int, implies an eral, we recommend that in vitro dissolu- assumption that chewable tablets will tion test conditions for chewable tablets always be chewed. be the same as for non-chewable tablets of the same active ingredient or moiety. 2. Is it necessary to test whether the Infrequently, different test conditions or same tablet is bioequivalent when it is acceptance criteria can be indicated for chewed or when it is swallowed whole? chewable and non-chewable tablets, but we recommend these differences, if they 3. Can tablets that are described as exist, be resolved with the appropriate chewable (meaning “may be chewed”) review division.” be considered bioequivalent to tablets for which the recommendation is only to A joint position paper (9) by the Internatio- swallow whole? nal Pharmaceutical Federation ( FIP) and American Association of Pharmaceutical 4. Should chewable tablets be required Scientists (AAPS) has reviewed some to comply with tests for dissolution rate? of these questions. Their paper includes If chewable tablets may be swallowed the statement “….In principle, the test whole, the same dissolution rate test and procedure employed for chewable tablets limit should apply as if the tablet were should be the same as that used for regu- intended to be swallowed whole. lar tablets. This concept is based on the possibility that a patient might swallow the 5. Should chewable tablets be required to dosage form without proper chewing, in comply with a test for disintegration time? which case the drug would still need to be It is established practice to exempt tablets released to ensure the desired pharma- from compliance with a test for disinte- cological action. Where applicable, test gration time if there is also a specification conditions would preferably be the same for dissolution rate. Consequently, this as used for conventional tablets of the question arises only if there is no dissolu- same active pharmaceutical ingredient, tion rate test. but because of the non-disintegrating na- ture of the dosage form, it may be neces- As noted in the above table, the USP sary to alter test conditions (e.g., increase states: “... no product, including suspen- the agitation rate) and specifications (e.g., sions and chewable tablets, should be increase the test duration). The reciproca- developed without dissolution or drug ting cylinder (USP apparatus 3) with the release characterization where a solid addition of glass beads may also provide

226 WHO Drug Information Vol. 25, No. 3, 2011 Quality Assurance Highlights more “intensive” agitation for in vitro • The term “chewable tablet“ should be dissolution testing of chewable tablets. defined as “a conventional tablet that As another option, mechanical breaking can also be chewed”. of chewable tablets prior to exposing the specimen to dissolution testing could • Because in practice chewable tablets be considered. While this option would may be swallowed without chew- more closely reflect the administration ing (even if the label states “must be of the product and the corresponding chewed”), they should be tested for the formulation and manufacturing features, release of the API(s) even when swal- no approach for validating such a method lowed whole. Tablets labelled as “chew- has been reported in the literature or pre- able” should be bioequivalent when sented during the workshops….” chewed or swallowed whole. Our comments are not intended to sug- • Tablets labelled as “chewable” should gest a final conclusion on the issue of be bioequivalent to any other chewable chewable tablets but rather to raise ideas or non-chewable tablets on the same for consideration. The current absence of market that contain the same APIs in clear guidance on dissolution rate requi- the same dose. rements has led to a situation in which there are no consistent and suitable qua- • In the absence of suitable requirements lity requirements with which the manufac- for testing release of the API(s) even turers of chewable tablets must conform. if swallowed whole, chewable tablets Many regulatory authorities in NTD ende- should not be used for potent medi- mic countries may be unable to insist on cines and especially not for those hav- requiring conformity to dissolution rate ing the potential for variable bioavail- testing for chewable tablets if internatio- ability such as mebendazole. For the nal references such as The International paediatric population, a better option Pharmacopoeia do not require it. would be dispersible solid oral dosage forms that must be dispersed before In addition, the current definition of chew- swallowing. It is probably reasonable to able tablet as it appears in The Internatio- assume that carers will be more reliable nal Pharmacopoeia, 4th edition, 2008 is as than patients. follows: • Medicines regulatory authorities should Tablets for use in the mouth (sublin- ensure that manufacturers justify and gual, buccal) and chewable tablets demonstrate the biopharmaceutical characteristics of the chewable dosage Definition form in each case. Tablets for use in the mouth and chew- able tablets are usually uncoated. They Comments or feedback on the above dis- are formulated to effect a slow release cussion paper would be welcome and can and local action of the active ingredient(s) be sent to the authors: Valerio Reggi at (for example, compressed lozenges) or [email protected] and Susan Walters at su- the release and absorption of the active [email protected] ingredient(s) under the tongue (sublingual tablets) or in other parts of the mouth References (buccal) for systemic action. 1. Albonico M, Mathema P, Montresor A et al. This does not address the problems iden- Comparative study of the quality and efficacy tified in the above mentioned survey. of originator and generic albendazole for mass treatment of soil-transmitted nematode Against this background, we make the infections in Nepal. Tr R Soc Trop Med & Hyg following propositions for discussion: 2007;101:454–460

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2. Prichard RK et al. Towards markers for International Health at http://www.festmih.eu/ anthelminthic resistance in helminths of im- document/1791. portance in animal and human health. Parasit 2009;134:1073–1076 6. Harhay MO et al. Epidemiology and Control of human gastrointestinal parasites in children. 3. Gaba S, Silvestre A. Mathematical models Exp Rev of Antiinfect Ther 2010;8:3,219–234. for the management of helminth parasites: th from biological processes to the evolution of 7. Chambers 20 Century Dictionary. Ed. anthelminthic resistance. Antiinfec Agents in Kirkpatrick EM. W & R Chambers Ltd, 1983; Med Chem 2011;9:3,139-147 Edinburgh.

4. James C et al. Drug Resistance mecha- 8. US Food and Drug Administration. htt:// nisms in helminths: is it survival of the fittest? www.fda.gov/downloads/Drugs/Guidance- Trends in Paras;25:7,328–335. ComplianceRegulatoryInformation/Guidances

5. Albonico M. Potential drug resistance in 9. American Association of Pharmaceutical helminth control programmes. 6th Interna- Scientists http://www.aapspharmscitech.org/ tional Conference on Tropical Medicine and articles/pt0401/pt040107/pt040107.pdf

Pharmacopoeial Discussion Group: update The need for international worldwide by avoiding duplication during harmonization the preparation of dossiers and studies, Globalization and expansion in interna- thus reducing the time required for inno- tional trade present a growing need to vative medicines to become available. develop global quality standards for medi- This conference takes place twice a year cines. As standards are a vital instrument with the location of meetings rotating for registration, market surveillance and between Europe, Japan and the United free movement and trade of medicines States of America. among as many countries as possible, harmonization among the world’s three Work of the Pharmacopoeial major pharmacopoeias— the European Discussion Group Pharmacopoeia (Ph.EU), the Japanese The Pharmacopoeial Discussion Group Pharmacopoeia (JP) and the United (PDG) comprises representatives from States Pharmacopoeia (USP) — is an the Ph.EU, the JP and the USP. It consi- important and challenging task. Within ders proposals made by national associa- the harmonization process, the European tions of manufacturers of pharmaceutical Directorate for the Quality of Medicines products and excipients in order to select and Healthcare (EDQM) represents the general methods of analysis and exci- Ph.EU. All the relevant groups of experts pient monographs for addition to its work of the European Pharmacopoeia are programme. To promote exchange and involved. synergy, the PDG has organized, since 2001, hearings for representatives of the International Conference pharmaceutical and excipient industries. on Harmonization In 1990, a trilateral programme, the Inter- Each pharmacopoeia is responsible for national Conference on Harmonization a programme of international harmoniza- (ICH), for the harmonization of testing of tion. Each text drafted by the three coor- medicines among the European Union, dinating pharmacopoeia’s is published for the United States and Japan was set public comment at stage four in each of up. This programme aims to reduce the the respective forums. overall cost of pharmaceutical research

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Latests developments Excipients Council The PDG met from 14–15 June 2011 A meeting with the International Phar- in Cincinnati, Ohio, USA. The Group maceutical Excipients Council (IPEC) reported on work achieved and progress Federation was held on June 14, 2011. made. To date, 28 of the 35 general chap- Topics, among others, included cellulo- ters and 41 of the 62 excipient monogra- sics, viscosity of cellulose derivatives, phs of the current work programme have polyethylene glycol, glycerin, povidone, been harmonized, including the chapter copovidone, the silicon dioxide monogra- on microcalorimetry. Revised general phs, and metal impurities. chapters include bacterial endotoxins and bulk and tapped density. Excipient sign- Future PDG activities offs include revisions to benzyl alcohol, The three Pharmacopoeias emphasized potato starch, wheat starch, calcium their commitment to further strengthen phosphate dibasic, and calcium phos- international harmonization. The PDG phate dibasic anhydrous monographs. will utilize its monthly teleconferences for The latter four revisions are the outcome discussion of technical topics in addition of PDG’s review of previously harmonized to monitoring status updates. The next excipient monographs. face-to-face PDG meeting will be hosted by EDQM on 8–9 November 2011 in Representatives from the three pharma- Strasbourg, France. copoeias discussed other topics, inclu- ding microbiological limits, additives in Reference: European Directorate for the Qua- excipients, and metal impurities. Also, the lity of Medicines and Healthcare at http://www. PDG decided to add the isomalt mono- edqm.eu/en/International-Harmonisation-614. graph to its work programme. html

Specifications for pharmaceutical preparations The WHO Medicines Quality Assurance adopted by the Expert Committee after Programme is pleased to announce that passage through its rigorous, interna- the 45th report of the Expert Committee tional and wide consultative process. on Specifications for Pharmaceutical Pre- parations is now available at http://www. From a wider perspective, the inter- who.int/medicines/publications/pharm- national guidelines, specifications and prep/en/index.html and http://whqlibdoc. nomenclature developed under the aegis who.int/trs/WHO_TRS_961_eng.pdf of the Expert Committee serve all Mem- ber States, international organizations, The Expert Committee on Specifications United Nations agencies, regional and for Pharmaceutical Preparations provides interregional harmonization efforts, and recommendations and tools to assure the underpin important initiatives, including quality of medicines from their develop- the prequalification of medicines, the ment phase to their final distribution to the Roll Back Malaria Programme, Stop TB, patients. The activities discussed during essential medicines and medicines for the Expert Committee meetings serve to children. The advice and recommenda- develop specific additional guidance and tions provided by the Expert Committee specifications as needed for the various are intended to help national and regional medicines recommended by WHO Pro- authorities and procurement agencies, grammes. as well as major international bodies and institutions, such as the Global Fund to The WHO Prequalification of Medicines Fight AIDS, Tuberculosis and Malaria, Programme functions are based on the and international organizations such as guidelines, standards and specifications UNICEF – to combat circulation of subs-

229 Quality Assurance Highlights WHO Drug Information Vol. 25, No. 3, 2011 tandard medicines and to work towards • GMP for sterile pharmaceutical access to quality medicines. products (Annex 6).

In conclusion, the Expert Committee on • Guiding principles on transfer of Specifications for Pharmaceutical Pre- technology in pharmaceutical manufac- parations gives recommendations and turing. (Annex 7). provides independent international stan- • Good Pharmacy Practice: standards dards and guidelines in the area of quality for quality of pharmacy services (joint assurance for implementation by WHO FIP/WHO, Annex 8). Member States, international organiza- tions, United Nations agencies, regional • Model guidance for the storage and and interregional harmonization efforts, transport of time- and temperature- as well as WHO’s medicines related pro- sensitive pharmaceutical products grammes and initiatives. (Annex 9). The following new recommendations • Procedure for prequalification of phar- were adopted at the 45th meeting of the maceutical products (Annex 10). Expert Committee on Specifications for Pharmaceutical Preparations. • Guidance on submission of documen- tation for prequalification of innova- • Monographs for inclusion in the Interna- tor finished pharmaceutical products tional Pharmacopoeia. (FPPs) approved by stringent regula- tory authorities (Annex 11). • International reference standards: • Procedure for prequalification of • New procedure for the release of laboratories (Annex 12). ICRS (see also Annex 1). • WHO guidelines for preparing a labora- • General policy regarding interna- tory information file (Annex 13). tional standards for human recom- binant insulin. • Guidelines for preparing a Site Master File (Annex 14). • Procedure for adoption of Interna- tional Chemical Reference Substances • Guideline for submission of documenta- (ICRS) (Annex 1). tion for a multisource (generic) finished product (Annex 15). • Good Practices for Pharmaceutical Microbiology Laboratories (Annex 2). Reference: World Health Organization 45th Expert Committee on Specifications for Phar- • GMP: main principles (Annex 3). maceutical Preparations. Information available at http://www.who.int/medicines/areas/quality_ • GMP for blood establishments safety/quality_assurance/en/index.html (jointly with ECBS) (Annex 4). • Supplementary GMP for HVAC (Annex 5)

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WHO Prequalification of Medicines Programme

Ensuring quality medicines: a decade of prequalification Reflections from A. J. van Zyl, First Programme Manager for the WHO Prequalification of Medicines Programme In March 2001, United Nations partners operating procedures (SOPs). Prequalifi- initiated a project, managed by the World cation (PQ) was based on existing WHO Health Organization, to facilitate access norms and standards approved by the to quality medicines used in the treat- ECSPP. In those cases where WHO did ment of HIV/AIDS. Partnering with WHO not have guidelines, relevant guidelines were UNICEF, UNAIDS, and UNFPA. The from ICH were used. A web site was also World Bank also supported this project. established to disseminate PQ vision, The first manager for the programme was mission, procedures, guidelines, training appointed by WHO on a six-month con- material, results and information (1). tract to establish, implement and manage the pilot project. The project was prin- The initial focus was to prequalify medi- cipally funded by donations and grants cines used in the treatment of HIV/ from Member States. AIDS. It was estimated that the number of people needing antiretroviral (ARV) Objectives of the WHO Prequalification of therapy in 2003 was in the range of Medicines Programme (PQP) were to: 100 000 with an ARV therapy coverage of only around 2%. It was further 1. Propose a list of prequalified products estimated that less than 10% of people manufactured in sites that meet WHO in most African countries had access to norms and standards. ARV treatment (2). Figure 1 shows the number of deaths per 100 000 in the US 2. Follow-up on products and manufactur- population in the period 1982–1993 (3). ing facilities for quality issues. 3. Ensure that prequalification and update Later on, due to the pressing need for of the original approved list is carried quality medicines in other disease areas, out periodically and that variations and the project was expanded to include changes are correctly controlled. products used in the treatment of tubercu- losis (TB) and malaria. 4. Assist national drug regulatory autho- rities to build capacity in assessment, Prequalifying medicines is achieved inspection and control of medicines for through an extensive evaluation pro- priority diseases. cedure that consists of assessment of product data and information that are In designing the project, a quality sys- voluntarily submitted by interested appli- tem was established consisting of a cants and manufacturers expressing their Procedure for Prequalification that was interest to participate in the project. This adopted by the WHO Expert Committee is followed by inspection of manufactur- on Specifications for Pharmaceutical ing and testing sites. No fees have been Preparations (ECSPP), various guide- charged by WHO since the beginning of lines, norms and standards, and standard prequalification but this practice is under

231 WHO Prequalification of Medicines Programme WHO Drug Information Vol. 25, No. 3, 2011

Figure 1: USA deaths per 100 000 population in the period 1982– 1993 40 35 HIV Infection Unintentional 30 Injuries Cancer 25 Heart 20 Disease 15 Suicide Homicide 10 Liver Disease 5 Stroke Diabetes 0 82 83 84 85 86 87 88 89 90 91 92 93* National Vital Statistics * Provisional Data review. Sites are inspected to verify data The organization chart in 2011 comprises: submitted in the product dossiers and to assess compliance with WHO good • one PQP manager manufacturing practices (GMP), good • one head of inspections with five in- clinical practices (GCP) and other appro- spectors priate guidelines. • one head of assessments with seven Reasons for initiating the PQ pilot project assessors was concern about low quality products circulating in the international market, • eight support staff the prevalence of spurious products and • one person each for liaison, capacity also as a result of the recommendation building and training, and sampling and in a report from a group of independ- monitoring (which includes prequalifica- ent experts. The report found that many tion of quality control laboratories). procurement organizations had no, or very limited, quality assurance systems in Expansion of the programme after 2006 place to ensure that good quality products was possible due to the financial support were procured. from the Bill & Melinda Gates Foundation. Today, the programme is largely financed Human resources by UNITAID but is seeking a broader In terms of staff appointments, the PQP donor base. team slowly grew from one manager in 2001 to a manager plus one coordina- External assessor group tor for assessments and one assistant From the initial one staff member with six during the first two years. One inspector external assessors present at the assess- was seconded from the French medi- ment meeting in June 2001, the group cines regulatory agency in 2003, and in has grown over the past ten years to subsequent years the team expanded to include on average seven internal as- include one manager, a coordinator for sessors and more than 20 external assessments and three inspectors. assessors at a group session.

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Assessments Complaints on prequalified products Data and specifications are submitted that are received in PQP are logged and and assessed by teams of assessors investigated by the inspectors. Inspec- from national medicines regulatory autho- tors and assessors must comply with the rities and WHO staff. Data and specifi- confidentiality and conflict of interest rules cations include but are not limited to the of WHO. active pharmaceutical ingredient (API), formulae, manufacturing process, stability Inspectors publish a quarterly newsletter (appropriate packaging and suitable for available on the PQP web site as well the intended market) and bio-equivalence as submitting articles to the WHO Phar- data (for generic products). maceuticals Newsletter and WHO Drug Information (see “Further reading” on Group assessment sessions are held page 239). every two months at the UNICEF offices in Copenhagen. Requirements for Monitoring product data and information have also Field sampling and testing projects have intensified over the years. In 2011, the been carried out by PQP in order to moni- recommendation is that manufacturers tor the quality of medicines (both WHO- should submit a dossier in the common prequalified and non-WHO prequalified) technical document (CTD) format (4–6). procured by UN agencies (8). Through To build capacity in developing countries, cooperation with medicines regulatory a unique three-month rotational post was authorities (MRAs), these projects also established in the area of dossier assess- contribute to national quality control of ment in 2006. Since then, 14 developing medicines, to strengthening of health country regulators from nine countries systems and capacity building. Samples have benefited from the arrangement. are collected by MRA staff and tested During assessment, multisource (generic) at WHO-prequalified laboratories and drug products are expected to satisfy the results are published. Several reports and same quality standards as those appli- publications in scientific journals have be- cable to the originator/reference product. come available over the ten-year period. In addition, assurance has to be provided that they are clinically interchangeable Brief overview with equivalent originator products (4). After the initial establishment of the project in 2001, the first list of prequalified Inspections products was published in March 2002. The inspection unit operates in accor- The project expanded to include prequali- dance with an established quality system fication of quality control laboratories and consisting of documented SOPs, formats tuberculosis and malaria medicines in for reports and letters, a training pro- 2003–2004. Due to inspection findings of gramme and related aspects as recom- non-compliance with GCP, some products mended in guidelines (7). Inspections were withdrawn from the list in 2004. In are performed at the facilities of finished order to improve patient compliance and product manufacturers, API manufac- ease of dosing, fixed dose combinations turers, quality control laboratories and were developed. PQP was instrumental in clinical sites including contract research providing the corresponding guideline. As organizations (CROs). Feedback on the the applicant of a prequalified medicinal implementation of norms and standards product invariably makes changes to a is given to the relative unit in WHO and supplied product during the product’s life recommendations are made for the cycle, a variation guideline was also de- development of new GMP guidelines (or veloped to ensure appropriate oversight revision of existing ones) as appropriate. of such changes.

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Table 1: Summary of main events

Year Event

2001 March: Appointment of first Manager for PQ (Dr AJ van Zyl). First expression of interest (EOI) published. Procedure for prequalification adopted by ECSPP. First assessment of product dossiers and inspections.

2002 First list of prequalified products published - March. Global publicity - New York Times and Wall Street Journal (9).

2003 Procedure for Prequalification of Quality Control Laboratories. Expand inspections to include API manufacturers. Donor: Bill and Melinda Gates Foundation

2004 Expand inspections to include CROs. WHO withdraws products form the List of PQ products due to non-compliance with GCP (10). Start the Programme of prequalification of quality control laboratories (restricted toAfrica).

2005 Annual report published. Fixed Dose Combination guideline TRS 929, 2005.

2006 Annual report published. Facilitate a new guideline for Contract Research Organizations. Publication of the Variations guideline TRS 943 Annex 6. Facilitate development of the guideline on comparative dissolution for biowaiver applications.Development, adoption and publication of a Model Quality Assurance System for Procurement Agencies, TRS 937, 2006. Donors: Bill and Melinda Gates Foundation and UNITAID.

2007 Annual report published. Appointment of the second Manager for PQP (Dr R Kiivet). Appointment of the Head of inspections, and Head of Assessments. Suspension of Viracept (Roche). Launching the PQP web site in Chinese.

2008 Implementation of the bio-waiver procedure. Contract PricewaterhouseCoopers to develop a business plan. First NOC issued by PQP - Sandoz SA. First suspension of products - Sandoz SA. NOS issued Wyeth Pakistan. First training workshop on pharmaceutical development with focus on pediatric formulations.

2009 Third Manager for PQP appointed (Mr A Gould). First inspection newsletter published NOC issued to Matrix. Undertake a manufacturer survey.

2010 Establish a joint assessment programme with EAC. Establish a collaborative procedure for inspections. Start inspections for comparative dissolution (bio-waiver applications). Prequalify the first influenza product. Issue NOC - BBRC. Implement the prequalification APIof procedure and first EOI published. Manufacturer’s meeting in Copenhagen .

2011 List 3 products in the list of prequalified APIs. Manufacturers’ meeting in Geneva. Issue NOC to Themis and Amsal. Publication on malaria medicines quality survey. Confidentiality agreement with EDQM signed.

As the PQP become successful, it was Drug Administration (FDA), PQP and the extended to include HIV/AIDS, TB and Quality Assurance and Safety: Medicines malaria, reproductive health products, Unit of WHO and in 2011 between the zinc sulphate for the treatment of diar- European Directorate for the Quality of rhoea in children, products used in treat- Medicines (EDQM) and WHO. ment of influenza and diethylcarbamazine (DEC). Within the biopharmaceutical classifica- tion system, PQP assisted in the devel- Mutual confidentiality agreements were opment of a guideline on comparative signed in 2005 between the US Food and dissolution for biowaiver applications.

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Due to cases of non-compliance identi- the PQP web site in Chinese followed, as fied during inspections at CROs, it was well as implementation of the biowaiver decided to facilitate the development of procedure. All NOC and NOS were also an additional guideline for CROs to assist published. In keeping interested parties in better understanding the application of informed of the activities of PQP, an in- GCP for bioequivalence studies. spection newsletter was regularly pub- lished as well as articles in publications. Due to reporting of low quality repro- To further ensure transparency and better ductive health products and problems serve clients, PQP undertook a manufac- in procuring good quality products, PQP turer’s survey in 2009. expanded its scope and included repro- ductive health products within the PQP in In an effort to expedite registration of cooperation with UNFPA. prequalified products, prevent duplication, and promote harmonization, PQP estab- In September 2008, the USA issued an lished and implemented a joint assess- import alert against Ranbaxy, a phar- ment programme with the East African maceutical company based in India. As Community (EAC) for product dossiers there were several of their products listed and a collaborative procedure for inspec- in PQP, a joint inspection with Canada, tions (joint inspections and recognition Australia and the United Kingdom was of inspection reports among regulators). undertaken at Ranbaxy to investigate Both initiatives deserve more in depth impact. At that time, to respond to World clarification. It is anticipated that activities Health Assembly Resolution 57.14 and will be described in more detail in future the request by Member States and inter- publications. national procurement organizations to enhance transparency, PQP published a With an increasing number of product first Notice of Concern (NOC) for manu- dossiers containing comparative disso- facturing sites. Provision was also made lution data, the inspection unit began for issuing Notices of Suspension (NOS) inspections at sites to verify reliability of for products. Resolution 57.14 requested dissolution data and GMP compliance WHO, among other actions to “ensure (biowaiver applications). that the prequalification review process and the results of inspection and assess- A major step forward in assisting MRAs to ment reports of the listed products, aside obtain information on the quality of APIs from proprietary and confidential informa- and API manufacturing sites, was imple- tion, are made publicly available”. mentation of the procedure for prequalifi- cation of APIs in 2010. This procedure is As a consequence, publication of WHO based on the assessment of API Master Public Inspection Reports (positive Files (also known as a Drug Master Files) outcomes of site inspections) and WHO and inspection of the sites. Public Assessment Reports (positive outcomes of dossier assessment) and the In further attempting to ensure the quality list of prequalified products provides the of products purchased, a model qual- public and regulators with extensive infor- ity assurance system for procurement mation on the PQ evaluation of products agencies was developed. This guideline and sites. was adopted by the ECSPP and the Interagency Pharmaceutical Coordina- The structure of PQP changed in 2007 tion group (IPC) and is used by different with the appointment of a new Pro- organizations including the World Bank. gramme Manager, appointment of a Head Following publication of the first Expres- of Inspections, and a Head of Assess- sion of Interest for HIV/AIDS products, ments. In the same year, the launching of more than 90 product dossiers were

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Table 2: Number of inspections by site, per year

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011*

APIs 1 2 11 8 6 11 7 5 15 FPPs 6 23 20 22 18 19 26 27 27 38 26 QC labs 1 7 3 1 10 8 9 6 CROs 6 13 17 13 14 10 7 7

Total 6 23 21 31 42 47 46 62 52 59 53

* Up to 15 July 2011 received for assessment in the first group cess; question/problem resolution during assessment session in Copenhagen. The assessment; consistency of membership number of product dossiers submitted for in the team of assessors throughout the assessment has varied from year to year, process, and local/national representation and between disease groups. in on-site inspection teams. Most manu- facturers view PQP GMP requirements Since 2001, more than 60 training as more stringent than those of the US workshops have been organized or co- FDA or European Medicines Agency. The organized in countries including Austria, findings from this survey indicate that Belgium, Brazil, China, Estonia, India, pharmaceutical manufacturers consider Kenya, Pakistan and Tanzania. Twenty PQP to be a well-designed, well-executed quality control laboratories (QCLs) have programme. PQP assessors and inspec- been prequalified and four sampling and tors are meeting or exceeding manufactu- testing projects have been undertaken. rer expectations for service delivery in all processes. In 2008, PricewaterhouseCoopers was appointed to assist in the development Table 2 reflects the number of inspections of a business plan. Recommendations by site, over the years, including for APIs, for improvement were made and it was finished pharmaceutical products (FPPs), calculated that the return on investment in CROs and quality control laboratories. PQ was 170.1 in the period 2009–2013. By 21 June 2011, a total of 253 finished products had been prequalified by WHO. Outcomes of the manufacturer survey This included 190 HIV/AIDS products, carried out in 2009 (11) were presented 31 TB; 17 malaria; seven influenza, and to a manufacturers’ meeting in Copenha- eight RPH products. gen in April 2010 and at the PQP Annual Stakeholders meeting in 2011. The report Conclusion concluded that both PQP assessors and The establishment and implementation of inspectors are meeting or exceeding a prequalification procedure for pharma- manufacturer expectations for service ceutical products, especially in the area delivery. The structure of PQP generally of HIV/AIDS, has significantly facilitated delivers levels of service at, or above, access to quality medicines. Moreover, it those expected by manufacturers. has also triggered harmonization between quality assurance policies of various However, the service process is falling organizations involved in procurement of short of manufacturer expectations with medicines for the developing world such respect to review/reply time for product as the Global Fund to Fight AIDS, Tuber- dossiers; opportunities for in-person com- culosis and Malaria, UNFPA, UNITAID, munication during the assessment pro- and beyond.

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Table 3: Number of products and quality control laboratories prequalified 2001–2010

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

HIV/AIDS 0 61 13 13 17 33 13 29 24 24 TB 0 0 6 2 0 0 5 5 7 5 Malaria 0 0 0 2 1 2 3 6 3 1 RPH 0 3 5 Influenza 0 7 1 Zn sulphate 0 0 DEC 0 0

Total 0 61 19 17 18 35 21 40 44 36

QC labs 0 3 0 0 6 3 6

Several publications reflect the increase lable. Where only 13% of patients were in number of patients on antiretroviral able to afford therapy in 1996, the num- treatment over the last decade, as well as ber increased to 44% in 2003. The most the reduction in price of these medicines common ARV regimen was 3FDC (lami- (see figure 2 below) (12). For example, in vudine, stavudine, nervirapine) which was 2005 it was reported that the cost of high- administered to 56% of patients receiving ly active antiretroviral therapy (HAART) HAART (13). This is supported by the decreased from US$ 778 per month in Global Fund’s quality assurance policy 1996 to US$ 100 per month in 2000, and (supporting procurement of prequalified further to US$ 33 per month in 2003 after products) and Global Fund reports on the first generic ARVs were made avai- procurement in countries (14).

Figure 2: Number of people receiving ARV therapy

North Africa and Middle East East, South and South-East Asia Europe and Central Asia Latin America and the Caribbean Sub-Saharan Africa 4.5 ) n s i o

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P 05

0 End 2002 End 2003 End 2004 End 2005 End 2006 End 2007 End 2008

237 WHO Prequalification of Medicines Programme WHO Drug Information Vol. 25, No. 3, 2011

According to a report from Médecins 3. US deaths per 100 000 population in the sans Frontières (MSF), the price of FDC period 1982–1993 at http://commons.wikime- lamivudine + nevirapine + stavudine per dia.org/wiki/File:US_cause_of_death.png patient per year dropped significantly 4. World Health Organization. Marketing from 2000–2001 and from 2008–2009. authorization of pharmaceutical products with The originator cost was US$ 10439 in special reference to multisource products. 2000, US$ 727 in 2001, US$ 331 in 2008 WHO/DMP/RGS/98.5 9 (1989). and US$ 531 in 2009. The corresponding generic product cost was US$ 2767, US$ 5. World Health Organization. Report of the 295, US$ 87 and US$ 80 in the corres- Expert Committee on Specifications for Phar- ponding years. The price dropped by 99% maceutical Preparations. Guidelines on sub- mission of documentation for prequalification from 2001 to 2010 (15, 16). of innovator finished pharmaceutical products approved by stringent regulatory authorities. The majority of products on the list of Annex 11. Technical Report Series, No. 961, prequalified medicines are multisource/ 2011. generic products. Generic manufacturers are the main suppliers of essential medi- 6. World Health Organization. Report of cines in developing countries: 67% of the Expert Committee on Specifications for medicines produced in India are exported Pharmaceutical Preparations. Guidelines on submission of documentation for a multisource to developing countries. Also, according (generic) finished product: general format: to PEPFAR – 73% of ARVs delivered in preparation of product dossiers in common focus countries are generic medicines technical document format. Annex 15. Techni- (17). cal Report Series, No. 961, 2011.

Acknowledgements 7. World Health Organization. Report of The prequalification programme has fa- the Expert Committee on Specifications for Pharmaceutical Preparations. Quality systems cilitated access to quality medicines and requirements for national good manufactur- created a mechanism for better medi- ing practice inspectorates. Annex 8. Technical cines at better prices. This was made Report Series, No. 902, 2002. possible by partners, donors, participat- ing industry and the kind assistance of 8. World Health Organization. Expert Commit- assessors and inspectors from many tee on Specifications for Pharmaceutical Pre- national medicines regulatory authorities. parations. Guidelines for sampling of pharma- WHO PQP would like to express a sin- ceutical products and related materials. Annex 15. Technical Report Series, No. 961, 2011. cere thank you to all involved as well as supporting staff in PQP and within WHO. 9. McNeill, DG. New List of Safe AIDS Drugs, The writer further wishes to thank all staff Despite Industry Lobby. The New York Times. members in WHO and in particular PQP 20 March 2002 at http://apps.who.int/prequal/ for their cooperation in the programme Press&Media/ Prequalification Update and their contribution to the writing of this 10. Alyman LK, McNeill, DG. UN Agency article. Drops Two Drugs for AIDS Care Worldwide. The New York Times, 16 June 2004, at http:// References apps.who.int/prequal/Press&Media/ Prequalifi- cation Update. 1. World Health Organization. Prequalification of Medicines Programme at http://www.who. 11. Interclarity Research and Consulting int/prequal Inc. at http://apps.who.int/prequal/trainingre- 2. Antiretroviral therapy coverage in sub- sources/pq_pres/stakeholders_2011/presen- Saharan Africa at http://www.who.int/hiv/data/ tations/Day_1/PQPSurvey.pdf and http://apps. art_coverage/en/index.html who.int/prequql/info_general/document/ARV_ survey.pdf and http://apps.who.int/prequql/

238 WHO Drug Information Vol. 25, No. 3, 2011 WHO Prequalification of Medicines Programme info_applicants/qclabs/monitoring_documents/ 3. Survey of service quality provided to manu- WHO_QAMS facturers. Volume 24, No. 4, p. 293 (2010). 12. WHO, UNICEF, UNAIDS. Towards uni- 4. WHO initiates pilot prequalification of active versal access: scaling up priority HIV/AIDS pharmaceutical ingredients. Volume 24, No. 4, interventions in the health sector. Progress p. 297 (2010). report 2009, p.55 at http://apps.who.int/pre- quql/info_general/document/ 5. Collaborative participation of national inspectors in WHO prequalification. Volume 13. Kumarasamy N et al. The changing natu- 24, No. 3, p. 201 (2010). ral history of HIV disease: before and after the introduction of generic antiretroviral therapy in 6. Inspection news report. Volume 24, No. 3, southern India. Clinical Infectious Diseases, p. 205 (2010). 2005;41:1525-8. 7. Inspection of finished pharmaceutical pro- 14. The Global Fund to Fight AIDS, Tubercu- duct manufacturers. Volume 24, No. 2, p. 87. losis and Malaria at http://www.theglobalfund. (2010). org/en/ 8. Facts and figures for 2009. Volume 24, 15. Medecins sans Fontières (MSF). Untan- No. 1, p. 3 (2010). gling the web at http://www.msfaccess.org/ main/hiv-aids/untangling-the-web/ 9. Prequalification of quality control laborato- ries. Volume 23, No. 4, p. 300 (2009). 16. Medecins sans Fontières (MSF). Examples of the importance of India as the 10. WHO medicines prequalification: progress “Pharmacy of the developing World” (2007) at in 2008. Volume 23, No. 1, p. 201 (2009). http://www.msfaccess.org/main 17. The US President’s Emergency Plan for 11. WHO Prequalification: GMP deviations AIDS Relief (PEPFAR) at http://www.pepfar. and suspension. Volume 22, No. 3, p. 203 gov.press/fourth_annual_report/ (2008). (2008).

Further reading 12. WHO prequalification: progress in 2007. Volume 22, No. 2, p. 79. 1. Dekker TG, van Zyl AJ, Gross O et al. Ongoing monitoring of antiretroviral products WHO Pharmaceuticals Newsletter as part of WHO’s Prequalification Project. J 1. Inspection of manufacturing sites for active Generic Med 2006;3:96-105 pharmaceutica ingredients within the WHO 2. Caudron JM et al. Substandard medicines Prequalification of Medicines Programme. in resource-poor settings: a problem that can Number 1, p. 12 (2011). no longer be ignored. Tropical Health and International Health Journal 2008;13(8):1062. 2. Collaborative participation of inspectors from medicines regulatory authorities (MRAs) 3. Strauch S, Jantratid E, Stahl M et al. in inspections coordinated by the The biowaiver procedure: its application to WHO Prequalification of Medicines Pro- antituberculosis products in the WHO Prequa- gramme. Number 3, p. 12 (2010). lification Programme. J Pharm Sci 2010:DOI 10.1002/jps.22349;Wiley Online Library at 3. WHO Prequalification of Medicines Pro- wileyonlinelibrary.com gramme: Inspection of finished pharmaceuti- cal product manufacturers to increase quality WHO Drug Information of medicines. Number 2, p. 16 (2010). 1. Facts and figures for 2010. Volume 25, No. 4. Prequalification of quality control laborato- 2, p. 101 (2011). ries. Number 1, p. 22 (2010).

2. Inspection of API manufacturing sites. 5. Inspections of bio-equivalence studies. Volume 25, No. 1, p. 24 (2011). Number 4, p. 11 (2009).

239 WHO Drug Information Vol. 25, No. 3, 2011

Regulatory Support

Paediatric medicines made at the 13th International Confe- rence of Drug Regulatory Authorities regulatory network (ICDRA) held in 2008. The Paediatric medicines Regulators’ What the network does Network (PmRN) is a network of repre- sentatives from medicines regulatory The PmRN is a forum for regulators to authorities (MRAs) established by WHO discuss and exchange information in rela- in 2010. Its overall objective is to sup- tion to paediatric medicines. The aim of port the availability of safe, effective and the PmRN is to promote the availability of affordable medicines for children through safe, effective and affordable medicines facilitation of communication, collabora- for children, by enhancing information tion and regulatory harmonization among sharing between MRAs, improving the regulators on aspects related to the transparency of the decision-making pro- manufacturing, licensing of medicines cess, promoting appropriate ethical and (including vaccines and biologicals) and clinical research standards for children, evaluation of clinical trials in children. strengthening paediatric pharmacovigi- lance and contributing to capacity building Why the network was established for the licensing of paediatric medicines. Currently, many medicines have not been How PmRN works studied and do not exist in appropriate formulations or dosage forms to allow The activities of the network focus on accurate and safe dosing of medicines key steps in paediatric medicines regu- for children. Lack of appropriate data on lation, including the review of clinical trial safety, efficacy and dosing in children applications or dossiers for application for has left healthcare professionals with no marketing authorization, the development other options than to use unauthorized or of appropriate formulations and dosage off-label medicines in this population. The forms of paediatric medicines, and the lack of development of paediatric spe- safety aspects of paediatric medicines. cific medicines, paired with inconsistent The work of the PmRN is coordinated by regulatory frameworks, poses significant a Steering Committee under the chair- health risks to a particularly vulnerable manship of Agnes Saint Raymond, from patient population. the European Medicines Agency (EMA). The Steering Committee comprises mem- A few years ago, initiatives were under- bers representing authorities from the taken to overcome this unsatisfactory EMA, Singapore, South Africa, the United situation, first in the United States then Republic of Tanzania, and the US Food in Europe, by introducing legislation on and Drug Administration (FDA). The Stee- paediatric medicines. In 2007, WHO ring Committee convenes on a monthly launched the global campaign ‘make me- basis via teleconference. dicines child size’ to raise awareness and accelerate action to address the need for A PmRN public web site has been esta- improved availability and access to safe blished to facilitate communication and child-specific medicines for children. The information-sharing and is available at establishment of the PmRN is part of this http://www.who.int/childmedicines/paedia- initiative and follows recommendations tric_regulators/en/

240 WHO Drug Information Vol. 25, No. 3, 2011 Regulatory Support

Members of the PmRN also have access children. All MRAs have a role to play to a restricted web site that can be used in the development, registration and to post questions and requests for help post-marketing surveillance of paediatric and advice from other network mem- medicines. bers. A bi-annual network newsletter is prepared and circulated to members By becoming a member of the PmRN, of the PmRN. The newsletter can also regulators can benefit from access to the be accessed via the PmRN web site. latest information related to the regula- It is anticipated that meetings of the tion of paediatric medicines. Members network members will take place every 12 can also request help from other PmRN months. The 2nd meeting of the PmRN will members on issues related to paediatric take place in Dar es Salaam, Tanzania, medicine regulation. It is hoped that the 3–5 October 2011. exchange of information between regu- latory authorities and the following of a Why a medicines regulatory authority common approach on identified topics should join the PmRN will help to strengthen regulatory capacity globally and lead to improvements in the The lack of availability of paediatric spe- availability of and access to paediatric cific medicines is a global issue. Interna- medicines. tionally, there is a growing focus on the need for research and development of To date, 27 MRAs have become mem- medicines specifically for children. bers of the PmRN and it is expected that more authorities will join. Notwithstanding differences in the needs and challenges faced by MRAs in res- How to become a member ponding to their domestic and regional All regulators are free to join the PmRN requirements, there is a pressing need and contribute to discussions. For more to support the global availability of safe, information about becoming a member effective and affordable medicines for please contact: [email protected].

241 WHO Drug Information Vol. 25, No. 3, 2011

Safety and Efficacy Issues

Dexrazoxane: contraindicated patients treated with dexrazoxane. Some in children and adolescents studies have observed a higher incidence of death in groups treated with dexra- United Kingdom — Dexrazoxane (Car- zoxane plus chemotherapy compared dioxane®) is now contraindicated for use with those given chemotherapy alone. in children and adolescents up to age 18 The possibility that dexrazoxane was a years due to evidence of serious harm contributing factor to this imbalance can- in this age-group. Use is restricted to not be ruled out. adults with advanced or metastatic breast cancer. Furthermore, a significant decrease in tumour response rate has been repor- Dexrazoxane (Cardioxane®) is indicated ted in a study of patients with advanced for the prevention of chronic cumulative breast cancer treated with doxorubicin cardiotoxicity caused by doxorubicin and dexrazoxane compared with those or epirubicin in patients with advanced treated with doxorubicin and placebo (4). or metastatic cancer after previous Since both dexrazoxane and doxorubicin anthracycline-containing treatment. An are topoisomerase inhibitors, it is pos- analogue of ethylene diamine-tetraace- sible that dexrazoxane may interfere with tic acid (EDTA), it is thought to reduce the antitumour efficacy of doxorubicin. anthracycline-induced cardiotoxicity by chelation of free iron-containing cations. Advice for healthcare professionals: The drug is also an inhibitor of topoiso- merase II and has cytotoxic properties. • Dexrazoxane is contraindicated for use Most controlled clinical studies of dexra- in children and adolescents up to age zoxane have been done in patients with 18 years. advanced breast cancer. • Use is restricted to adults with ad- Evidence of harm in children vanced or metastatic breast cancer. Two randomized open studies reported • Use of dexrazoxane in combination a three-fold increase in the incidence of with adjuvant breast cancer therapy or second primary malignancies (particularly chemotherapy intended as curative is acute myeloid leukaemia [AML] and mye- not recommended. lodysplastic syndrome) in dexrazoxane- treated children compared with controls • Patients should be counselled about (1–2). A significantly increased risk of the risk of leukaemia. other toxicities compared with controls, including severe myelosuppression and • Patients with breast cancer should severe infection, was also reported in one have received a cumulative dose of at study (3). least 300 mg/m2 doxorubicin or 540 mg/m2 epirubicin before starting dexra- Use in adults zoxane. Four postmarketing case reports of AML have been reported from France in adults • The dose ratio is now 10:1 for with breast cancer. There is also evi- dexrazoxane:doxorubicin and for dence of increased myelosuppression in dexrazoxane:epirubicin.

242 WHO Drug Information Vol. 25, No. 3, 2011 Safety and Eficacy Issues

Reference: Medicines Healthcare Regula- been suggested in the literature and com- tory Agency, Drug Safety Update, Volume 4, municated by other regulatory authorities Issue 12, July 2011 at http://www.mhra.gov.uk/ (1–8). Recent studies have suggested Safetyinformation that hypomagnesemia can be induced by several if not all PPIs (1,2,4,6). Pioglitazone: risk of bladder The mechanism by which PPIs induce cancer hypomagnesemia is unclear. It may European Union — Following its review involve defects in magnesium absorption on pioglitazone-containing antidiabetic in the small intestine by affecting the medicines and the occurrence of bladder function of the transient receptor poten- cancer, the European Medicines Agency’s tial melastin 6 (TRPM6) channel (1,2,6). Committee for Medicinal Products for Effects on magnesium absorption have Human Use (CHMP) confirmed that these not been reported with short-term use of medicines remain a valid treatment option PPIs. Published case reports suggest that for certain patients with type 2 diabetes PPI-induced hypomagnesemia occurs but that there is a small increased risk of after prolonged use (≥ 1 year) (1–6). bladder cancer. However, the CHMP also Magnesium is involved in bone metabo- concluded that the small increased risk lism. Its deficiency may induce parathy- could be reduced by appropriate patient roid dysfunction and hypoparathyroidism, selection and exclusion, including a requi- thereby affecting the regulation of calcium rement for periodic review of the efficacy levels (9–11). Hypomagnesemia may also and safety of the individual patient’s trigger hypokalemia via activation of the treatment. potassium channel of the thick ascending limb of the loop of Henle, resulting in Prescribers are advised not to use these urinary potassium wasting (4,12). medicines in patients with current or a history of bladder cancer or in patients The effects of PPIs on serum magne- with uninvestigated macroscopic hae- sium levels seem to be reversible (1–6). maturia. Risk factors for bladder cancer In all published cases, electrolyte levels should be assessed before initiating returned to normal following cessation treatment. In light of age-related risks, the of PPI treatment (positive dechallenge). balance of benefits and risks should be Recurrence of hypomagnesemia fol- considered both before initiating and du- lowing reintroduction of the PPI (positive ring treatment in the elderly. Prescribers rechallenge) was documented in three should review the treatment of patients cases (1,3,6). In most cases, secondary on pioglitazone after three to six months hypokalemia or hypocalcemia, or both, (and regularly afterwards) to ensure that accompanied hypomagnesemia, with only patients who are deriving sufficient some patients presenting with symptoms benefit continue to take it. of potentially life-threatening cardiac ar- rhythmias and neurologic manifestations Reference: EMA Press Release, EMA/ (e.g., seizures, loss of consciousness and CHMP/568262/2011, 21 July 2011 at http:// tetany). www.ema.europa.eu As of 31 January 2011, Health Canada had received five reports of hypomagne- Proton pump inhibitors: semia. One case was life threatening hypomagnesemia, hypo- and four patients required hospital care. calcemia and hypokalemia Secondary hypokalemia was reported in three of the cases. Canada — The potential association between proton pump inhibitor (PPI) Health professionals are reminded that, treatment and hypomagnesemia has in some patients, hypomagnesemia may

243 Safety and Eficacy Issues WHO Drug Information Vol. 25, No. 3, 2011 occur after prolonged treatment with 11. Anast CS, Mohs JM, Kaplan SL, et al. PPIs, and it may be accompanied by Evidence for parathyroid failure in magnesium hypocalcemia and hypokalemia. This deficiency. Science 1972;177(49):606-8. adverse reaction may be underdiagnosed and underreported because of the low 12. Agus ZS. Hypomagnesemia. J Am Soc Nephrol 1999;10(7):1616-22. frequency of magnesium measurement in routine clinical practice (1,6). Floseal® hemostatic matrix: Extracted from the Canadian Adverse misinterpretation of recurrent Reactions Newsletter, Volume 21, Issue 3, July 2011. malignant disease Canada — Floseal® is a granular hemos- References tatic agent that consists of a bovine-de- 1. Broeren MA, Geerdink EA, Vader HL, rived gelatin matrix component and a hu- et al. Hypomagnesemia induced by seve- man-derived thrombin component. Before ral proton-pump inhibitors. Ann Intern Med application, these two components are 2009;151(10):755-6. combined to allow the mixing and recons- titution of the thrombin into the gelatin 2. Cundy T, Dissanayake A. Severe hypo- matrix. Floseal® is indicated in surgical magnesaemia in long-term users of pro- ton-pump inhibitors. Clin Endocrinol (Oxf) procedures (other than ophthalmic) as 2008;69(2):338-41. an adjunct to hemostasis when control of bleeding by ligature or conventional 3. Epstein M, McGrath S, Law F. Proton-pump methods is ineffective or impractical. Flo- inhibitors and hypomagnesemic hypoparathy- seal® is expected to resorb in the tissues roidism. N Engl J Med 2006;355(17):1834-6. within 6 to 8 weeks (1). In Canada, the 4. Hoorn EJ, van der Hoek J, de Man RA, et product is regulated as a class IV medical al. A case series of proton pump inhibitor- device (highest risk class). induced hypomagnesemia. Am J Kidney Dis 2010;56(1):112-6. In 2010, Health Canada received two 5. Shabajee N, Lamb EJ, Sturgess I, et al. reports of adverse incidents in which Omeprazole and refractory hypomagnesae- Floseal® was suspected of persisting at mia. BMJ 2008;337:425. surgical sites following partial nephrec- tomy for cancer. In both cases, follow-up 6. Regolisti G, Cabassi A, Parenti E, et al. Severe hypomagnesemia during long-term radiographic imaging several months treatment with a proton pump inhibitor. Am J after surgery revealed an asymptomatic Kidney Dis 2010;56(1):168-74. mass malignant disease. The physician later reinterpreted the mass as a possible 7. Proton pump inhibitor drugs (PPIs): Drug persistence of Floseal®. In both cases, Safety Communication -- low magnesium the report suggested that the mass could levels can be associated with long-term use. have been related to excess use of Flo- Rockville (MD): US Food and Drug Adminis- seal® without adequate irrigation. Other tration; 2011. cases have been reported in the medical 8. Omeprazole and risk of hypomagnesaemia. literature in which Floseal® persisted in Prescriber Update 2010;31(2):13-4. the tissues after tumour resection and was misinterpreted as recurrent mali- 9. Rude RK, Singer FR, Gruber HE. Skeletal gnant disease during follow-up (2,3). and hormonal effects of magnesium deficien- cy. J Am Coll Nutr 2009;28(2):131-41. Extracted from the Canadian Adverse 10. Paunier L, Radde IC, Kooh SW, et Reactions Newsletter, Volume 21, Issue al. Primary hypomagnesemia with secon- 3, July 2011. dary hypocalcemia in an infant. Pediatrics 1968;41(2):385-402.

244 WHO Drug Information Vol. 25, No. 3, 2011 Safety and Eficacy Issues

References difficulty in feeding. These symptoms can vary in seriousness. In some new- 1. Floseal Hemostatic Matrix [Canadian ins- borns, the symptoms may go away within tructions for use]. Zurich (Switzerland): Baxter hours or days and not require specific Healthcare SA; 2010. treatment, while in others the symptoms 2. Henkel A, Cooper RA, Ward KA, et al. may be more severe and require medical Malignant-appearing microcalcifications at attention. the lumpectomy site with the use of FloSeal hemostatic sealant. AJR Am J Roentgenol Reference: Health Canada Media Advisory 2008;191(5):1371-3. 2011-78, 15 June 2011 at http://www.hc-sc. gc.ca 3. Shashoua AR, Gill D, Barajas R, et al. Caseating granulomata caused by hemostatic agent posing as metastatic leiomyosarcoma. Rituximab: fatal infusion-related JSLS 2009;13(2):226-8. reactions Canada — The manufacturer of rituximab Antipsychotic drugs update: (Rituxan®) has released important new newborns safety information regarding fatal infusion related reactions following use of rituxi- Canada — Health Canada is informing mab in rheumatoid arthritis patients. healthcare professionals and consumers that the prescribing information for the Rituximab is a chimeric mouse/human entire class of antipsychotic drugs is monoclonal antibody that binds specifical- being updated. The updated labelling will ly to the transmembrane antigen CD20. contain safety information on the potential It is authorized to reduce the signs and risk of abnormal muscle movements and symptoms in adult patients with modera- withdrawal symptoms in newborns whose tely to severely active rheumatoid arthritis mothers were treated with these drugs who have had an inadequate response or during the third trimester of pregnancy. intolerance to one or more tumour necro- Antipsychotic drugs are used to treat sis factor (TNF) inhibitor therapies. symptoms of psychiatric disorders such as schizophrenia and bipolar disorder. An analgesic/antipyretic (e.g., aceta- Health Canada has notified the Canadian minophen) and an antihistaminic drug manufacturers of antipsychotic drugs (e.g., diphenhydramine) should always (typical and atypical) to update the Pro- be administered before each infusion of duct Monographs to include this safety rituximab. Patients should receive 100 mg information. IV methylprednisolone 30 minutes prior to each infusion. Women taking an antipsychotic and who are pregnant or thinking of becoming Healthcare professionals must be vigilant pregnant should talk to their doctor about for signs of hypersensitivity or anaphy- their treatment. Patients should not laxis in all patients experiencing an infu- stop taking their medication without first sion reaction during or following rituximab speaking to a healthcare practitioner, as administration. abruptly stopping an antipsychotic drug can cause serious adverse events. • If anaphylaxis or other serious hyper- sensitivity/infusion reaction occurs, Abnormal muscle movements and with- administration of rituximab should be drawal symptoms in newborns include stopped immediately, and appropriate agitation, abnormally increased or medical management should be initi- decreased muscle tone, tremor, slee- ated. piness, severe difficulty breathing, and

245 Safety and Eficacy Issues WHO Drug Information Vol. 25, No. 3, 2011

• Infusions should not be administered dose response relationship was apparent, unless they are in a setting where with relative increases in death related to resuscitation equipment is easily and breast cancer associated with increased immediately available. time of overlapping tamoxifen and paroxetine treatment. • Patients with pre-existing cardiac condi- tions and those who experienced prior An association did not extend to other cardiopulmonary adverse reactions SSRIs in this study such as citalopram, need to be monitored closely following escitalopram, sertraline, mirtazapine and the rituximab infusion. venlafaxine. Reference: Health Canada Advisory, Commu- nication from Hoffmann-La Roche Limited , 2 Advice for prescribers: June 2011 at http://www. hc-sc.gc.ca • Avoid concomitant use of potent CYP2D6 inhibitors in women taking Tamoxifen: CYP2D6 interactions tamoxifen for breast cancer (e.g., par- and variable clinical response oxetine). New Zealand — Recent evidence sug- • If antidepressant treatment is required, gests there is a potential risk for higher preference should be given to those rates of disease recurrence and death that show little or no inhibition of related to breast cancer in women taking CYP2D6. tamoxifen concomitantly with CYP2D6 Further information is available in two inihibitors. It is noted in the literature that recently published reviews (3, 4). CYP2D6 inhibitors such as selective serotonin reuptake inhibitors (SSRIs) References are commonly used concomitantly with tamoxifen. 1. Medco Health Solutions Inc., and the Indiana University School of Medicine (2009) The interaction centers on endoxifen. Increased risk of breast cancer recurrence Endoxifen is an important active meta- in women initiating tamoxifen with CYP2D6 bolite that contributes significantly to the inhibitors. Presentation at the 2009 American efficacy of tamoxifen and is produced by Society of Clinical Oncology (ASCO) Annual the metabolism of tamoxifen via CYP2D6. Meeting. Drugs that inhibit CYP2D6 can therefore 2. Kelly CM, Juurlink DN, Gomes T, et al. lead to reduced plasma concentrations of Selective serotonin reuptake inhibitors and endoxifen and reduced action. breast cancer mortality in women receiving tamoxifen: a population based cohort study. A study (1) involving over 1200 women BMJ 2010;340:693. found that the two-year breast cancer recurrence rate was 1.9 times higher 3. Desmarais, JE, and Looper KJ. Interac- in patients receiving both tamoxifen tions between tamoxifen and antidepressants and a CYP2D6 inhibitor, compared to via cytochrome P450 2D6. J Clin Psych those receiving tamoxifen only (13.9% 2009;70(12):1688–1697 vs 7.5%). In addition the breast cancer 4. Henry NL, Stearns V, Flockhart DA, et al. recurrence rate was 2.2 times higher in Drug interactions and pharmacogenomics in women receiving a moderate to potent the treatment of breast cancer and depres- CYP2D6 inhibitor. sion. Am J Psych 2008;165(10):1251–1255. A more recent population based cohort 5. Tamoxifen: CYP2D6 interactions and study (2) found an increased risk of death variable clinical response. Prescriber Update, related to breast cancer in women taking 32(2) 2011 at http://www.medsafe.govt.nz/ tamoxifen and concomitant paroxetine. A profs/PUarticles.asp

246 WHO Drug Information Vol. 25, No. 3, 2011 Safety and Eficacy Issues

Thalidomide: risk of arterial and Evidence from postmarketing case venous thromboembolism reports suggests that the risk of arterial thrombotic and thromboembolic reactions United Kingdom — Patients treated is greatest during the first five months with thalidomide have an increased risk of therapy. Antithrombotic prophylaxis of arterial thromboembolism, including should therefore be administered for at myocardial infarction and cerebrovascular least the first five months of treatment, events, in addition to the established risk especially in patients with thrombotic risk of venous thromboembolism. Healthcare factors in addition to multiple myeloma. professionals should consider venous and arterial thrombotic risk and adminis- Antithrombotic prophylactic measures ter antithrombotic prophylaxis for at least should be prescribed after careful as- the first five months in patients commen- sessment of the individual’s underlying cing thalidomide. risk factors. A history of thromboembolic events, or concomitant use of erythro- Thalidomide (Thalidomide Celgene®) is poietic agents or other agents such as licensed throughout the European Union hormone-replacement therapy, may for use in combination with melphalan increase the risk of thromboembolic and prednisone as first-line treatment for events. patients with untreated multiple myeloma who are age 65 years or older, or those Advice for healthcare professionals: who are ineligible for high-dose chemo- therapy. Thalidomide is an immunomo- • Action should be taken to minimize all dulatory agent, which has antineoplastic, modifiable risk factors for thromboem- antiangiogenic, and antierythropoietic bolic events (eg, smoking, hyperten- properties. sion, and hyperlipidaemia). Information has been published to • Healthcare professionals should con- highlight the key risk of teratogenicity and sider venous and arterial thrombotic risk-minimization measures to prevent risk and administer antithrombotic pro- exposure of pregnant women to thalido- phylaxis for at least the first five months mide. At that time, serious, or potentially in patients commencing thalidomide. serious, side effects were identified as venous thromboembolism, neutropenia, Reference: Medicines and Healthcare Pro- thrombocytopenia, peripheral neuropa- ducts Regulatory Agency. Drug Safety Update, Volume 4, Issue 12, July 2011 at http://www. thy (which may be permanent), syncope mhra.gov.uk/Safetyinformation and bradycardia, serious skin reactions including Stevens-Johnson syndrome, and somnolence and dizziness. A recent Use of 2011 seasonal influenza review of global postmarketing data has vaccines in children shown that approximately one third of all thromboembolic reactions reported in Australia — The 2011 seasonal influenza association with thalidomide were arterial, vaccines vary in their approved indica- most of which were myocardial infarction tions and recommendations for use in and cerebrovascular events. children. These variations relate to the availability of Australian safety informa- Myeloma is clearly a risk factor for throm- tion for the vaccines and the ability of bosis. However, the pathophysiology of sponsors to meet requirements for active arterial thrombosis in patients treated surveillance of children. The Therapeutic with thalidomide is not fully understood. It Goods Administration (TGA) requests seems to be an effect associated with this that consumers and healthcare professio- drug class. nals report all adverse events associated

247 Safety and Eficacy Issues WHO Drug Information Vol. 25, No. 3, 2011 with influenza vaccination in patients of years. ATAGI advises that Fluvax® may any age and any instances of inadvertent be used in children aged five years to administration to a child of a vaccine not less than 10 years when no timely alter- currently recommended for use in child- native vaccine is available (2). ren, regardless of whether the child has a reaction. References

During the 2010 influenza season an 1.Therapeutic Goods Administration. Investi- gation into febrile reactions in young children excess number of cases of febrile reac- following 2010 seasonal trivalent influenza tions and febrile convulsions was obser- vaccination. Status report as at 2 July 2010, ved in paediatric populations following updated 2010 Sep 24. Canberra: TGA; 2010. immunization with one of the registered seasonal trivalent influenza vaccine (1). 2.Australian Technical Advisory Group on Consequently, the TGA imposed a condi- Immunization. Clinical advice for immunisation tion on the registration of all 2011 seaso- providers regarding the administration of 2011 nal influenza vaccines with a paediatric trivalent seasonal influenza vaccines. Can- berra: ATAGI; 2011. indication which were not supplied in Aus- tralia in 2010. Sponsors were required to 3. Therapeutic Goods Administration (TGA). undertake active surveillance of children Medicines Safety Update, at http://www.tga. from six months to nine years of age, to gov.au ensure effective monitoring of paediatric populations in Australia previously unex- posed to these vaccines. Addiction to benzodiazepines and codeine: safer use

Two sponsors were unable to meet this United Kingdom — Since the 1980s, condition of registration. Although the there have been concerns about the risk safety of Agrippal® and Fluarix® has of dependence and withdrawal reactions been demonstrated in the Northern after long term use of benzodiazepines. Hemisphere 2010–11 influenza season, For more than 20 years, the duration of the TGA does not have any safety data use of these products has been limited to on the use of these vaccines in Australian 2–4 weeks. children. Hence, the TGA recommends that these vaccines are not used in any Two reports commissioned by the De- child under the age of nine years. partment of Health have recently been published on addiction to prescribed and For children under the age of nine years it over-the-counter medicines. Data from is recommended that they be vaccinated reports of the National Treatment Agency with either Influvac® or Vaxigrip®. These and National Addiction Centre showed two vaccines were not associated with that the overall level of prescribing of ben- increased rates of fever or febrile reac- zodiazepines decreased between 1991 tions in 2010. and 2009. This fall was mainly in the use of benzodiazepines as hypnotics. Use Fluvax® is not approved for use in child- of anxiolytic benzodiazepines increased ren under the age of five years for the during this period. The data also showed 2011 influenza season. Although CSL has a gradual increase in sales of over-the- an active surveillance system in place counter codeine-containing medicines to actively monitor children aged 5–18 since these were placed on the market in years, the Australian Technical Advisory 2006. Group on Immunization (ATAGI) has ad- vised that there is a strong preference for Given the risks associated with the use the use of either Vaxigrip® or Influvac® of benzodiazepines, patients should be in children aged five years to less than 10 prescribed the lowest effective dose for

248 WHO Drug Information Vol. 25, No. 3, 2011 Safety and Eficacy Issues the shortest time possible. Maximum The CHMP reviewed results of epidemio- duration of treatment should be 4 weeks, logical studies conducted by the marke- including the dose-tapering phase. ting authorization holder at the request of the Committee in 2007, all available Over-the-counter codeine-containing me- reports on adverse drug reactions and dicines should be used for the short-term data from the published literature. (three days) treatment of acute, moderate pain which is not relieved by paracetamol, The Committee noted that, in treatment of ibuprofen, or aspirin alone. acute pain, nimesulide is as effective as other NSAID pain killers, such as diclofe- Reference: Medicines and Healthcare Pro- nac, ibuprofen and naproxen. ducts Regulatory Agency, Drug Safety Update, Volume 4, Issue 12, July 2011 at http://www. In terms of safety, the CHMP noted that mhra.gov.uk/Safetyinformation nimesulide has the same risk of gas- trointestinal toxicity as other NSAIDs. Nimesulide-containing The CHMP concluded that nimesulide was associated with an increased risk of medicines: restricted use liver toxicity compared with other anti- European Union — The European Medi- inflammatory treatments and had pre- cines Agency’s Committee for Medicinal viously imposed several restrictions on Products for Human Use (CHMP) has the use of systemic nimesulide in order concluded that the benefits of systemic to reduce risks of liver injury. Having nimesulide-containing medicines continue reviewed all available data, the CHMP is to outweigh their risks in the treatment of now recommending, as a further restric- patients with acute pain and primary dys- tion, that systemic nimesulide should no menorrhoea. However, these medicines longer be used for the treatment of painful should no longer be used for the sympto- osteoarthritis. The Committee considered matic treatment of osteoarthritis. that the use of systemic nimesulide for the treatment of this chronic condition, Nimesulide is a non-steroidal anti-inflam- would increase the risk of the medicines matory drug (NSAID) that has been used being used for long-term treatment, with to treat acute pain, painful osteoarthritis a consequent increase in the risk of liver and primary dysmenorrhoea. injury. The Committee started a full assessment Reference: European Medicines Agency, of the benefits and risks of nimesulide- Press Release, EMA/CHMP/486983/2011, 23 containing medicines for systemic use at June 2011 at http://www.ema.europa.eu/ema/ the request of the European Commission, index. because of ongoing concerns over their gastrointestinal and hepatic safety.

Spontaneous monitoring systems are useful in detecting signals of relatively rare, serious or unexpected adverse drug reactions. A signal is defined as “reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented pre- viously. Usually, more than a single report is required to generate a signal, depending upon the seriousness of the event and the quality of the information”. All signals must be vaidated before any regulatory decision can be made.

249 WHO Drug Information Vol. 25, No. 3, 2011

Regulatory Action and News

Artemisinin-based malaria Reference: European Medicines Agency, Press Release, CHMP/496931/2011, 24 June treatment approved 2011 at http://www.ema.europa.eu/ema/index. European Union — The European Medi- cines Agency (EMA) has recommended Pandemrix®: restriction in use approval of Eurartesim®, a fixed combi- nation product consisting of dihydroar- European Union — Following its review temisinin and piperaquine phosphate. of Pandemrix® and narcolepsy the Eurartesim® is intended for the treatment European Medicines Agency Committee of uncomplicated Plasmodium falciparum for Medicinal Products for Human Use malaria in adults, children and infants (CHMP) has recommended that in per- aged 6 months or over and weighing 5 kg sons under 20 years of age Pandemrix® or more. may only be used if the recommended seasonal trivalent influenza vaccine is The World Health Organization (WHO) not available and if immunization against estimates that in 2009, malaria caused H1N1 is still needed (e.g., in persons at nearly 800 000 deaths, mostly among risk of complications of infection). The African children. The disease is present CHMP confirmed that the benefit-risk in over 100 countries and threatens half balance of Pandemrix® remains positive. of the world’s population. Plasmodium falciparum, the parasite causing the most The review of Pandemrix® was initiated lethal type of human malaria has become to investigate a possible link between resistant to many conventional treatments Pandemrix vaccination and narcolepsy, in most parts of the world. WHO’s 2010 following an increased number of repor- Malaria Treatment Guidelines recom- ted cases of narcolepsy among children mend artemisinin combination therapies and adolescents in Finland and Swe- (ACTs) as the most effective treatment for den. The reported cases of narcolepsy malaria. occurred following the H1N1 pandemic vaccination campaign in late 2009 and In the European Union (EU), the medi- early 2010. The current review has been cine is recommended for approval as an conducted in the context of seasonal use. orphan medicine due to the limited num- Reference: EMA Press Release, CHMP/ ber of patients affected in this region. The 496931/2011, 24 June 2011 at http://www. framework for orphan medicines provides ema.europa.eu incentives to encourage the development of medicines for neglected diseases that would not be developed under normal Indacaterol: approved for market conditions. While malaria affects chronic obstructive pulmonary hundreds of millions of people world- disease wide, it is considered a rare disease in the EU, affecting approximately one in United States of America — The Food 33 000 people. The orphan status will be and Drug Administration (FDA) has reviewed at the next meeting of the Com- approved indacaterol inhalation powder mittee for Orphan Medicinal Products. (Arcapta Neohaler®) for long term, once- daily maintenance bronchodilator treat-

250 WHO Drug Information Vol. 25, No. 3, 2011 Regulatory Action and News ment of airflow obstruction in people with Ticagrelor: approved to treat chronic obstructive pulmonary disease acute coronary syndromes (COPD) including chronic bronchitis and/ or emphysema. Arcapta Neohaler® is a United States of America — The Food new molecular entity in the beta2 adrener- and Drug Administration (FDA) has gic agonist class approved the blood-thinning drug ticagre- lor (Brilinta®) to reduce cardiovascular Arcapta Neohaler® carries a boxed death and heart attack in patients with warning that long-acting beta2 adrener- acute coronary syndromes (ACS). gic agonists (LABA) increase the risk of asthma-related death. LABA, including ACS includes a group of symptoms for Arcapta Neohaler®, should not be used any condition, such as unstable angina in patients with asthma, unless used with or heart attack, that could result from a long-term asthma control medication. reduced blood flow to the heart. Ticagre- lor works by preventing the formation of Reference: FDA News Release, 1 July 2011 new blood clots, thus maintaining blood at http://fda.www.gov/NewsEvents/Newsroom/ flow in the body to help reduce the risk of PressAnnouncements/ucm261649.htm another cardiovascular event.

Rivaroxaban approved to Ticagrelor has been studied in combina- reduce risk of blood clots tion with aspirin. A boxed warning to heal- thcare professionals and patients warns United States of America — The Food that aspirin doses above 100 milligrams and Drug Administration (FDA) has ap- per day decrease the effectiveness of the proved rivaroxaban (Xarelto®) to reduce medication. the risk of blood clots, deep vein throm- bosis, and pulmonary embolism following The boxed warning also says that, like knee or hip replacement surgery. other blood-thinning agents, ticagre- lor increases the rate of bleeding and The safety and effectiveness of rivaroxa- can cause significant, sometimes fatal, ban was evaluated in patients undergoing bleeding. The most common adverse hip replacement surgery and patients reactions reported in clinical trials were undergoing knee replacement surgery. bleeding and dyspnea. Ticagrelor was The most common side effect observed approved with a Risk Evaluation and Miti- in patients treated with rivaroxaban was gation Strategy. In addition, ticagrelor will bleeding. be dispensed with a Medication Guide.

Reference: FDA News Release, July 5, 2011 Reference: FDA News Release, 20 July 2011 at http://fda.www.gov/NewsEvents/Newsroom/ at http://fda.www.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm261649.htm PressAnnouncements/ucm261649.htm

251 WHO Drug Information Vol. 25, No. 3, 2011

Consultation Documents

The International Pharmacopoeia

3.3 Microbial purity of pharmaceutical preparations

Draft proposal for revision of a General Method in the 4th Edition of the International Pharmacopoeia (June 2011). Please addess any comments to Quality Assurance and Safety: Medicines, World Health Organization, 1211 Geneva 27, Switzerland. Fax: +41 22 791 4730 or e-mail schmidth@ who.int. Working documents are available for comment at http://who.int/ medicines.

[Note from Secretariat. During its meeting in October 2010, the Expert Committee on Specifications for Pharmaceutical Preparations recommended that the current method described in The International Pharmacopoeia (Ph.Int.) for the microbial quality of pharmaceutical preparations should be replaced by the internationally-harmonized general test available. To this effect the following revision of method 3.3 Microbial purity of pharmaceutical preparations is proposed.

Microbiological examination of non-sterile products has been a subject for Interna- tional Pharmacopoeial harmonization, which has resulted in three texts: (i) Microbial enumeration tests; (ii) Tests for specified microorganisms, and (iii) Acceptance criteria for pharmaceutical preparations and substances for pharmaceutical use. The text on acceptance criteria is published in the European Pharmacopoeia, Japanese Pharma- copoeia and United States Pharmacopeia as a non-mandatory information chapter.

The International Pharmacopoeia currently has no method text on microbial enume- ration tests and tests for specified microorganisms. The text on 3.3 Microbial purity of pharmaceutical preparations is provided to give information and guidance, and is not regarded as an analytical requirement.

It is proposed to introduce the package of the three internationally-harmonized texts in the Ph.Int. The texts on microbial enumeration tests and tests for specified microorga- nisms are new (3.3.1 and 3.3.2) in the Methods of Analysis section. Furthermore, it is proposed to replace the current 3.3 text on microbial purity by the internationally-har- monized text on acceptance criteria for non-sterile preparations and substances. The text will be provided for information and will, therefore, be moved to the Supplemen- tary Information section.

The European Pharmacopoeia contains acceptance criteria for oral dosage forms, other than herbal medicinal products, containing raw materials of natural origin (ani- mal, vegetable, mineral) for which antimicrobial treatment is not feasible and for which the competent authority accepts TAMC exceeding 103CFU per gram or millilitre. Should similar acceptance criteria be considered for inclusion in the Ph.Int.?]

252 WHO Drug Information Vol. 25, No. 3, 2011 Consultation Documents

Proposed text for supplementary information

Microbiological examination of non-sterile products: acceptance criteria for pharmaceutical preparations and substances for pharmaceutical use

The text is provided to give information and guidance, and is not regarded as an ana- lytical requirement. The acceptance criteria do not apply to herbal drugs and herbal drug preparations. For such preparations reference should be made to “Quality control methods for medicinal plant materials: Determination of microorganisms (WHO 1998)”. The presence of certain microorganisms in non-sterile preparations may have the potential to reduce or even inactivate the therapeutic activity of the product and has a potential to adversely affect the health of the patient. Manufacturers have, therefore, to ensure a low bioburden of finished dosage forms by implementing current guidelines on good manufacturing practice during the manufacture, storage and distri- bution of pharmaceutical preparations.

Microbial examination of non-sterile products is performed according to the methods given in the texts on “3.3.1 Microbial enumeration tests” and “3.3.2 Tests for specified microorganisms”. Acceptance criteria for non-sterile pharmaceutical products based upon the total aerobic microbial count (TAMC) and the total combined yeasts/moulds count (TYMC) are given in Tables 1 and 2. Acceptance criteria are based on individual results or on the average of replicate counts when replicate counts are performed (e.g. direct plating methods).

Table 1 includes a list of specified microorganisms for which acceptance criteria are set. The list is not necessarily exhaustive and for a given preparation it may be neces- sary to test for other microorganisms depending on the nature of the starting materials and the manufacturing process.

When an acceptance criterion for microbiological quality is prescribed it is interpreted as follows:

— 101 CFU: maximum acceptable count = 20 — 102 CFU: maximum acceptable count = 200 — 103 CFU: maximum acceptable count = 2000, and so forth.

If it has been shown that none of the prescribed tests will allow valid enumeration of microorganisms at the level prescribed, a validated method with a limit of detection as close as possible to the indicated acceptance criterion is used.

In addition to the microorganisms listed in Table 1, the significance of other microorga- nisms recovered should be evaluated in terms of:

• use of the product: hazard varies according to the route of administration (eye, nose, respiratory tract); • nature of the product: does the product support growth, does it have adequate anti- microbial preservation; • method of application; • intended recipient: risk may differ for neonates, infants, the debilitated;

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Table 1. Acceptance criteria for microbiological quality of non-sterile dosage forms

Route of adminis- Total aerobic Total combined Specified microor- tration microbial count yeasts/moulds ganism (CFU/g or CFU/ ml) count (CFU/g or CFU/ ml) 3 2 Non-aqueous prepa- 10 10 Absence of Esch- rations for oral use erichia coli (1 g or 1 ml)

Aqueous prepara- 102 101 Absence of Esch- tions for oral use erichia coli (1 g or 1 ml)

3 2 Rectal use 10 10

Oromucosal use 102 101 Absence of Staphylo- Gingival use coccus aureus Cutaneous use (1 g or 1 ml) Nasal use Absence of Pseudo- Auricular use monas aeruginosa (1 g or 1 ml)

Vaginal use 102 101 Absence of Pseudo- monas aeruginosa (1 g or 1 ml) Absence of Staphylo- coccus aureus (1 g or 1 ml) Absence of Candida albicans (1 g or 1 ml)

Transdermal patches 102 101 Absence of Staphylo- (limits for one patch coccus aureus including adhesive (1 patch) layer and backing) Absence of Pseudo- monas aeruginosa (1 patch)

Inhalation use (spe- 102 101 Absence of Staphylo- cial requirements coccus aureus apply to liquid prepa- (1 g or 1 ml) rations for nebuliza- Absence of Pseudo- tion) monas aeruginosa (1 g or 1 ml) Absence of bile-tole- rant Gram-negative bacteria (1g or 1 ml)

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Table 2. Acceptance criteria for microbiological quality of non-sterile substances for pharmaceutical use

Total aerobic Total combined yeasts/ microbial count moulds count (CFU/g or CFU/ ml) (CFU/g or CFU/ ml)

Substances for 103 102 pharmaceutical use

• use of immunosuppressive agents, corticosteroids, and • presence of disease, wounds, organ damage. Where warranted, a risk-based assessment of the relevant factors is conducted by personnel with specialized training in microbiology and the interpretation of microbiolo- gical data. For raw materials the assessment takes account of processing to which the product is subjected, the current technology of testing and the availability of materials of the desired quality.presence of disease, wounds, organ damage.

3.3.1. Microbiological examination of non-sterile products: microbial enumeration tests

Draft proposal for revision of a General Method in the 4th Edition of the International Pharmacopoeia (June 2011). Please addess any comments to Quality Assurance and Safety: Medicines, World Health Organization, 1211 Geneva 27, Switzerland. Fax: +41 22 791 4730 or e-mail mendyc@ who.int. Working documents are available for comment at http://who.int/ medicines.

[Note from Secretariat. During its meeting in October 2010 the Expert Committee on Specifications for Pharmaceutical Preparations recommended that requirements for microbial enumeration tests be added in The International Pharmacopoeia (Ph.Int.) us- ing as a basis the internationally-harmonized general tests available on microbiologi- cal examination of non-sterile products.

Discussions for the international harmonization of requirements for the microbiological examination of non-sterile products has led to the elaboration of three general texts: (i) Microbial enumeration tests; (ii) Tests for specified microorganisms, and (iii) Accep- tance criteria for pharmaceutical preparations and substances for pharmaceutical use, the latter text on acceptance criteria being published as non-mandatory information. At present, The International Pharmacopoeia (Ph.Int) has no method text on micro- bial enumeration tests and tests for specified microorganisms. The current text (3.3 Microbial purity of pharmaceutical preparations) is provided to give information and guidance and is not regarded as an analytical requirement.

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It is proposed to introduce these three internationally harmonized general texts in the Ph.Int. The texts on microbial enumeration tests and tests for specified microorga- nisms are new (3.3.1 and 3.3.2) in the Methods of Analysis section. Furthermore, it is proposed to replace the current text 3.3 on microbial purity by the internationally-har- monized one on acceptance criteria for non-sterile preparations and substances. This text will be provided for information and will, therefore, be moved to the Supplemen- tary Information section.

If the proposed 3.3.1 and 3.3.2 texts are adopted for inclusion in the Ph.Int. a review will be carried out on the application of these methods within the existing Ph.Int. texts. Such a review would include excipients and consider in which Ph.Int. monographs the methods would be invoked and would propose limits.] The tests described hereafter will allow quantitative enumeration of mesophilic bacte- ria and fungi which may grow under aerobic conditions.

The tests are designed primarily to determine whether a substance or preparation complies with an established specification for microbiological quality. (When used for such purposes follow the instructions given below, including the number of samples to be taken and interpret the results as stated below.)

The methods are not applicable to products containing viable microorganisms as active ingredients.

Alternative microbiological procedures, including automated methods, may be used, provided that their equivalence to the pharmacopoeial method has been demonstra- ted.

The recommended test solutions and media are described in “3.3.2 Tests for specified microorganisms”.

General procedures Carry out the determination under conditions designed to avoid extrinsic microbial contamination of the product to be examined. The precautions taken to avoid conta- mination must be such that they do not affect any microorganisms which are to be revealed in the test.

If the product to be examined has antimicrobial activity, this is insofar as possible removed or neutralized. If inactivators are used for this purpose their efficacy and their absence of toxicity for microorganisms must be demonstrated.

If surface-active substances are used for sample preparation, their absence of toxicity for microorganisms and their compatibility with inactivators used must be demonstra- ted.

Enumeration methods Use the membrane filtration method or the plate-count methods, as prescribed.The most probable number (MPN) method is generally the least accurate method for microbial counts; however, for certain product groups with very low bioburden, it may be the most appropriate method.

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The choice of a method is based on factors such as the nature of the product and the required limit of microorganisms. The method chosen must allow testing of a sufficient sample size to judge compliance with the specification. The suitability of the chosen method must be established.

Growth promotion test, suitability of the counting method and negative controls General considerations The ability of the test to detect microorganisms in the presence of the product to be tested must be established. Suitability must be confirmed if a change in testing performance, or the product, which may affect the outcome of the test is introduced. Preparation of test strains Use standardized stable suspensions of test strains or prepare as stated below. Seed- lot culture maintenance techniques (seed-lot systems) are used so that the viable microorganisms used for inoculation are not more than 5 passages removed from the original master seed-lot. Grow each of the bacterial and fungal test strains separately as described in Table 1. Use buffered sodium chloride-peptone solution, sterile, pH 7.0, TS or phosphate buf- fer, sterile, pH 7.2, TS to make test suspensions; to suspend A. niger spores, 0.05% of polysorbate 80 may be added to the buffer. Use the suspensions within 2 h or within 24 h if stored at 2–8 °C. As an alternative to preparing and then diluting a fresh suspension of vegetative cells of A. niger or B. subtilis, a stable spore suspension is prepared and then an appropriate volume of the spore suspension is used for test inoculation. The stable spore suspension may be maintained at 2–8 °C for a validated period of time. Negative control To verify testing conditions a negative control is performed using the chosen diluent in place of the test preparation. There must be no growth of microorganisms. A negative control is also performed when testing the products as described under 5. A failed negative control requires an investigation. Growth promotion of the media Test each batch of ready-prepared medium and each batch of medium, prepared either from dehydrated medium or from the ingredients described.

Inoculate portions/plates of casein soya bean digest broth and casein soya bean digest agar with a small number (not more than 100 CFU) of the microorganisms indicated in Table 1, using a separate portion/plate of medium for each. Inoculate plates of Sabouraud-dextrose agar with a small number (not more than 100 CFU) of the microorganisms indicated in Table 1, using a separate plate of medium for each. Incubate in the conditions described in Table 1.

For solid media, growth obtained must not differ by a factor greater than 2 from the calculated value for a standardized inoculum. For a freshly prepared inoculum, growth of the microorganisms comparable to that previously obtained with a previously tested

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Table 1. Preparation and use of test microorganisms

Suitability of counting Micro Preparation Growth promotion method in the presence of organism of test strain the product Total aerobic Total yeasts Total aerobic Total yeasts microbial and moulds microbial and moulds count count count count Staphylococ- Casein Casein soya Casein soya cus aureus soya bean bean digest bean digest such as digest agar or agar and agar/ MPN ATCC 6538, casein soya casein soya casein soya NCIMB 9518, bean digest bean digest bean digest CIP 4.83 or broth broth broth NBRC 13276 30–35 °C ≤ 100 CFU/ ≤ 100 CFU/ 18–24 h 30–35 °C 30–35 °C ≤ 3 days ≤ 3 days Pseudomo- Casein Casein soya Casein soya nas aerugi- soya bean bean digest bean digest nosa digest agar or agar and agar/MPN such as casein soya casein soya casein soya ATCC 9027, bean digest bean digest bean digest NCIMB 8626, broth broth broth CIP 82.118 30–35 °C ≤ 100 CFU/ ≤ 100 CFU/ or NBRC 18–24 h 30–35 °C 30–35 °C 13275 ≤ 3 days ≤ 3 days Bacillus Casein Casein soya Casein soya subtilis soya bean bean digest bean digest such as digest agar or agar and agar/MPN ATCC 6633, casein soya casein soya casein soya NCIMB 8054, bean digest bean digest bean digest CIP 52.62 broth broth broth or NBRC 30–35 °C ≤ 100 CFU ≤ 100 CFU 3134 18–24 h 30–35 °C 30–35 °C ≤ 3 days ≤ 3 days Candida Sabouraud- Casein soya Sabouraud- Casein soya Sabouraud- albicans dextrose agar bean digest dextrose agar bean digest dextrose agar such as or Sabou- agar ≤ 100 CFU agar ≤ 100 CFU ATCC 10231, raud-dextrose ≤ 100 CFU 20–25 °C ≤ 100 CFU 20–25 °C NCPF 3179, broth 30–35 °C ≤ 5 days 30–35 °C ≤ 5 days IP 48.72 or 20–25 °C ≤ 5 days ≤ 5 days NBRC 1594 2–3 MPN: not days applicable Aspergillus Sabouraud- Casein soya Sabouraud- Casein soya Sabouraud- niger dextrose agar bean digest dextrose bean digest dextrose such as or potato- agar agar agar agar ATCC 16404, dextrose agar ≤ 100 CFU ≤ 100 CFU ≤ 100 CFU ≤ 100 CFU IMI 149007, 20–25 °C 30–35 °C 20–25 °C 30–35 °C 20–25 °C IP 1431.83 or 5–7 days, or NBRC 9455 ≤ 5 days ≤ 5 days ≤ 5 days ≤ 5 days until good MPN: not sporulation applicable is achieved

258 WHO Drug Information Vol. 25, No. 3, 2011 Consultation Documents and approved batch of medium occurs. Liquid media are suitable if clearly visible growth of the microorganisms comparable to that previously obtained with a previously tested and approved batch of medium occurs.

Suitability of the counting method in the presence of product

Preparation of the sample. The method for sample preparation depends on the physical characteristics of the product to be tested. If none of the procedures descri- bed below can be demonstrated to be satisfactory, an alternative procedure must be developed. Water-soluble products. Dissolve or dilute (usually a 1 in 10 dilution is prepared) the product to be examined in buffered sodium chloride-peptone solution, sterile, pH 7.0, TS, phosphate buffer sterile, pH 7.2, TS or casein soya bean digest broth. If neces- sary adjust to pH 6–8. Further dilutions where necessary are prepared with the same diluent. Non-fatty products insoluble in water. Suspend the product to be examined (usually a 1 in 10 dilution is prepared) in buffered sodium chloride-peptone solution, sterile, pH 7.0 TS, phosphate buffer , sterile, pH 7.2, TS or casein soya bean digest broth. A surface-active agent such as 1 g/l of polysorbate 80 may be added to assist the sus- pension of poorly wettable substances. If necessary adjust to pH 6–8. Further dilutions where necessary are prepared with the same diluent.

Fatty products. Dissolve in isopropyl myristate R, (new reagent.) sterilized by fil- tration, or mix the product to be examined with the minimum necessary quantity of sterile polysorbate 80 or another non-inhibitory sterile surface-active reagent, heated if necessary to not more than 40 °C, or in exceptional cases to not more than 45 °C. Mix carefully and if necessary maintain the temperature in a water-bath. Add sufficient of the prewarmed chosen diluent to make a 1 in 10 dilution of the original product. Mix carefully whilst maintaining the temperature for the shortest time necessary for the formation of an emulsion. Further serial ten-fold dilutions may be prepared using the chosen diluent containing a suitable concentration of sterile polysorbate 80 or another non-inhibitory sterile surface-active reagent.

Fluids or solids in aerosol form. Aseptically transfer the product into a membrane filter apparatus or a sterile container for further sampling. Use either the total contents or a defined number of metered doses from each of the containers tested.

Transdermal patches. Remove the protective cover sheets (“release liner”) of the transdermal patches and place them, adhesive side upwards, on sterile glass or plas- tic trays. Cover the adhesive surface with sterile porous material, for example, sterile gauze, to prevent the patches from sticking together, and transfer the patches to a suitable volume of the chosen diluent containing inactivators such as polysorbate 80 and/or lecithin. Shake the preparation vigorously for at least 30 min.

Inoculation and dilution. Add to the sample prepared as described above under “Preparation of the sample” and to a control (with no test material included) a sufficient volume of the microbial suspension to obtain an inoculum of not more than 100 CFU. The volume of the suspension of the inoculum should not exceed 1% of the volume of diluted product.

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To demonstrate acceptable microbial recovery from the product, the lowest possible dilution factor of the prepared sample must be used for the test. Where this is not possible due to antimicrobial activity or poor solubility, further appropriate protocols must be developed. If inhibition of growth by the sample cannot otherwise be avoided, the aliquot of the microbial suspension may be added after neutralization, dilution or filtration.

Neutralization/removal of antimicrobial activity. The number of microorganisms recovered from the prepared sample diluted as described above under Inoculation and dilution and incubated following the procedure described below under Recovery of microorganism, is compared to the number of microorganisms recovered from the control preparation.

If growth is inhibited (reduction by a factor greater than 2), then modify the procedure for the particular enumeration test to ensure the validity of the results. Modification of the procedure may include, for example (1) an increase in the volume of the diluent or culture medium, (2) incorporation of a specific or general neutralizing agents into the diluent, (3) membrane filtration, or (4) a combination of the above measures.

Neutralizing agents. Neutralizing agents may be used to neutralize the activity of an- timicrobial agents (Table 2). They may be added to the chosen diluent or the medium preferably before sterilization. If used, their efficacy and their absence of toxicity for microorganisms must be demonstrated by carrying out a blank with neutralizer and without product.

If no suitable neutralizing method can be found, it can be assumed that the failure to isolate the inoculated organism is attributable to the microbial activity of the product. This information serves to indicate that the article is not likely to be contaminated with the given species of the microorganism. However, it is possible that the product only inhibits some of the microorganisms specified herein, but does not inhibit others not included amongst the test strains or for which the latter are not representative. Then, perform the test with the highest dilution factor compatible with microbial growth and the specific acceptance criterion.

Recovery of microorganism in the presence of product. For each of the microor- ganisms listed, separate tests are performed. Only microorganisms of the added test strain are counted. Table 2. Common neutralizing agents for interfering substances

Interfering substance Potential neutralizing method

Glutaraldehyde, Mercurials Sodium hydrogensulfite (Sodium bisulfite) Phenolics, Alcohol, Aldehydes, Sorbate Dilution Aldehydes Glycine Quaternary Ammonium Compounds (QACs) Lecithin Parahydroxybenzoates (Parabens), Bis- biguanides QAC, Iodine, Parabens Polysorbate Mercurials Thioglycollate Mercurials, Halogens, Aldehydes Thiosulfate EDTA (edetate) Mg or Ca ions

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Membrane filtration Use membrane filters having a nominal pore size not greater than 0.45 µm.The type of filter material is chosen in such a way that the bacteria-retaining efficiency is not affected by the components of the sample to be investigated. For each of the microor- ganisms listed, one membrane filter is used. Transfer a suitable amount of the sample prepared as described above under “Suitabi- lity of the counting method in the presence of product” (preferably representing 1 g of the product, or less if large numbers of CFU are expected) to the membrane filter, filter immediately and rinse the membrane filter with an appropriate volume of diluent. For the determination of total aerobic microbial count (TAMC), transfer the mem- brane filter to the surface of casein soya bean digest agar. For the determination of total combined yeasts/moulds count (TYMC) transfer the membrane to the surface of Sabouraud-dextrose agar. Incubate the plates as indicated in Table 1. Perform the counting.

Plate-count methods Perform plate-count methods at least in duplicate for each medium and use the mean count of the result.

Pour-plate method For Petri dishes 9 cm in diameter add to the dish 1 ml of the sample prepared as des- cribed under “Suitability of the counting method in the presence of product” and 15–20 ml of casein soya bean digest agar or Sabouraud-dextrose agar, both media being at not more than 45 °C. If larger Petri dishes are used, the amount of agar medium is increased accordingly. For each of the microorganisms listed in Table 1, at least 2 Petri dishes are used. Incubate the plates as indicated in Table 1. Take the arithmetic mean of the counts per medium and calculate the number of CFU in the original inoculum. Surface-spread method For Petri dishes 9 cm in diameter, add 15–20 ml of casein soya bean digest agar or Sabouraud-dextrose agar at about 45 °C to each Petri dish and allow to solidify. If larger Petri dishes are used, the volume of the agar is increased accordingly. Dry the plates, for example, in a laminar airflow cabinet or in an incubator. For each of the mi- croorganisms listed in Table 1, at least two Petri dishes are used. Spread a measured volume of not less than 0.1 ml of the sample prepared as described under “Suitability of the counting method in the presence of product” over the surface of the medium. Incubate and count as prescribed under “Pour-plate method”.

Most-probable-number (MPN) method The precision and accuracy of the MPN method is less than that of the membrane filtration method or the plate-count method. Unreliable results are obtained particularly for the enumeration of moulds. For these reasons the MPN method is reserved for the enumeration of TAMC in situations where no other method is available. If the use of the method is justified, proceed as follows.

Prepare a series of at least three serial ten-fold dilutions of the product as described under “Suitability of the counting method in the presence of product”. From each level of dilution, 3 aliquots of 1 g or 1 ml are used to inoculate 3 tubes with 9–10 ml of

261 Consultation Documents WHO Drug Information Vol. 25, No. 3, 2011 casein soya bean digest broth. If necessary a surface-active agent such as polysor- bate 80, or an inactivator of antimicrobial agents may be added to the medium. Thus, if three levels of dilution are prepared nine tubes are inoculated. Incubate all tubes at 30–35 °C for not more than 3 days. If reading of the results is dif- ficult or uncertain owing to the nature of the product to be examined, subculture in the same broth, or casein soya bean digest agar, for 1–2 days at the same temperature and use these results. Determine the most probable number of microorganisms per gram or millilitre of the product to be examined from Table 3. Results and interpretation When verifying the suitability of the membrane filtration method or the plate-count method, a mean count of any of the test organisms not differing by a factor greater than 2 from the value of the control defined above under Inoculation and dilution in the absence of the product must be obtained. When verifying the suitability of the MPN method the calculated value from the inoculum must be within 95% confidence limits of the results obtained with the control. If the above criteria cannot be met for one or more of the organisms tested with any of the described methods, the method and test conditions that come closest to the criteria are used to test the product.

Testing of products Amount used for the test Unless otherwise prescribed, use 10 g or 10 ml of the product to be examined taken with the precautions referred to above. For fluids or solids in aerosol form, sample 10 containers. For transdermal patches, sample 10 patches. The amount to be tested may be reduced for active substances that will be formulated in the following conditions: the amount per dosage unit (e.g., tablet, capsule, injection) is less than or equal to 1 mg or the amount per gram or millilitre (for preparations not presented in dose units) is less than 1 mg. In these cases, the amount of sample to be tested is not less than the amount present in 10 dosage units or 10 g or 10 ml of the product. For materials used as active substances where sample quantity is limited or batch size is extremely small (i.e. less than 1000 ml or 1000 g), the amount tested shall be 1% of the batch unless a lesser amount is prescribed or justified and authorized. For products where the total number of entities in a batch is less than 200 (e.g. samples used in clinical trials), the sample size may be reduced to 2 units, or 1 unit if the size is less than 100. Select the sample(s) at random from the bulk material or from the available containers of the preparation. To obtain the required quantity, mix the contents of a sufficient number of containers to provide the sample.

Examination of the product Membrane filtration Use a filtration apparatus designed to allow the transfer of the filter to the medium. Prepare the sample using a method that has been shown suitable as described in sec-

262 WHO Drug Information Vol. 25, No. 3, 2011 Consultation Documents tion 4 and transfer the appropriate amount to each of two membrane filters and filter immediately. Wash each filter following the procedure shown to be suitable.

For the determination of TAMC, transfer one of the membrane filters to the surface of casein soya bean digest agar. For the determination of TYMC, transfer the other membrane to the surface of Sabouraud-dextrose agar. Incubate the plate of casein soya bean digest agar at 30–35 °C for 3–5 days and the plate of Sabouraud-dextrose agar at 20–25 °C for 5–7 days. Calculate the number of CFU per gram or per millilitre of product.

When examining transdermal patches, filter 10% of the volume of the preparation described under 4.5.1 separately through each of 2 sterile filter membranes.Transfer one membrane to casein soya bean digest agar for TAMC and the other membrane to Sabouraud-dextrose agar for TYMC.

Plate-count methods

Pour-plate method. Prepare the sample using a method that has been shown to be suitable as described in section 4. Prepare for each medium at least two Petri dishes for each level of dilution. Incubate the plates of casein soya bean digest agar at 30–35 °C for 3–5 days and the plates of Sabouraud-dextrose agar at 20–25 °C for 5–7 days. Select the plates corresponding to a given dilution and showing the highest number of colonies less than 250 for TAMC and 50 for TYMC. Take the arithmetic mean per culture medium of the counts and calculate the number of CFU per gram or per milli- litre of product.

Surface-spread method. Prepare the sample using a method that has been shown to be suitable as described in section 4. Prepare at least 2 Petri dishes for each medium and each level of dilution. For incubation and calculation of the number of CFU pro- ceed as described for the pour-plate method.

Most-probable-number method. Prepare and dilute the sample using a method that has been shown to be suitable as described in section 4. Incubate all tubes for 3–5 days at 30–35 °C. Subculture if necessary, using the procedure shown to be suitable. Record for each level of dilution the number of tubes showing microbial growth. Deter- mine the most probable number of microorganisms per gram or millilitre of the product to be examined from Table 3.

Interpretation of the results

The total aerobic microbial count (TAMC) is considered to be equal to the number of CFU found using casein soya bean digest agar; if colonies of fungi are detected on this medium, they are counted as part of TAMC. The total combined yeasts/ mould count (TYMC) is considered to be equal to the number of CFU found using Sabouraud-dextrose agar; if colonies of bacteria are detected on this medium, they are counted as part of TYMC. When the TYMC is expected to exceed the acceptance criterion due to the bacterial growth, Sabouraud-dextrose agar containing antibiotics may be used. If the count is carried out by the MPN method the calculated value is the TAMC.

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Table 3. Most-probable-number values of microorganisms

Observed combinations of numbers of tubes showing growth in each set MPN per g 95% Number of g or ml of product per tube or per ml confidence limits of product 0.1 0.01 0.001 0 0 0 Less than 3 0–9.4 0 0 1 3 0.1–9.5 0 0 1 3 0.1–10 0 1 1 6.1 1.2–17 0 2 0 6.2 1.2–17 1 0 2 11 4–35 1 1 0 7.4 1.3–20 1 1 1 11 4–35 1 2 0 11 4–35 1 2 1 15 5–38 1 3 0 16 5–38 2 0 0 9.2 1.5–35 2 0 1 14 4–35 2 0 2 20 5–38 2 1 0 15 4–38 2 1 1 20 5–38 2 1 1 27 9–94 2 2 0 21 5–40 2 2 1 28 9–94 2 2 2 35 9–94 2 3 0 29 9–94 2 3 1 36 9–94 3 0 0 23 5–94 3 0 1 38 9–104 3 0 2 64 16–181 3 1 0 43 9–181 3 1 1 75 17–199 3 1 2 120 30–360 3 1 3 160 30–380 3 2 0 93 18–360 3 2 1 150 30–380 3 2 2 210 30–400 3 2 3 290 90–990 3 3 0 240 40–990 3 3 1 460 90–1980 3 3 2 1100 200–4000 3 3 3 More than 1100

264 WHO Drug Information Vol. 25, No. 3, 2011 Consultation Documents

When an acceptance criterion for microbiological quality is prescribed it is interpreted as follows:

— 101 microorganisms: maximum acceptable count = 20 — 102 microorganisms: maximum acceptable count = 200 — 103 microorganisms: maximum acceptable count = 2000, and so forth. New reagent to be added to Ph.Int.

Isopropyl myristate R. Propan-2-yl tetradecanoate. C17H34O2. Description: A clear, colourless, oily liquid. Miscibility: Immiscible with water, miscible with ethanol, fatty oils, liquid paraffin. Relative density: About 0.853

3.3.2 Microbial examination of non sterile products: tests for specified microorganisms Draft proposal for revision of a General Method in the 4th Edition of the International Pharmacopoeia (June 2011). Please addess any comments to Quality Assurance and Safety: Medicines, World Health Organization, 1211 Geneva 27, Switzerland. Fax: +41 22 791 4730 or e-mail mendyc@ who.int. Working documents are available for comment at http://who.int/ medicines.

[Note from Secretariat. During its meeting in October 2010 the Expert Committee on Specifications for Pharmaceutical Preparations recommended that requirements for tests for specified microorganisms be added in The International Pharmacopoeia (Ph. Int.) using as a basis the internationally-harmonized general tests available on micro- biological examination of non-sterile products.

Discussions for the international harmonization of requirements for the microbiological examination of non-sterile products has led to the elaboration of three general texts: (i) Microbial enumeration tests; (ii) Tests for specified microorganisms, and (iii) Accep- tance criteria for pharmaceutical preparations and substances for pharmaceutical use, the latter text on acceptance criteria being published as non-mandatory information.

At present, The International Pharmacopoeia has no method text on microbial enu- meration tests and tests for specified microorganisms. The text 3.3 Microbial purity of pharmaceutical preparations is provided to give information and guidance and is not regarded as an analytical requirement.

It is proposed to introduce these three internationally-harmonized general texts in the Ph.Int. The texts on microbial enumeration tests and tests for specified microor- ganisms are new (3.3.1 and 3.3.2) in the Methods of Analysis section. Furthermore, it is proposed to replace the current text 3.3 on microbial purity by the internationally harmonized one on acceptance criteria for non-sterile preparations and substances. This text will be provided for information and will, therefore, be moved to the Supple- mentary Information section.

If the proposed 3.3.1 and 3.3.2 texts are adopted for inclusion in the Ph.Int a review will be carried out on the application of these methods within the existing Ph.Int texts.

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Such a review would include excipients and consider in which Ph.Int. monographs the methods would be invoked and would propose limits.] The tests described hereafter will allow determination of the absence of, or limited occurrence of specified microorganisms which may be detected under the conditions described. The tests are designed primarily to determine whether a substance or preparation complies with an established specification for microbiological quality. When used for such purposes follow the instructions given below, including the number of samples to be taken and interpret the results as stated below. Alternative microbiological procedures, including automated methods may be used, provided that their equivalence to the pharmacopoeial method has been demonstra- ted.

General Procedures The preparation of samples is carried out as described in 3.3.1 Microbial enumeration tests.

If the product to be examined has antimicrobial activity, this is insofar as possible removed or neutralized as described in 3.3.1 Microbial enumeration tests.

If surface-active substances are used for sample preparation, their absence of toxicity for microorganisms and their compatibility with inactivators used must be demonstra- ted as described in Microbial enumeration tests.

Growth promoting and inhibitory properties of the media, suitability of the test and negative controls The ability of the test to detect microorganisms in the presence of the product to be tested must be established. Suitability must be confirmed if a change in testing perfor- mance, or the product, which may affect the outcome of the test is introduced. Preparation of test strains Use standardized stable suspensions of test strains or prepare as stated below. Seed- lot culture maintenance techniques (seed-lot systems) are used so that the viable microorganisms used for inoculation are not more than 5 passages removed from the original master seed-lot. Aerobic microorganisms Grow each of the bacterial test strains separately in containers containing casein soya bean digest broth or on casein soya bean digest agar at 30–35 °C for 18–24 h. Grow the test strain for Candida albicans separately on Sabouraud-dextrose agar or in Sabouraud-dextrose broth at 20–25 °C for 2–3 days.

Staphylococcus aureus such as ATCC 6538, NCIMB 9518, CIP 4.83 or NBRC 13276, Pseudomonas aeruginosa such as ATCC 9027, NCIMB 8626, CIP 82.118 or NBRC 13275

Escherichia coli such as ATCC 8739, NCIMB 8545, CIP 53.126 or NBRC 3972, Salmonella enterica subsp. enterica serovar Typhimurium such as ATCC 14028 or,

266 WHO Drug Information Vol. 25, No. 3, 2011 Consultation Documents as an alternative, Salmonella enterica subsp. enterica serovar Abony such as NBRC 100797, NCTC 6017 or CIP 80.39 Candida albicans such as ATCC 10231, NCPF 3179, IP 48.72 or NBRC 1594. Use buffered sodium chloride-peptone solution, sterile, pH 7.0, TS or phosphate buffer sterile, pH 7.2 , TS to make test suspensions. Use the suspensions within 2 h or within 24 h if stored at 2–8 °C. Clostridia Use Clostridium sporogenes such as ATCC 11437 (NBRC 14293, NCIMB 12343, CIP 100651) or ATCC 19404 (NCTC 532 or CIP 79.3). Grow the clostridial test strain under anaerobic conditions in reinforced medium for Clostridia at 30–35 °C for 24–48 h. As an alternative to preparing and then diluting down a fresh suspension of vegetative cells of Cl. sporogenes, a stable spore suspension is used for test inoculation. The stable spore suspension may be maintained at 2–8 °C for a validated period.

Negative control To verify testing conditions a negative control is performed using the chosen diluent in place of the test preparation. There must be no growth of microorganisms. A negative control is also performed when testing the products as described under 4. A failed negative control requires an investigation.

Growth-promoting and inhibitory properties of the media Test each batch of ready-prepared medium and each batch of medium prepared either from dehydrated medium or from ingredients.

Verify suitable properties of relevant media as described in Table 1.

Test for growth promoting properties, liquid media: inoculate a portion of the appropri- ate medium with a small number (not more than 100 CFU) of the appropriate microor- ganism. Incubate at the specified temperature for not more than the shortest

Table 1. Growth-promoting, inhibitory and indicative properties of media

Medium Property Test strains

Test for bile-tolerant Gram-negative bacteria Growth-promoting E. coli Enterobacteria enrichment P. aeruginosa broth-Mossel Inhibitory S. aureus Violet red bile glucose agar Growth-promoting E. coli + Indicative P. aeruginosa Test for Escherichia coli MacConkey broth Growth-promoting E. coli Inhibitory S. aureus MacConkey agar Growth-promoting E. coli + Indicative

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Test for Salmonella Growth-promoting Salmonella enterica subsp. Rappaport Vassiliadis enterica serovar Salmonella enrichment broth Typhimurium or Salmonella enterica subsp. enterica serovar Abony Inhibitory S. aureus Growth-promoting Salmonella enterica subsp. Xylose, lysine, deoxycholate + Indicative enterica serovar agar Typhimurium or Salmonella enterica subsp. enterica serovar Abony Test for Pseudomonas aeruginosa Cetrimide agar Growth-promoting P. aeruginosa Inhibitory E. coli

Test for Staphylococcus aureus Mannitol salt agar Growth-promoting S. aureus + Indicative Inhibitory E. coli Test for Clostridia Reinforced medium for Growth-promoting Cl. sporogenes Clostridia Columbia agar Growth-promoting Cl. sporogenes Test for Candida albicans Sabouraud dextrose broth Growth-promoting C. albicans Sabouraud dextrose agar Growth-promoting C. albicans + Indicative period of time specified in the test. Clearly visible growth of the microorganism com- parable to that previously obtained with a previously tested and approved batch of medium occurs.

Test for growth promoting properties, solid media: perform surface-spread method, in- oculating each plate with a small number (not more than 100 CFU) of the appropriate microorganism. Incubate at the specified temperature for not more than the shortest period of time specified in the test. Growth of the microorganism comparable to that previously obtained with a previously tested and approved batch of medium occurs.

Test for inhibitory properties, liquid or solid media: inoculate the appropriate medium with at least 100 CFU of the appropriate microorganism. Incubate at the specified temperature for not less than the longest period of time specified in the test. No growth of the test microorganism occurs.

Test for indicative properties: perform surface-spread method, inoculating each plate with a small number (not more than 100 CFU) of the appropriate microorganism. Incu-

268 WHO Drug Information Vol. 25, No. 3, 2011 Consultation Documents bate at the specified temperature for a period of time within the range specified in the test. Colonies are comparable in appearance and indication reactions to those previ- ously obtained with a previously tested and approved batch of medium.

Suitability of the test method For each product to be tested perform sample preparation as described in the relevant paragraph in the section below on “Testing of products”. Add each test strain at the time of mixing, in the prescribed growth medium. Inoculate the test strains individually. Use a number of microorganisms equivalent to not more than 100 CFU in the inocula- ted test preparation.

Perform the test as described in the relevant paragraph in section 4 using the shortest incubation period prescribed.

The specified microorganisms must be detected with the indication reactions as des- cribed below under “Testing of products”.

Any antimicrobial activity of the product necessitates a modification of the test proce- dure (see “Neutralization/removal of antimicrobial activity” in “3.3.1 Microbial Enume- ration Tests”).

If for a given product the antimicrobial activity with respect to a microorganism for which testing is prescribed cannot be neutralized, then it is to be assumed that the inhibited microorganism will not be present in the product.

Testing of products Bile-tolerant Gram-negative bacteria

Sample preparation and pre-incubation Prepare a sample using a 1 in 10 dilution of not less than 1 g of the product to be exa- mined as described in “3.3.1 Microbial enumeration tests”, but using casein soya bean digest broth as the chosen diluent, mix and incubate at 20–25 °C for a time sufficient to resuscitate the bacteria but not sufficient to encourage multiplication of the orga- nisms (usually 2 h. but not more than 5 h.).

Test for absence Unless otherwise prescribed use the volume corresponding to 1g of the product, as prepared in Sample preparation and pre-incubation to inoculate enterobacteria enrich- ment broth-Mossel. Incubate at 30–35 °C for 24–48 h. Subculture on plates of violet red bile glucose agar. Incubate at 30–35 °C for 18–24 h.

The product complies with the test if there is no growth of colonies.

Quantitative test Selection and subculture. Inoculate suitable quantities of enterobacteria enrichment broth-Mossel with the preparation as described under Sample preparation and pre- incubation and/or dilutions of it containing, respectively 0.1 g, 0.01 g and 0.001 g (or 0.1 ml, 0.01 ml and 0.001 ml) of the product to be examined. Incubate at 30–35 °C for 24–48 h. Subculture each of the cultures on a plate of violet red bile glucose agar. Incubate at 30–35 °C for 18–24 h.

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Interpretation Growth of colonies constitutes a positive result. Note the smallest quantity of the product that gives a positive result and the largest quantity that gives a negative result. Determine from Table 2 the probable number of bacteria. Table 2. Interpretation of results

Probable number of Results for each quantity of product bacteria per gram or ml of product 0.1 g or 0.01 g or 0.001 g or 0.1 ml 0.01 ml 0.001 ml + + + more than 103 + + - less than 103 and more than 102 + - - less than 102 and more than 10 - - - less than 10

Escherichia coli

Sample preparation and pre-incubation Prepare a sample using a 1 in 10 dilution of not less than 1 g of the product to be exa- mined as described in 3.3.1 Microbial enumeration tests and use 10 ml or the quantity corresponding to 1 g or1mL to inoculate a suitable amount (determined as described under Suitability of the test method) of casein soya bean digest broth, mix and incu- bate at 30–35 °C for 18–24 h. Selection and subculture Shake the container, transfer 1 mL of casein soya bean digest broth to 100 mL of MacConkey broth and incubate at 42–44 °C for 24–48 h. Subculture on a plate of MacConkey agar at 30–35 °C for 18–72 h. Interpretation Growth of colonies indicates the possible presence of E. coli. This is confirmed by identification tests. The product complies with the test if no colonies are present or if the identification tests are negative. Salmonella

Sample preparation and pre-incubation Prepare the product to be examined as described in 3.3.1 Microbial enumeration tests and use the quantity corresponding to not less than 10 g or 10 ml to inoculate a sui- table amount (determined as described under Suitability of the test method) of casein soya bean digest broth, mix and incubate at 30–35 °C for 18–24 h. Selection and subculture Transfer 0.1 ml of casein soya bean digest broth to 10 ml of Rappaport vassiliadis Sal- monella enrichment broth and incubate at 30–35 °C for 18–24 h. Subculture on plates of xylose, lysine, deoxycholate agar. Incubate at 30–35 °C for 18–48 h.

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Interpretation The possible presence of Salmonella is indicated by the growth of well-developed, red colonies, with or without black centres. This is confirmed by identification tests.

The product complies with the test if colonies of the types described are not present or if the confirmatory identification tests are negative. Pseudomonas aeruginosa

Sample preparation and pre-incubation Prepare a sample using a 1 in 10 dilution of not less than 1 g of the product to be examined as described in “3.3.1 Microbial enumeration tests” and use 10 ml or the quantity corresponding to 1 g or 1 ml to inoculate a suitable amount (determined as described under Suitability of the test method) of casein soya bean digest broth and mix. When testing transdermal patches, filter the volume of sample corresponding to 1 patch of the preparation described under Preparation of the sample in “3.3.1 Micro- bial enumeration tests” through a sterile filter membrane and place in 100 ml of casein soya bean digest broth. Incubate at 30–35 °C for 18–24 h.

Selection and subculture Subculture on a plate of cetrimide agar and incubate at 30–35 °C for 18–72 h. Interpretation Growth of colonies indicates the possible presence of P. aeruginosa. This is confirmed by identification tests.

The product complies with the test if colonies are not present or if the confirmatory identification tests are negative. Staphylococcus aureus

Sample preparation and pre-incubation Prepare a sample using a 1 in 10 dilution of not less than 1 g of the product to be examined as described in “3.3.1 Microbial enumeration tests” and use 10 ml or the quantity corresponding to 1 g or 1 ml to inoculate a suitable amount (determined as described under “Suitability of the test method”) of casein soya bean digest broth and homogenize. When testing transdermal patches, filter the volume of sample corres- ponding to one patch of the preparation described under “Preparation of the sample” in “3.3.1 Microbial enumeration tests” through a sterile filter membrane and place in 100 ml of casein soya bean digest broth. Incubate at 30–35 °C for 18–24 h.

Selection and subculture Subculture on a plate of mannitol salt agar and incubate at 30–35 °C for 18–72 h.

Interpretation The possible presence of S. aureus is indicated by the growth of yellow/white colonies surrounded by a yellow zone. This is confirmed by identification tests.

The product complies with the test if colonies of the types described are not present or if the confirmatory identification tests are negative.

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Clostridia

Sample preparation and heat treatment Prepare a sample using a 1 in 10 dilution (with a minimum total volume of 20 ml) of not less than 2 g or 2 ml of the product to be examined as described in “3.3.1 Micro- bial enumeration tests”. Divide the sample into two portions of at least 10 ml. Heat one portion at 80 °C for 10 min and cool rapidly. Do not heat the other portion.

Selection and subculture Use 10 ml or the quantity corresponding to 1 g or 1 ml of the product to be examined of both portions to inoculate suitable amounts (determined as described under “Suita- bility of the test method”) of Reinforced clostridium medium. Incubate under anaerobic conditions at 30–35 °C for 48 h. After incubation, make subcultures from each contai- ner on Columbia agar and incubate under anaerobic conditions at 30–35 °C for 48 h–72h.

Interpretation The occurrence of anaerobic growth of rods (with or without endospores) giving a negative catalase reaction indicates the presence of Clostridia. This is confirmed by identification tests. The product complies with the test if colonies of the types described are not present or if the confirmatory identification tests are negative.

Candida albicans

Sample preparation and pre-incubation Prepare the product to be examined as described in “3.3.1 Microbial enumeration tests” and use 10 ml or the quantity corresponding to not less than 1 g or 1 ml to inoculate 100 ml of Sabouraud-dextrose broth and mix. Incubate at 30–35 °C for 3–5 days.

Selection and subculture Subculture on a plate of Sabouraud-dextrose agar and incubate at 30–35 °C for 24–48h. Interpretation Growth of white colonies may indicate the presence of C. albicans. This is confirmed by identification tests. The product complies with the test if such colonies are not present or if the confirma- tory identification tests are negative.

Recommended test solutions and culture media The following test solutions and culture media have been found satisfactory for the purposes for which they are prescribed in the test for microbial contamination in the pharmacopoeia. Other media may be used provided that their suitability can be demonstrated.

• Stock buffer solution. Transfer 34 g of potassium dihydrogen phosphate to a 1000 ml volumetric flask, dissolve in 500 ml of purified water, adjust to pH 7.2 ± 0.2 with sodium hydroxide, add purified water to volume and mix. Dispense in containers and sterilize. Store at a temperature of 2–8 °C.

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• Phosphate buffer, sterile, pH 7.2, TS. Prepare a mixture of purified water and stock buffer solution (800:1 V/V) and sterilize. • Buffered sodium chloride-peptone solution pH 7.0 Potassium dihydrogen phosphate 3.6 g Disodium hydrogen phosphate dihydrate 7.2 g equivalent to 0.067 M phosphate Sodium chloride 4.3 g Peptone (meat or casein) 1.0 g Purified water 1000 ml Sterilize in an autoclave using a validated cycle.

• Casein soya bean digest broth Pancreatic digest of casein 17.0 g Papaic digest of soya bean 3.0 g Sodium chloride 5.0 g Dipotassium hydrogen phosphate 2.5 g Glucose monohydrate 2.5 g Purified water 1000 ml Adjust the pH so that after sterilization it is 7.3 ± 0.2 at 25 °C. Sterilize in an autoclave using a validated cycle.

• Casein soya bean digest agar Pancreatic digest of casein 15.0 g Papaic digest of soya bean 5.0 g Sodium chloride 5.0 g Agar 15.0 g Purified water 1000 ml Adjust the pH so that after sterilization it is 7.3 ± 0.2 at 25 °C. Sterilize in an autoclave using a validated cycle.

• Sabouraud-dextrose agar Dextrose 40.0 g Mixture of peptic digest of animal tissue and pancreatic digest of casein (1:1) 10.0 g Agar 15.0 g Purified water 1000 ml Adjust the pH so that after sterilization it is 5.6 ± 0.2 at 25 °C. Sterilize in an autoclave using a validated cycle.

• Potato dextrose agar Infusion from potatoes 200 g Dextrose 20.0 g Agar 15.0 g Purified water 1000 ml

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Adjust the pH so that after sterilization it is 5.6 ± 0.2 at 25 °C. Sterilize in an autoclave using a validated cycle.

• Sabouraud-dextrose broth Dextrose 20.0 g Mixture of peptic digest of animal tissue and pancreatic digest of casein (1:1) 10.0 g Purified water 1000 ml Adjust the pH so that after sterilization it is 5.6 ± 0.2 at 25 °C. Sterilize in an autoclave using a validated cycle.

• Enterobacteria enrichment broth-Mossel Pancreatic digest of gelatin 10.0 g Glucose monohydrate 5.0 g Dehydrated ox bile 20.0 g Potassium dihydrogen phosphate 2.0 g Disodium hydrogen phosphate dihydrate 8.0 g Brilliant green 15 mg Purified water 1000 ml Adjust the pH so that after heating it is 7.2 ± 0.2 at 25 °C. Heat at 100 °C for 30 min and cool immediately.

• Violet red bile glucose agar Yeast extract 3.0 g Pancreatic digest of gelatin 7.0 g Bile salts 1.5 g Sodium chloride 5.0 g Glucose monohydrate 10.0 gl Agar 15.0 g Neutral red 30 mg Crystal violet 2 mg Purified water 1000 ml Adjust the pH so that after heating it is 7.4 ± 0.2 at 25 °C. Heat to boiling; do not heat in an autoclave.

• MacConkey broth Pancreatic digest of gelatin 20.0 g Lactose monohydrate 10.0 g Dehydrated ox bile 5.0 g Bromocresol purple 10 mg Purified water 1000 ml Adjust the pH so that after sterilization it is 7.3 ± 0.2 at 25 °C. Sterilize in an autoclave using a validated cycle.

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• MacConkey agar Pancreatic digest of gelatin 17.0 g Peptones (meat and casein) 3.0 g Lactose monohydrate 10.0 g Sodium chloride 5.0 g Bile salts 1.5 g Agar 13.5 g Neutral red 30.0 mg Crystal violet 1 mg Purified water 1000 ml Adjust the pH so that after sterilization it is 7.1 ± 0.2 at 25 °C. Boil for 1 min with constant shaking then sterilize in an autoclave using a validated cycle. • Rappaport Vassiliadis Salmonella Enrichment Broth Soya peptone 4.5 g Magnesium chloride hexahydrate 29.0 g Sodium chloride 8.0 g Dipotassium phosphate 0.4 g Potassium dihydrogen phosphate 0.6 g Malachite green 0.036 g Purified water 1000 ml Dissolve, warming slightly. Sterilize in an autoclave using a validated cycle, at a temperature not exceeding 115 °C. The pH is to be 5.2 ± 0.2 at 25 °C after heating and autoclaving. • Xylose, lysine, deoxycholate agar Xylose 3.5 g L-Lysine 5.0 g Lactose monohydrate 7.5 g Sucrose 7.5 g Sodium chloride 5.0 g Yeast extract 3.0 g Phenol red 80 mg Agar 13.5 g Sodium deoxycholate 2.5 g Sodium thiosulfite 6.8 g Ferric ammonium citrate 0.8 g Purified water 1000 ml Adjust the pH so that after heating it is 7.4 ± 0.2 at 25 °C. Heat to boiling, cool to 50 °C and pour into Petri dishes. Do not heat in an autoclave. • Cetrimide agar Pancreatic digest of gelatin 20.0 g Magnesium chloride 1.4 g Dipotassium sulfite 10.0 g Cetrimide 0.3 g

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Agar 13.6 g Purified water 1 000 ml Glycerol 10.0 ml Heat to boiling for 1 min with shaking. Adjust the pH so that after sterilization it is 7.2 ± 0.2 at 25 °C. Sterilize in an autoclave using a validated cycle. • Mannitol salt agar Pancreatic digest of casein 5.0 g Peptic digest of animal tissue 5.0 g Beef extract 1.0 g D-Mannitol 10.0 g Sodium chloride 75.0 g Agar 15.0 g Phenol red 0.025 g Purified water 1000 mL Heat to boiling for 1 min with shaking. Adjust the pH so that after sterilization it is 7.4 ± 0.2 at 25 °C. Sterilize in an autoclave using a validated cycle. • Reinforced medium for Clostridia Beef extract 10.0 g Peptone 10.0 g Yeast extract 3.0 g Soluble starch 1.0 g Glucose monohydrate 5.0 g Cysteine hydrochloride 0.5 g Sodium chloride 5.0 g Sodium acetate 3.0 g Agar 0.5 g Purified water 1000 ml Hydrate the agar, dissolve by heating to boiling with continuous stirring. If necessary, adjust the pH so that after sterilization it is about 6.8 ± 0.2 at 25 °C. Sterilize in an autoclave using a validated cycle. • Columbia agar Pancreatic digest of casein 10.0 g Meat peptic digest 5.0 g Heart pancreatic digest 3.0 g Yeast extract 5.0 g Maize starch 1.0 g Sodium chloride 5.0 g Agar, according to gelling power 10.0 g to 15.0 g Purified water 1000 ml Hydrate the agar, dissolve by heating to boiling with continuous stirring. If necessary, adjust the pH so that after sterilization it is 7.3 ± 0.2 at 25 °C. Sterilize in an autoclave using a validated cycle. Allow to cool to 45–50 °C; add, where necessary, gentamicin sulfite corresponding to 20 mg of gentamicin base and pour into Petri dishes.

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5.3 Disintegration test for tablets and capsules Draft proposal for revision of a General Method in the 4th Edition of the International Pharmacopoeia (April 2011). Please addess any comments to Quality Assurance and Safety: Medicines, World Health Organization, 1211 Geneva 27, Switzerland. Fax: +41 22 791 4730 or e-mail schmidth@ who.int. Working documents are available for comment at http://who.int/ medicines. [Note from Secretariat. During its meeting in October 2010, the Expert Committee on Specifications for Pharmaceutical Preparations recommended that the current method described in The International Pharmacopoeia for the disintegration test for tablets and capsules should be replaced by the internationally harmonized general test available. To this effect the following revision of method “5.3 Disintegration test for tablets and capsules” is proposed. The revision implies both changes of and additions to dimensions and tolerances in the description of the disintegration apparatus. The possibility for retesting when one or two units fail in the first step of the procedure is introduced, as is the possibility to use automatic detection employing modified discs in cases where the use of discs is prescribed.] This test is provided to determine whether tablets or capsules disintegrate within the prescribed time when placed in a liquid medium under the experimental conditions presented below.

For the purposes of this test, disintegration does not imply complete dissolution of the unit or even of its active constituent. Complete disintegration is defined as that state in which any residue of the unit, except fragments of insoluble coating or capsule shell, remaining on the screen of the test apparatus or adhering to the lower surface of the discs, if used, is a soft mass having no palpably firm core.

Apparatus The apparatus consists of a basket-rack assembly, a 1000-ml, low-form beaker, 138 to 160 mm in height and having an inside diameter of 97 to 115 mm for the immer- sion fluid, a thermostatic arrangement for heating the fluid between 35 °C and 39 °C, and a device for raising and lowering the basket in the immersion fluid at a constant frequency rate between 29 and 32 cycles per minute, through a distance of not less than 53 mm and not more than 57 mm. The volume of the fluid in the vessel is such that at the highest point of the upward stroke the wire mesh remains at least 15 mm below the surface of the fluid, and descends to not less than 25 mm from the bottom of the vessel on the downward stroke. At no time should the top of the basket-rack assembly become submerged. The time required for the upward stroke is equal to the time required for the downward stroke, and the change in stroke direction is a smooth transition, rather than an abrupt reversal of motion. The basket-rack assembly moves vertically along its axis. There is no appreciable horizontal motion or movement of the axis from the vertical. Basket-rack assembly. The basket-rack assembly consists of 6 open-ended trans- parent tubes, each 75.0 mm to 80 mm long and having an inside diameter of 20.7 to 23 mm and a wall 1.0 to 2.8 mm thick; the tubes are held in a vertical position by two plates, each 88 to 92 mm in diameter and 5 to 8.5 mm in thickness, with 6 holes, each 22 to 26 mm in diameter, equidistant from the centre of the plate and equally

277 Consultation Documents WHO Drug Information Vol. 25, No. 3, 2011 spaced from one another. Attached to the under surface of the lower plate is a woven stainless steel wire cloth, which has a plain square weave with 1.8 to 2.2-mm aper- tures and with a wire diameter of 0.57 to 0.66 mm. The parts of the apparatus are assembled and rigidly held by means of three bolts passing through the two plates. A suitable means is provided to suspend the basket-rack assembly from the raising and lowering device using a point on its axis.

The design of the basket-rack assembly may be varied somewhat provided the spe- cifications for the glass tubes and the screen mesh size are maintained.The basket- rack assembly conforms to the dimensions shown in Figure 1. Discs. The use of discs is permitted only where specified or allowed. Each tube is pro- vided with a cylindrical disc 9.35 mm to 9.65 mm thick and 20.55 mm to 20.85 mm in diameter. The disc is made of a suitable, transparent plastic material having a specific gravity of 1.18 to 1.20. Five parallel 1.9 mm to 2.1 mm holes extend between the ends of the cylinder. One of the holes is centered on the cylindrical axis. The other holes are centered 5.8 mm to 6.2 mm from the axis on imaginary lines perpendicular to the axis and parallel to each other. Four identical trapezoidal-shaped planes are cut into the wall of the cylinder, nearly perpendicular to the ends of the cylinder. The trapezoidal shape is symmetrical; its parallel sides coincide with the ends of the cylinder and are parallel to an imaginary line connecting the centres of two adjacent holes 6 mm from the cylindrical axis. The parallel side of the trapezoid on the bottom of the cylinder has a length of 1.5 mm to 1.7 mm and its bottom edges lie at a depth of 1.5 mm to 1.8 mm from the cylinder’s circumference. The parallel side of the trapezoid on the top of the

Figure 1. Diagram for disintegration apparatus

Basket-Rack Disk Assembly

2.6 ± 0.1 6 ± 0.2

Top 1.9 21.85 View ± 0.9 ± 1.15 2 ± 0.1

9.4 ± 0.2 6.75 ± 1.75 77.5 ± 2.5 Side

6.75 ± 1.75 View

90 ± 2 9.5 ± 0.15 20.7 ± 0.15

1.6 Bottom 2 View 1.65 ± 0.15 ± 0.1 24

278 WHO Drug Information Vol. 25, No. 3, 2011 Consultation Documents cylinder has a length of 9.2 mm to 9.6 mm and its centre lies at a depth of 2.5 mm to 2.7 mm from the cylinder’s circumference. All surfaces of the disc are smooth. If the use of discs is specified, add a disc to each tube, and operate the apparatus as direc- ted under procedure. The discs conform to the dimensions found in Figure 1. The use of automatic detection employing modified discs is permitted where the use of discs is specified or allowed. Such discs must comply with the requirements of density and dimension given in this chapter. Procedure Place 1 dosage unit in each of the six tubes of the basket, and if specified add a disc. Operate the apparatus using water as the immersion fluid unless another liquid is spe- cified and maintain its temperature at 35 °C to 39 °C. At the end of the specified time, lift the basket from the fluid and observe the dosage units: all of the dosage units have disintegrated completely. If 1 or 2 dosage units fail to disintegrate, repeat the test on 12 additional dosage units. The requirements of the test are met if not less than 16 of the 18 dosage units tested are disintegrated.

5.6 Extractable volume of parenteral preparations Draft proposal for revision of a General Method in the 4th Edition of the International Pharmacopoeia (April 2011). Please addess any comments to Quality Assurance and Safety: Medicines, World Health Organization, 1211 Geneva 27, Switzerland. Fax: +41 22 791 4730 or e-mail mendyc@who. int. Working documents are available at http://who.int/medicines. [Note from Secretariat. During its meeting in October 2010, the Expert Committee on Specifications for Pharmaceutical Preparations recommended that the current method described in The International Pharmacopoeia for the test of extractable volume of parenteral preparations should be replaced by the internationally harmonized general test available. To this effect the following revision of method “5.6 Extractable volume of parenteral preparations” is proposed.

During the revision of the general monograph for “Parenteral preparations”, consider- ation will be given to requiring compliance with this test; currently the general mono- graph does not refer to method 5.6.]

Suspensions and emulsions must be shaken before withdrawal of the contents and before the determination of the density. Oily and viscous preparations may be warmed according to the instructions on the label, if necessary, and thoroughly shaken imme- diately before removing the contents. The contents are then cooled to 20 °C – 25 °C before measuring the volume. Single-dose containers Select one container if the volume is 10 ml or more, three containers if the nominal volume is more than 3 ml and less than 10 ml, or five containers if the nominal volume is 3 ml or less. Take up individually the total contents of each container selected into a dry syringe of a capacity not exceeding three times the volume to be measured, and fitted with a 21-gauge needle not less than 2.5 cm in length. Expel any air bubbles from the syringe and needle, then discharge the contents of the syringe without emp- tying the needle into a standardized dry cylinder (graduated to contain rather than to deliver the designated volumes) of such size that the volume to be measured occupies

279 Consultation Documents WHO Drug Information Vol. 25, No. 3, 2011 at least 40 per cent of its graduated volume. Alternatively, the volume of the contents in millilitres may be calculated as the mass in grams divided by the density.

For containers with a nominal volume of 2 ml or less the contents of a sufficient number of containers may be pooled to obtain the volume required for the measure- ment provided that a separate, dry syringe assembly is used for each container. The contents of containers holding 10 ml or more may be determined by opening them and emptying the contents directly into the graduated cylinder or tared beaker. The volume is not less than the nominal volume in case of containers examined indivi- dually, or, in case of containers with a nominal volume of 2 ml or less, is not less than the sum of the nominal volumes of the containers taken collectively. Multidose containers For injections in multidose containers labelled to yield a specific number of doses of a stated volume, select one container and proceed as directed for single-dose contai- ners using the same number of separate syringe assemblies as the number of doses specified. The volume is such that each syringe delivers not less than the stated dose. Cartridges and prefilled syringes Select one container if the volume is 10 ml or more, three containers if the nominal volume is more than 3 ml and less than 10 ml, or 5 containers if the nominal volume is 3 ml or less. If necessary, fit the containers with the accessories required for their use (needle, piston, syringe) and transfer the entire contents of each container without emptying the needle into a dry tared beaker by slowly and constantly depressing the piston. Determine the volume in millilitres calculated as the mass in grams divided by the density. The volume measured for each of the containers is not less than the nominal volume. Parenteral infusions Select one container. Transfer the contents into a dry measuring cylinder of such a capacity that the volume to be determined occupies at least 40 per cent of the nominal volume of the cylinder. Measure the volume transferred. The volume is not less than the nominal volume.

5.7 Tests for particulate contamination Draft proposal for revision of a General Method in the 4th Edition of the International Pharmacopoeia (May 2011). Please addess any comments to Quality Assurance and Safety: Medicines, World Health Organization, 1211 Geneva 27, Switzerland. Fax: +41 22 791 4730 or e-mail schmidth@ who.int. Working documents are available for comment at http://who.int/ medicines.

[Note from Secretariat. During its meeting in October 2010 the Expert Committee on Specifications for Pharmaceutical Preparations recommended that the current method described in The International Pharmacopoeia for the tests for particulate contamina- tion should be replaced by the internationally harmonized general test available. To this effect the following revision of method “5.7 Tests for particulate contamination” is proposed. Section 5.7 will be entitled “Tests for particulate contamination”, the PDG text will be introduced as “5.7.1 Subvisible particles” and the existing text of 5.7 re- tained as “5.7.2 Visible particles”.

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The current general monograph for “Parenteral preparations” does not contain analyti- cal requirements on particulate contamination. Consideration will be given to requiring compliance with these tests during revision of the general monograph.

The proposed test makes a distinction between small volume parenterals and large volume parenterals with a limit at 100 ml. The 100 ml preparation is exempted from the pharmacopoeial harmonization. It is proposed to include 100 ml preparation among small volume parenterals.]

5.7.1 Subvisible particles

Particulate contamination of injections and parenteral infusions consists of extraneous, mobile undissolved particles, other than gas bubbles, unintentionally present in the solutions. For the determination of particulate contamination two procedures, Method 1 (“Light Obscuration Particle Count Test”) and Method 2 (“Microscopic Particle Count Test”), are specified hereinafter. When examining injections and parenteral infusions for sub- visible particles Method 1 is preferably applied. However, it may be necessary to test some preparations by the light obscuration particle count test followed by the micros- copic particle count test to reach a conclusion on conformance to the requirements. Not all parenteral preparations can be examined for sub-visible particles by one or both of these methods. When Method 1 is not applicable, e.g., in case of preparations having reduced clarity or increased viscosity, the test should be carried out according to Method 2. Emulsions, colloids, and liposomal preparations are examples. Similarly, products that produce air or gas bubbles when drawn into the sensor may also require microscopic particle count testing. If the viscosity of the preparation to be tested is sufficiently high so as to preclude its examination by either test method, a quantitative dilution with an appropriate diluent may be made to decrease viscosity, as necessary, to allow the analysis to be performed. The results obtained in examining a discrete unit or group of units for particulate contamination cannot be extrapolated with certainty to other units that remain untested. Thus, statistically sound sampling plans must be developed if valid infe- rences are to be drawn from observed data to characterize the level of particulate contamination in a large group of units.

Method A. Light obscuration particle count test Use a suitable apparatus based on the principle of light blockage which allows an automatic determination of the size of particles and the number of particles according to size. The apparatus is calibrated using dispersions of spherical particles of known sizes between 10 µm and 25 µm. These standard particles are dispersed in particle-free water TS. Care must be taken to avoid aggregation of particles during dispersion.

General precautions The test is carried out under conditions limiting particulate contamination, preferably in a laminar-flow cabinet.

Very carefully wash the glassware and filtration equipment used, except for the mem- brane filters, with a warm detergent solution and rinse with abundant amounts of water

281 Consultation Documents WHO Drug Information Vol. 25, No. 3, 2011 to remove all traces of detergent. Immediately before use, rinse the equipment from top to bottom, outside and then inside, with particle-free water TS.

Take care not to introduce air bubbles into the preparation to be examined, especially when fractions of the preparation are being transferred to the container in which the determination is to be carried out.

In order to check that the environment is suitable for the test, that the glassware is properly cleaned and that the water to be used is particle-free, the following test is carried out: determine the particulate contamination of 5 samples of particle-free water TS, each of 5 ml, according to the method described below. If the number of particles of 10 µm or greater size exceeds 25 for the combined 25 ml, the precautions taken for the test are not sufficient. The preparatory steps must be repeated until the environ- ment, glassware and water are suitable for the test.

Method Mix the contents of the sample by slowly inverting the container 20 times successi- vely. If necessary, cautiously remove the sealing closure. Clean the outer surfaces of the container opening using a jet of particle-free water TS and remove the closure, avoiding any contamination of the contents. Eliminate gas bubbles by appropriate measures such as allowing to stand for 2 min. or sonicating.

For large-volume parenterals, single units are tested. For small-volume parenterals less than 25 ml in volume, the contents of 10 or more units are combined in a cleaned container to obtain a volume of not less than 25 ml; where justified and authorized, the test solution may be prepared by mixing the contents of a suitable number of vials and diluting to 25 ml with particle-free water TS or with an appropriate solvent without contamination of particles when particle-free water TS is not suitable. Small-volume parenterals having a volume of 25 ml or more may be tested individually.

Powders for parenteral use are reconstituted with particle-free water TS or with an appropriate solvent without contamination of particles when particle-free water TS is not suitable.

The number of test specimens must be adequate to provide a statistically sound assessment. For large-volume parenterals or for small-volume parenterals having a volume of 25 ml or more, fewer than 10 units may be tested, based on an appropriate sampling plan.

Remove four portions, each of not less than 5 ml, and count the number of particles equal to or greater than 10 µm and 25 µm. Disregard the result obtained for the first portion, and calculate the mean number of particles for the preparation to be exami- ned.

Evaluation For preparations supplied in containers with a nominal volume of more than 100 ml, apply the criteria of test A.1.

For preparations supplied in containers with a nominal volume of 100 ml or less, apply the criteria of test 1.B.

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If the average number of particles exceeds the limits, test the preparation by the “Microscopic Particle Count Test”.

Test 1.A — Solutions for parenteral infusion or solutions for injection supplied in containers with a nominal content of more than 100 ml The preparation complies with the test if the average number of particles present in the units tested does not exceed 25 per milliliter equal to or greater than 10 µm and does not exceed 3 per milliliter equal to or greater than 25 µm.

Test 1.B — Solutions for parenteral infusion or solutions for injection supplied in containers with a nominal content of 100 ml or less The preparation complies with the test if the average number of particles present in the units tested does not exceed 6000 per container equal to or greater than 10 µm and does not exceed 600 per container equal to or greater than 25 µm.

Method B. Microscopic particle count test Use a suitable binocular microscope, filter assembly for retaining particulate contami- nation and membrane filter for examination. The microscope is equipped with an ocular micrometer calibrated with an objective micrometer, a mechanical stage capable of holding and traversing the entire filtration area of the membrane filter, two suitable illuminators to provide episcopic illumination in addition to oblique illumination, and is adjusted to 100 ± 10 magnifications. The ocular micrometer is a circular diameter graticule (see Figure 1) and consists of a large circle divided by crosshairs into quadrants, transparent and black reference circles 10 µm and 25 µm in diameter at 100 magnifications, and a linear scale gra- duated in 10 µm increments. It is calibrated using a stage micrometer that is certified by either a domestic or international standard institution. A relative error of the linear scale of the graticule within ± 2 per cent is acceptable. The large circle is designated the graticule field of view (GFOV). Two illuminators are required. One is an episcopic bright-field illuminator internal to the microscope, the other is an external, focusable auxiliary illuminator adjustable to give reflected oblique illumination at an angle of 10° to 20°. The filter assembly for retaining particulate contamination consists of a filter holder made of glass or other suitable material, and is equipped with a vacuum source and a suitable membrane filter. The membrane filter is of suitable size, black or dark grey in colour, non-gridded or gridded, and 1.0 µm or finer in nominal pore size.

General precautions The test is carried out under conditions limiting particulate contamination, preferably in a laminar-flow cabinet.

Very carefully wash the glassware and filter assembly used, except for the mem- brane filter, with a warm detergent solution and rinse with abundant amounts of water to remove all traces of detergent. Immediately before use, rinse both sides of the membrane filter and the equipment from top to bottom, outside and then inside, with particle-free water TS.

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Figure 1. Circular diameter graticule

GFOV Cicle

Reference Circle

Cross Hairs

Linear Scale

In order to check that the environment is suitable for the test, that the glassware and the membrane filter are properly cleaned and that the water to be used is particle-free, the following test is carried out: determine the particulate contamination of a 50 ml volume of particle-free water TS according to the method described below. If more than 20 particles 10 µm or larger in size or if more than 5 particles 25 µm or larger in size are present within the filtration area, the precautions taken for the test are not sufficient. The preparatory steps must be repeated until the environment, glassware, membrane filter and water are suitable for the test. Method Mix the contents of the samples by slowly inverting the container 20 times successi- vely. If necessary, cautiously remove the sealing closure. Clean the outer surfaces of the container opening using a jet of particle-free water and remove the closure, avoi- ding any contamination of the contents. For large-volume parenterals, single units are tested. For small-volume parenterals less than 25 ml in volume, the contents of 10 or more units is combined in a cleaned container; where justified and authorized, the test solution may be prepared by mixing the contents of a suitable number of vials and diluting to 25 ml with particle-free water or with an appropriate solvent without contamination of particles when particle-free water is not suitable. Small-volume parenterals having a volume of 25 ml or more may be tested individually. Powders for parenteral use are constituted with particle-free water TS or with an appropriate solvent without contamination of particles when particle-free water TS is not suitable.

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The number of test specimens must be adequate to provide a statistically sound assessment. For large-volume parenterals or for small-volume parenterals having a volume of 25 ml or more, fewer than 10 units may be tested, based on an appropriate sampling plan.

Wet the inside of the filter holder fitted with the membrane filter with several millilitre of particle-free water TS. Transfer to the filtration funnel the total volume of a solution pool or of a single unit, and apply vacuum. If needed add stepwise a portion of the so- lution until the entire volume is filtered. After the last addition of solution, begin rinsing the inner walls of the filter holder by using a jet of particle-free waterTS. Maintain the vacuum until the surface of the membrane filter is free from liquid. Place the filter in a Petri dish and allow the filter to air-dry with the cover slightly ajar. After the filter has been dried, place the Petri dish on the stage of the microscope, scan the entire mem- brane filter under the reflected light from the illuminating device, and count the number of particles that are equal to or greater than 10 µm and the number of particles that are equal to or greater than 25 µm. Alternatively, partial filter count and determination of the total filter count by calculation is allowed. Calculate the mean number of par- ticles for the preparation to be examined.

The particle sizing process with the use of the circular diameter graticule is carried out by transforming mentally the image of each particle into a circle and then comparing it to the 10 µm and 25 µm graticule reference circles. Thereby the particles are not moved from their initial locations within the graticule field of view and are not superim- posed on the reference circles for comparison. The inner diameter of the transparent graticule reference circles is used to size white and transparent particles, while dark particles are sized by using the outer diameter of the black opaque graticule reference circles.

In performing the microscopic particle count test do not attempt to size or enumerate amorphous, semi-liquid, or otherwise morphologically indistinct materials that have the appearance of a stain or discoloration on the membrane filter. These materials show little or no surface relief and present a gelatinous or film-like appearance. In such cases the interpretation of enumeration may be aided by testing a sample of the solution by the light obscuration particle count test. Evaluation For preparations supplied in containers with a nominal volume of more than 100 ml, apply the criteria of test B.1.

For preparations supplied in containers with a nominal volume of 100 ml or less, apply the criteria of test B.2.

Test B.1— Solutions for parenteral infusion or solutions for injection supplied in containers with a nominal content of more than 100 ml

The preparation complies with the test if the average number of particles pres- ent in the units tested does not exceed 12 per millilitre equal to or greater than 10 µm and does not exceed 2 per millilitre equal to or greater than 25 µm.

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Test B.2 — Solutions for parenteral infusion or solutions for injection supplied in containers with a nominal content of 100 ml or less

The preparation complies with the test if the average number of particles pres- ent in the units tested does not exceed 3000 per container equal to or greater than 10 µm and does not exceed 300 per container equal to or greater than 25 µm.

5.7.2 Visible particles Particulate contamination of injections and parenteral infusions consists of extraneous, mobile, undissolved particles unintentionally present in the solutions. Disregard any gas bubbles. The types of preparation for which compliance with this test is required are stated in the individual monograph. This test provides a simple method for the detection of visible particles. It is performed in accordance with the provisions of good manufacturing practices. The test is not intended for use by a manufacturer for batch release purposes. To ensure that a pro- duct will meet pharmacopoeial specifications with respect to visible particulate matter, if and when tested, manufacturers should carry out a 100% inspection and rejection of unsatisfactory items prior to release or use other appropriate means.

Subvisible particles and the nature of the particles are not identified by this method. Figure 2. Apparatus for visible particles*

Adjustable lampholder

Matt Non-glare black white panel panel

Non-glare white panel

WHO 98430

*Reproduced with the permission of the European Pharmacopoeia Commission, European Directorate for the Quality of Medicines, Council of Europe.

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Apparatus This method was developed by WHO in collaboration with Group 12 of the European Pharmacopoeia Commission.

The apparatus (Figure 2) consists of a viewing station comprising:

• a matt black panel of appropriate size held in a vertical position; • a non-glare white panel of appropriate size held in a vertical position next to the black panel; • an adjustable lamp holder fitted with a shaded, white-light source and with a light diffuser (a viewing illuminator containing two 13-W fluorescent tubes, each 525 mm in length is suitable). The intensity of illumination at the viewing point is maintained between 2000 lux and 3750 lux for clear glass ampoules. Higher values are prefer- able for coloured glass and plastic containers. Recommended procedure Gently swirl or invert each individual container, making sure that no air bubbles are introduced, and observe for about 5 seconds in front of the white panel. Repeat the procedure in front of the black panel.

Record the presence of any particles. Repeat the procedure for a further 19 contai- ners.

The preparation fails the test if one or more particles are found in more than one container.

When the test is applied to reconstituted solutions from powder for injections, the test fails if particles are found in more than two containers.

2.3 Sulfated ash

Draft proposal for revision of a General Method in the 4th Edition of the International Pharmacopoeia (April 2011). Please addess any comments to Quality Assurance and Safety: Medicines, World Health Organization, 1211 Geneva 27, Switzerland. Fax: +41 22 791 4730 or e-mail mendyc@ who.int. Working documents are available for comment at http://who.int/ medicines.

[Note from Secretariat. During its meeting in October 2010, the Expert Committee on Specifications for Pharmaceutical Preparations recommended that the current method described in The International Pharmacopoeia for the test of sulfated ash should be replaced progressively by the internationally harmonized general test available on residue on ignition/sulphated ash test. To this effect the following revision of method “2.3 Sulfated Ash” is proposed.

Both methods will be included in The International Pharmacopoeia for an interim period. The internationally harmonized test will be specified in new monographs while, for existing monographs, the current test will be specified until it is replaced during the revision of the monographs in question.]

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The sulfated ash test utilizes a procedure to measure the amount of residual subs- tance not volatilized from a sample when the sample is ignited in the presence of sulfuric acid. The test is usually used for determining the content of inorganic impuri- ties in an organic substance. Unless otherwise indicated in the individual monograph, Method A is used. Method A Accurately weigh about 1 g of the substance, or the quantity specified in the mono- graph, into a suitable dish (usually platinium) and moisten with sulfuric acid (~1760 g/l) TS. Heat gently to remove the excess of acid and ignite at about 800 °C until all the black particles have disappeared; again moisten with sulfuric acid (~1760 g/l) TS and reignite. Add a small amount of ammonium carbonate R and ignite to constant weight. Method B Procedure. Ignite a suitable crucible (for example silica, platinium, quartz or porcelain) at 550 °C to 650 °C for 30 minutes, cool the crucible in a desiccator (silica gel or other suitable desiccant) and weigh it accurately. Take the amount of test sample specified in the individual monograph in the crucible and weigh the crucible accurately. Moisten the sample with a small amount (usually 1 ml) of sulfuric acid (~1760 g/l) TS, heat gently at a temperature as low as practicable until the sample is thoroughly charred. After cooling, moisten the residue with a small amount (usually 1 ml) of sulfuric acid (~1760 g/l) TS, heat gently until white fumes are no longer evolved, and ignite at 550 °C to 650 °C until the residue is completely incinerated. Ensure that flames are not produced at any time during the procedure. Cool the crucible in a desiccator (silica gel or other suitable desiccant), weigh accurately, and calculate the percentage of residue.

Unless otherwise specified, if the amount of residue so obtained exceeds the limit specified in the individual monograph, repeat the moistening with sulfuric acid, hea- ting and ignition as before, using a 30-minute ignition period, until two consecutive weighings of the residue do not differ by more than 0.5 mg or until the percentage of residue complies with the limit in the individual monograph.

Pyrantel embonate chewable tablets

Draft proposal for the International Pharmacopoeia (February 2011). Please addess any comments to Quality Assurance and Safety: Medicines, World Health Organization, 1211 Geneva 27, Switzerland; fax: (+41 22 791 4730 or e-mail to [email protected]. Working documents are available for comment at http://www.who.int/medicines.

Category. Anthelminthic.

Storage. Pyrantel embonate chewable tablets should be kept in a tight, light-resis- tant container.

Labelling. The designation on the container of Pyrantel embonate chewable tablets should state that the active ingredient is in the embonate form, and the quantity should be indicated in terms of equivalent amount of pyrantel and should state that the tablets may be chewed or swallowed whole.

288 WHO Drug Information Vol. 25, No. 3, 2011 Consultation Documents

Additional information. Strength in the current WHO Model List of Essential Medi- cines: 250 mg of pyrantel.

Requirements

Comply with the monograph for “Tablets”. Definition. Pyrantel embonate chewable tablets contain not less than 90.0% and not more than 110.0% of the amount of C11H14N2S stated on the label. Identity tests Either tests A and E, or tests B, C and D, or tests C and E may be applied.

To a quantity of the powdered tablets equivalent to about 17 mg of Pyrantel add a mix- ture of 10 ml of dichloromethane R, 10 ml of methanol R, and about 1 ml of ammonia (~260 g/l) TS, shake and filter. Evaporate the filtrate to dryness on a water-bath, dis- solve in a small volume of methanol R (about 3 ml), and allow to recrystallize. Sepa- rate the crystals, dry at 80 °C for 2 hours, and use the dried crystals for the “Identity tests A, B, C and D “ and “Related substances A”. A. Carry out the examination with the dried crystals as described under 1.7 Spectro- photometry in the infrared region. The infrared absorption spectrum is concordant with the spectrum obtained from pyrantel embonate RS or with the reference spectrum of pyrantel embonate. B. See the test described under “Related substances A”. The principal spots obtained with solution A corresponds in position, appearance, and intensity with that obtained with solution B.

C. Dissolve about 5 mg of the dried crystals in 1 ml of hydrochloric acid (~70 g/l) TS and add 1 ml of formaldehyde/sulfuric acid TS; a violet-red colour is produced.

D. The absorption spectrum of a 13 μg/ml solution of dried crystals in methanol R, when observed between 230 nm and 360 nm, exhibits 2 maxima at about 288 nm and 300 nm. The ratio of the absorbance at 288 nm to that at 300 nm is about 1.0. E. See the test described under “Assay B”. Retention times of the principal peaks in the chromatogram obtained from solution A are similar to that obtained from solution B.

Related substances Either method A or B may be applied.

A. TLC Carry out the test as described under “1.14.1 Thin-layer chromatography”, using silica gel R6 as the coating substance and a mixture of 3 volumes of ethyl acetate R, 1 volume of water R, and 1 volume of glacial acetic acid R as the mobile phase. Apply separately to the plate 5 μl of each of 4 solutions in dimethylformamide R containing (A) 10 mg of the dried crystals per ml, (B) 10 mg of the pyrantel embonate RS (equi- valent to about 3.5 mg of pyrantel) per ml, (C) 0.10 mg of the dried crystals per ml, (D) a quantity of solution B being exposed under 2000 lx illumination for 24 hours. After removing the plate from the chromatographic chamber, allow it to dry in a current of air for 10 minutes, and examine the chromatogram in ultraviolet light (254 nm).

289 Consultation Documents WHO Drug Information Vol. 25, No. 3, 2011

The chromatograms obtained from solution A and solution C exhibit spots for pyrantel and pamoic acid at relative positions corresponding to those obtained from the chro- matogram of solution B. Any spot obtained with solution A, other than the principal spots, is not more intense than the pyrantel spot obtained with solution C. The test is not valid unless solution D exhibits three well separated spots (the Rf values of pyran- tel, pamoic acid and impurity A are about 0.3, 0.9 and 0.2, respectively).

B. HPLC Carry out the test as described under “1.14.4 High-performance liquid chromatogra- phy”, using the conditions given under “Assay B”. The operations described below must be carried out in subdued light and without any prolonged interruptions, preferably using low-actinic glassware. Prepare the following solutions. For solution (A) transfer a quantity of the powdered tablets containing the equivalent of about 28 mg of pyrantel, accurately weighed, into a 100 ml volumetric flask. Add 7 ml of a mixture composed of 5 volumes of glacial acetic R, 5 volumes of water R and 2 volumes of diethylamine R. Shake and dilute to volume with acetonitrile R, mix and filter. For solution (B), dilute 1.0 ml of the solution (A) to 100 ml with mobile phase. Inject alternately 20 μl each of solution (A) and (B) and record the chromatograms for 4 times the retention time of pyrantel. In the chromatograph obtained with solution (A): the sum of the areas of all peaks, other than the principal peaks and the solvent peak, is not greater than the area of the pyrantel peak obtained with solution (B) (1.0%). Disregard any peak with an area less than 0.05 times the area of the principal peak obtained with solution (B) (0.05%).

Assay Either method A or B may be applied.

A. UV The operations described below must be carried out in subdued light and without any prolonged interruptions, preferably using low-actinic glassware.

Weigh and powder 20 tablets. Transfer a quantity of the powdered chewable tablets containing the equivalent of about 35 mg pyrantel, accurately weighed, into a 100 ml volumetric flask, dissolve in a mixture of 10 ml of dioxan R and 10 ml of ammo- nia (~100 g/l) TS. Shake for 10 minutes and dilute to volume with perchloric acid (~140 g/l) TS. Filter, discard the first 10 ml of the filtrate, and transfer 5 ml of the subsequent filtrate to a 50 ml volumetric flask. Dilute to volume with perchloric acid (~140 g/l) TS and mix. Transfer 25.0 ml to a 250 ml separatory funnel, and extract with two quantities, each of 100 ml of dichloromethane R. Combine the dichloromethane extracts into the same separatory funnel, and extract with three quantities, each of 50 ml of hydrochloric acid (0.05 mol/l) VS. Combine the aqueous phases in a 200 ml volumetric flask, rinse the separatory funnel draining into the volumetric flask, and dilute to volume with hydrochloric acid (0.05 mol/l) VS. Measure the absorbance of a 1 cm layer at the maximum at about 311 nm against a solvent cell containing hydrochlo- ric acid (0.05mol/l) VS.

Calculate the percentage content of C11H14N2S by comparison with pyrantel embonate RS, similarly and concurrently examined.

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B. HPLC Carry out the test as described under “1.14.4 High-performance liquid chromatogra- phy”, using a stainless steel column (25 cm×4.6 mm) packed with high purity base particles of silica gel for chromatography R (5 μm). Shim-pack HRS-SIL column (25 cm×4.6 mm, 5 μm) has been found suitable.

As the mobile phase, use a mixture of 92.8 volumes of acetonitrile R and 7.2 volumes of a solvent mixture composed of 5 volumes of glacial acetic R, 5 volumes of water R and 2 volumes of diethylamine R. Filter the mobile phase through a 0.45 μm mem- brane and make adjustment if necessary.

The operations described below must be carried out in subdued light and without any prolonged interruptions, preferably using low-actinic glassware.

Prepare the following solutions. For solution (A), weigh and powder 20 tablets. Trans- fer a quantity of the chewable tablets containing the equivalent of about 6.9 mg of pyrantel, accurately weighed, into a 50 ml volumetric flask. Add about 30 ml of mobile phase, dissolve by shaking and dilute with mobile phase to volume, mix and filter. Transfer 2.0 ml of the clear filtrate to 10 ml volumetric flask, dilute with mobile phase to volume and mix. For solution (B), prepare a solution of 0.40 mg of pyrantel embonate RS (equivalent to about 0.14 mg of pyrantel) per ml mobile phase. Transfer 2.0 ml of this solution to a 10 ml volumetric flask, dilute with mobile phase to volume, and mix to obtain a standard preparation having a known concentration of 80 μg of pyrantel embonate RS (equivalent to about 28 μg of pyrantel) per ml. For solution (C), expose 10 ml of solution (A) under 2000 lx illumination for 24 hours.

Operate with a flow rate of 1.0 ml per minute. As a detector, use an ultraviolet spectro- photometer set at a wavelength of about 288 nm.

Inject 20 μl of the solution (C). With reference to pyrantel (retention time of pyrantel is about 14 minutes), the relative retention time for impurity A is about 1.3, and the rela- tive retention time for pamoic acid is about 0.5. The test is not valid unless the resolu- tion factor between the pyrantel peak and the impurity A peak is not less than 4.0. Inject alternately 20 μl each of solution (A) and (B) and record the chromatograms Measure the areas of the peak responses obtained in the chromatograms from solution (A) and solution (B), and calculate the content of pyrantel (C11H14N2S) in the chewable tables.

Impurity A is 1-methyl-2-[(Z)-2-(thiophen-2-yl) ethenyl]-1,4,5, 6-tetrahydropyrimidine.

Pyrantel embonate oral suspension

Draft proposal for the International Pharmacopoeia (February 2011). Please addess any comments to Quality Assurance and Safety: Medicines, World Health Organization, 1211 Geneva 27, Switzerland; fax: +41 22 791 4730 or e-mail to [email protected]. Working documents are available for comment at http://www.who.int/medicines.

Category. Anthelminthic.

291 Consultation Documents WHO Drug Information Vol. 25, No. 3, 2011

Storage. Pyrantel embonate oral suspension should be kept in a tight, light-resistant container. Labelling. The designation on the container of Pyrantel embonate oral suspension should state that the active ingredient is in the embonate form, and the quantity should be indicated in terms of the equivalent amount of pyrantel.

Additional information. Strength in the current WHO Model List of Essential Medi- cines: 50 mg of Pyrantel/ml. Requirements

Complies with the monograph for “Liquid preparations for oral use”.

Definition. Pyrantel embonate oral suspension contains not less than 90.0% and not more than 110.0% of the amount of C11H14N2S stated on the label.

Identity tests Either tests A and E, or tests B, C and D, or tests C and E may be applied.

To a quantity of the oral suspension equivalent to about 17 mg of pyrantel add a mix- ture of 10 ml of dichloromethane R, 10 ml of methanol R, and about 1 ml of ammonia (~260 g/l) TS, shake, and filter. Evaporate the filtrate to dryness on a water-bath, dis- solve in a small volume of methanol R (about 3 ml), and allow to recrystallize. Sepa- rate the crystals, dry at 80 °C for 2 hours, and use the dried crystals for the “Identity tests A, B, C and D” and “Related substances A”.

A. Carry out the examination with the dried crystals as described under 1.7 Spectro- photometry in the infrared region. The infrared absorption spectrum is concordant with the spectrum obtained from pyrantel embonate RS or with the reference spectrum of pyrantel embonate.

B. See the test described under “Related substances A”. The principal spots obtained with solution A correspond in position, appearance, and intensity with that obtained with solution B.

C. Dissolve about 5 mg of the dried crystals in 1 ml of hydrochloric acid (~70 g/l) TS and add 1 ml of formaldehyde/sulfuric acid TS; a violet-red colour is produced.

D. The absorption spectrum of a 13 μg/ml solution of dried crystals in methanol R, when observed between 230 nm and 360 nm, exhibits 2 maxima at about 288 nm and 300 nm. The ratio of the absorbance at 288 nm to that at 300 nm is about 1.0.

E. See the test described under “Assay B”. The retention times of the principal peaks in the chromatogram obtained from solution A are similar to that obtained from solution B. pH. 4.5 to 6.0.

Related substances Either method A or B may be applied.

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A. TLC Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R6 as the coating substance and a mixture of 3 volumes of ethyl acetate R, 1 volume of water R, and 1 volume of glacial acetic acid R as the mobile phase. Apply separately to the plate 5 μl of each of 4 solutions in dimethylformamide R containing (A) 10 mg of the dried crystals per ml, (B) 10 mg of the pyrantel embonate RS (equi- valent to about 3.5 mg of Pyrantel) per ml, (C) 0.10 mg of the dried crystals per ml, (D) a quantity of solution B being exposed under 2000 lx illumination for 24 hours. After removing the plate from the chromatographic chamber, allow it to dry in a current of air for 10 minutes, and examine the chromatogram in ultraviolet light (254 nm).

The chromatograms obtained from solution A and solution C exhibit spots for pyrantel and pamoic acid at relative positions corresponding to those obtained from the chro- matogram of solution B. Any spot obtained with solution A, other than the two principal spots, is not more intense than the pyrantel spot obtained with solution C. The test is not valid unless solution D exhibits three well separated spots (the Rf values of pyran- tel, pamoic acid and impurity A are about 0.3, 0.9 and 0.2, respectively).

B. HPLC Carry out the test as described under 1.14.4 High-performance liquid chromatography, using the conditions given under “Assay B”.

The operations described below must be carried out in subdued light and without any prolonged interruptions, preferably using low-actinic glassware.

Prepare the following solutions. For solution (A) transfer a quantity of the oral suspen- sion containing the equivalent of about 28 mg of pyrantel, accurately weighed, into a 100 ml volumetric flask. Add 7 ml of a mixture composed of 5 volumes of glacial acetic R, 5 volumes of water R and 2 volumes of diethylamine R. Shake and dilute to volume with acetonitrile R, mix and filter. For solution (B), dilute 1.0 ml of the solution (A) to 100 ml with mobile phase. Inject alternately 20 μl each of solution (A) and (B) and record the chromatograms for 4 times the retention time of pyrantel. In the chromatograph obtained with solution (A): the sum of the areas of all peaks, other than the principal peaks and the solvent peak, is not greater than the area of the pyrantel peak obtained with solution (B) (1.0%). Disregard any peak with an area less than 0.05 times the area of the principal peak obtained with solution (B) (0.05%).

Assay Either method A or B may be applied.

A. UV The operations described below must be carried out in subdued light and without any prolonged interruptions, preferably using low-actinic glassware. Transfer a quantity of the oral suspension containing the equivalent of about 35 mg pyrantel, accurately weighed, into a 100 ml volumetric flask, dissolve in a mixture of 10 ml of dioxan R and 10 ml of ammonia (~100 g/l) TS. Shake for 10 minutes and dilute to volume with perchloric acid (~140 g/l) TS. Filter, discard the first 10 ml of the filtrate, and transfer 5 ml of the subsequent filtrate to a 50 ml volumetric flask. Dilute

293 Consultation Documents WHO Drug Information Vol. 25, No. 3, 2011 to volume with perchloric acid (~140 g/l) TS and mix. Transfer 25.0 ml to a 250 ml separatory funnel, and extract with two quantities, each of 100 ml of dichloromethane R. Combine the dichloromethane extracts into the same separatory funnel, and extract with three quantities, each of 50 ml of hydrochloric acid (0.05 mol/l) VS. Combine the aqueous phases in a 200 ml volumetric flask, rinse the separatory funnel draining into the volumetric flask, and dilute to volume with hydrochloric acid (0.05 mol/l) VS. Measure the absorbance of a 1 cm layer at the maximum at about 311 nm against a solvent cell containing hydrochloric acid (0.05 mol/l) VS.

Calculate the percentage content of C11H14N2S by comparison with pyrantel embonate RS, similarly and concurrently examined.

B. HPLC Carry out the test as described under 1.14.4 High-performance liquid chromatography, using a stainless steel column (25 cm×4.6 mm) packed with high purity base particles of silica gel for chromatography R (5 μm ). (Shim-pack HRS-SIL column (25 cm× 4.6 mm, 5 μm) has been found suitable).

As the mobile phase, use a mixture of 92.8 volumes of acetonitrile R and 7.2 volumes of a solvent mixture composed of 5 volumes of glacial acetic R, 5 volumes of water R and 2 volumes of diethylamine R. Filter the mobile phase through a 0.45 μm mem- brane and make adjustment if necessary.

The operations described below must be carried out in subdued light and without any prolonged interruptions, preferably using low-actinic glassware.

Prepare the following solutions. For solution (A), transfer a quantity of the oral sus- pension equivalent of about 6.9 mg of pyrantel, accurately weighed, into a 50 ml volumetric flask. Add about 30 ml of mobile phase, dissolve by shaking and dilute with mobile phase to volume, mix and filter. Transfer 2.0 ml of the clear filtrate to a 10 ml volumetric flask, dilute with mobile phase to volume and mix. For solution (B), prepare a solution of 0.40 mg of pyrantel embonate RS (equivalent to about 0.14 mg of pyran- tel) per ml mobile phase. Transfer 2.0 ml of this solution to a 10 ml volumetric flask, dilute with mobile phase to volume, and mix to obtain a standard preparation having a known concentration of 80 μg of pyrantel embonate RS (equivalent to about 28 μg of pyrantel) per ml. For solution (C), expose 10 ml of solution (A) under 2000 lx illumina- tion for 24 hours.

Operate with a flow rate of 1.0 ml per minute. As a detector, use an ultraviolet spectro- photometer set at a wavelength of about 288 nm.

Inject 20 μl of solution (C). With reference to pyrantel (retention time of pyrantel is about 14 minutes), the relative retention time for impurity A is about 1.3, and the rela- tive retention time for pamoic acid is about 0.5. The test is not valid unless the resolu- tion factor between the pyrantel peak and the impurity A peak is not less than 4.0. Inject alternately 20 μl each of solution (A) and (B) and record the chromatograms. Measure the areas of the peak responses obtained in the chromatograms from solu- tion (A) and solution (B), and calculate the content of pyrantel (C11H14N2S) in the oral suspension. Impurity A is 1-methyl-2-[(Z)-2-(thiophen-2-yl)ethenyl]-1,4,5, 6-tetrahydropyrimidine.

294 WHO Drug Information Vol. 25, No. 3, 2011 Recommended INN: List 66

International Nonproprietary Names for Pharmaceutical Substances (INN)

RECOMMENDED International Nonproprietary Names: List 66

Notice is hereby given that, in accordance with paragraph 7 of the Procedure for the Selection of Recommended International Nonproprietary Names for Pharmaceutical Substances [Off. Rec. Wld Health Org., 1955, 60, 3 (Resolution EB15.R7); 1969, 173, 10 (Resolution EB43.R9); Resolution EB115.R4 (EB115/2005/REC/1)], the following names are selected as Recommended International Nonproprietary Names. The inclusion of a name in the lists of Recommended International Nonproprietary Names does not imply any recommendation of the use of the substance in medicine or pharmacy. Lists of Proposed (1–101) and Recommended (1–62) International Nonproprietary Names can be found in Cumulative List No. 13, 2009 (available in CD-ROM only).

Dénominations communes internationales des Substances pharmaceutiques (DCI)

Dénominations communes internationales RECOMMANDÉES: Liste 66

Il est notifié que, conformément aux dispositions du paragraphe 7 de la Procédure à suivre en vue du choix de Dénominations communes internationales recommandées pour les Substances pharmaceutiques [Actes off. Org. mond. Santé, 1955, 60, 3 (résolution EB15.R7); 1969, 173, 10 (résolution EB43.R9); résolution EB115.R4 (EB115/2005/REC/1)] les dénominations ci-dessous sont choisies par l’Organisation mondiale de la Santé en tant que dénominations communes internationales recommandées. L’inclusion d’une dénomination dans les listes de DCI recommandées n’implique aucune recommandation en vue de l’utilisation de la substance correspondante en médecine ou en pharmacie. On trouvera d’autres listes de Dénominations communes internationales proposées (1–101) et recommandées (1–62) dans la Liste récapitulative No. 13, 2009 (disponible sur CD-ROM seulement).

Denominaciones Comunes Internacionales para las Sustancias Farmacéuticas (DCI)

Denominaciones Comunes Internacionales RECOMENDADAS: Lista 66

De conformidad con lo que dispone el párrafo 7 del Procedimiento de Selección de Denominaciones Comunes Internacionales Recomendadas para las Sustancias Farmacéuticas [Act. Of. Mund. Salud, 1955, 60, 3 (Resolución EB15.R7); 1969, 173, 10 (Resolución EB43.R9); Résolution EB115.R4 (EB115/2005/REC/1) EB115.R4 (EB115/2005/REC/1)], se comunica por el presente anuncio que las denominaciones que a continuación se expresan han sido seleccionadas como Denominaciones Comunes Internacionales Recomendadas. La inclusión de una denominación en las listas de las Denominaciones Comunes Recomendadas no supone recomendación alguna en favor del empleo de la sustancia respectiva en medicina o en farmacia. Las listas de Denominaciones Comunes Internacionales Propuestas (1–101) y Recomendadas (1–62) se encuentran reunidas en Cumulative List No. 13, 2009 (disponible sólo en CD-ROM).

295 Recommended INN: List 66 WHO Drug Information Vol. 25, No. 3, 2011

Latin, English, French, Spanish: Recommended INN Chemical name or description; Molecular formula; Graphic formula

DCI Recommandée Nom chimique ou description; Formule brute; Formule développée

DCI Recomendada Nombre químico o descripción; Fórmula molecular; Fórmula desarrollada

abediterolum abediterol 5-[(1R)-2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}- 1-hydroxyethyl]-8-hydroxyquinolin-2(1H)-one

abéditérol 5-[(1R)-2-{[6-(2,2-difluoro-2-phényléthoxy)hexyl]amino}- 1-hydroxyéthyl]-8-hydroxyquinoléin-2(1H)-one

abediterol 5-[(1R)-2-{[6-(2,2-difluoro-2-feniletoxi)hexil]amino}-1-hidroxietil]- 8-hidroxiquinolin-2(1H)-ona

C25H30F2N2O4

H OH H N O FF HO HN

O

adomiparinum natricum adomiparin sodium sodium salt of a low molecular mass heparin obtained by enzymatic depolymerization of heparin from porcine intestinal mucosa; the majority of the components have a 4-deoxy-α-L-threo-hex- 4-enopyranuronic acid or it 4-hydroxy saturated derivative at the non-reducing end and a 2-amino-2-deoxy-D-glucopyranose derivative structure at the reducing end of their chain; the relative average molecular mass range is 5,500 to 9,000 daltons and a polydispersity of less than 1.5; the degree of sulfation is about 2.6 per disaccharidic unit

adomiparine sodique sel sodique d'héparine de faible masse moléculaire obtenu par dépolymérisation enzymatique d'héparine de muqueuse intestinale de porc ; la majorité des composants possèdent une structure acide 4-déoxy-α-L-thréo-hex-4-énopyranuronique ou son dérivé saturé 4-hydroxylé à l'extrémité non réductrice de leur chaîne et une structure 2-amino-2-désoxy-D-glucopyranose à l'extrémité réductrice de leur chaîne ; la masse moléculaire relative est en moyenne comprise entre 5500 et 9000 et son indice de polymolécularité est inférieure à 1,5 ; le degré de sulfatation est d'environ 2,6 par unité disaccharide.

296 WHO Drug Information Vol. 25, No. 3, 2011 Recommended INN: List 66

adomiparina sódica sal sódica de heparina de baja masa molecular obtenida por despolimerización enzimática de heparina de mucosa intestinal de cerdo; la mayoría de cuyos componentes tienen un ácido 4-desoxi- α-L-treo-hex-4-enopiranurónico o su derivado saturado 4-hidroxilado en el extremo no reductor de la cadena y una 2-amino-2-desoxi- D-glucopiranosa en el reductor; la masa molecular relativa media está comprendida entre 5500 y 9000 y su índice de polidispersión es inférior a 1,5; el grado de sulfatación es aproximadamente 2,6 par unidad de disacárido.

aganepagum aganepag 5-{3-[(2S)-1-{4-[(1S)-1-hydroxyhexyl]phenyl}-5-oxopyrrolidin- 2-yl]propyl}thiophene-2-carboxylic acid

aganépag acide 5-{3-[(2S)-1-{4-[(1S)-1-hydroxyhexyl]phényl}-5-oxopyrrolidin- 2-yl]propyl}thiophène-2-carboxylique

aganepag ácido 5-{3-[(2S)-1-{4-[(1S)-1-hidroxihexil]fenil}-5-oxopirrolidin- 2-il]propil}tiofeno-2-carboxílico

C24H31NO4S

H S CO2H

N

O CH3

HOH

alisertibum alisertib 4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4- d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid

alisertib acide 4-{[9-chloro-7-(2-fluoro-6-méthoxyphényl)-5H-pyrimido[5,4- d][2]benzazépin-2-yl]amino}-2-méthoxybenzoïque

alisertib ácido 4-{[9-cloro-7-(2-fluoro-6-metoxifenil)-5H-pirimido[5,4- d][2]benzazepin-2-il]amino}-2-metoxibenzoico

C27H20ClFN4O4

Cl H3C O H N N

N N CO2H F OCH3

297 Recommended INN: List 66 WHO Drug Information Vol. 25, No. 3, 2011

alvelestatum alvelestat N-{[5-(methanesulfonyl)pyridin-2-yl]methyl}-6-methyl-5-(1-methyl- 1H-pyrazol-5-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]- 1,2-dihydropyridine-3-carboxamide

alvélestat N-{[5-(méthanesulfonyl)pyridin-2-yl]méthyl}-6-méthyl-5-(1-méthyl- 1H-pyrazol-5-yl)-2-oxo-1-[3-(trifluorométhyl)phényl]- 1,2-dihydropyridine-3-carboxamide

alvelestat N-{[5-(metanosulfonil)piridin-2-il]metil}-6-metil-5-(1-metil-1H-pirazol- 5-il)-2-oxo-1-[3-(trifluorometil)fenil]-1,2-dihidropiridina-3-carboxamida

C25H22F3N5O4S

F3C

O O

H3C N O S CH3 H N N

N N O CH3

amatuximabum # amatuximab immunoglobulin G1-kappa, anti-[Homo sapiens MSLN (mesothelin, pre-pro-megakaryocyte-potentiating factor, megakaryocyte- potentiating factor, MPF, CAK1)], chimeric monoclonal antibody; gamma1 heavy chain (1-449) [Mus musculus VH (IGHV1-37*01 - (IGHD)-IGHJ2*01) [8.8.12] (1-119) -Homo sapiens IGHG1*01 (120- 449)], (222-213')-disulfide with kappa light chain (1'-213') [Mus musculus V-KAPPA (IGKV4-59*01 -IGKJ4*01) [5.3.9] (1'-106') - Homo sapiens IGKC*01 (107'-213')]; (228-228'':231-231'')- bisdisulfide dimer

amatuximab immunoglobuline G1-kappa, anti-[Homo sapiens MSLN (mésothéline, facteur de potentialisation du pré-pro-mégacaryocyte, facteur de potentialisation des mégacaryocytes, MPF, CAK1)], anticorps monoclonal chimérique; chaîne lourde gamma1 (1-449) [Mus musculus VH (IGHV1-37*01 - (IGHD)-IGHJ2*01) [8.8.12] (1-119) -Homo sapiens IGHG1*01 (120- 449)], (222-213')-disulfure avec la chaîne légère kappa (1'-213') [Mus musculus V-KAPPA (IGKV4-59*01 -IGKJ4*01) [5.3.9] (1'-106') -Homo sapiens IGKC*01 (107'-213')]; dimère (228-228'':231-231'')- bisdisulfure

amatuximab inmunoglobulina G1-kappa, anti-[MSLN de Homo sapiens (mesotelina, factor de potenciación del pre-pro-megacariocito, factor de potenciación de megacariocitos, MPF, CAK1)], anticuerpo monoclonal quimérico; cadena pesada gamma1 (1-449) [Mus musculus VH (IGHV1-37*01 - (IGHD)-IGHJ2*01) [8.8.12] (1-119) -Homo sapiens IGHG1*01 (120- 449)], (222-213')-disulfuro con la cadena ligera kappa (1'-213') [Mus musculus V-KAPPA (IGKV4-59*01 -IGKJ4*01) [5.3.9] (1'-106') - Homo sapiens IGKC*01 (107'-213')]; dímero (228-228'':231-231'')- bisdisulfuro

298 WHO Drug Information Vol. 25, No. 3, 2011 Recommended INN: List 66

Heavy chain / Chaîne lourde / Cadena pesada QVQLQQSGPE LEKPGASVKI SCKASGYSFT GYTMNWVKQS HGKSLEWIGL 50 ITPYNGASSY NQKFRGKATL TVDKSSSTAY MDLLSLTSED SAVYFCARGG 100 YDGRGFDYWG SGTPVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD 150 YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY 200 ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK 250 DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS 300 TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV 350 YTLPPSRDEL TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL 400 DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK 449 Light chain / Chaîne légère / Cadena ligera DIELTQSPAI MSASPGEKVT MTCSASSSVS YMHWYQQKSG TSPKRWIYDT 50 SKLASGVPGR FSGSGSGNSY SLTISSVEAE DDATYYCQQW SKHPLTFGSG 100 TKVEIKRTVA APSVFIFPPS DEQLKSGTAS VVCLLNNFYP REAKVQWKVD 150 NALQSGNSQE SVTEQDSKDS TYSLSSTLTL SKADYEKHKV YACEVTHQGL 200 SSPVTKSFNR GEC 213 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 146-202 263-323 369-427 22''-96'' 146''-202'' 263''-323'' 369''-427'' Intra-L 23'-87' 133'-193' 23'''-87''' 133'''-193''' Inter-H-L 222-213' 222''-213''' Inter-H-H 228-228'' 231-231''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 299, 299''

arbaclofenum arbaclofen (3R)-4-amino-3-(4-chlorophenyl)butanoic acid

arbaclofène (-)-acide (3R)-4-amino-3-(4-chlorophényl)butanoïque

arbaclofeno ácido (3R)-4-amino-3-(4-clorofenil)butanoico

C10H12ClNO2

H2N H CO2H

Cl

asfotasum alfa # asfotase alfa tissue-nonspecific alkaline phosphatase-IgG1 fusion protein; human tissue-nonspecific isozyme alkaline phosphatase (AP-TNAP, EC=3.1.3.1) fusion protein with leucyl-lysyl-human immunoglobulin G1 Fc region {(6-15)-H-CH2-CH3 of IGHG1*03} fusion protein with aspartyl-isoleucyl-deca(aspartic acid), dimer (493-493':496-496')- bisdisulfide

asfotase alfa protéine de fusion phosphatase alcaline humaine isozyme tissulaire non-spécifique-IgG1; phosphatase alcaline humaine isozyme tissulaire non-spécifique (AP-TNAP, EC=3.1.3.1) protéine de fusion avec la leucyl-lysyl-région Fc {(6-15)-H-CH2-CH3 de l'IGHG1*03} de l'immunoglobuline G1 humaine protéine de fusion avec l'aspartyl-isoleucyl-déca(acide aspartique), (493-493':496-496')-bisdisulfure du dimère

299 Recommended INN: List 66 WHO Drug Information Vol. 25, No. 3, 2011

asfotasa alfa proteína de fusión fosfatasa alcalina humana isozima tisular inespecífica-IgG1; fosfatasa alcalina humana isozima tisular inespecífica (AP-TNAP, EC=3.1.3.1) proteína de fusión con la leucil-lisil-región Fc {(6-15)-H- CH2-CH3 del IGHG1*03} de la inmunoglobulinea G1 humana proteína de fusión con aspartil-isoleucil-deca(acide aspártico), (493- 493':496-496')-bisdisulfuro del diméro

C7108H11008N1968O2206S56 (peptide)

Monomer / Monomère / Monómero LVPEKEKDPK YWRDQAQETL KYALELQKLN TNVAKNVIMF LGDGMGVSTV 50 TAARILKGQL HHNPGEETRL EMDKFPFVAL SKTYNTNAQV PDSAGTATAY 100 LCGVKANEGT VGVSAATERS RCNTTQGNEV TSILRWAKDA GKSVGIVTTT 150 RVNHATPSAA YAHSADRDWY SDNEMPPEAL SQGCKDIAYQ LMHNIRDIDV 200 IMGGGRKYMY PKNKTDVEYE SDEKARGTRL DGLDLVDTWK SFKPRYKHSH 250 FIWNRTELLT LDPHNVDYLL GLFEPGDMQY ELNRNNVTDP SLSEMVVVAI 300 QILRKNPKGF FLLVEGGRID HGHHEGKAKQ ALHEAVEMDR AIGQAGSLTS 350 SEDTLTVVTA DHSHVFTFGG YTPRGNSIFG LAPMLSDTDK KPFTAILYGN 400 GPGYKVVGGE RENVSMVDYA HNNYQAQSAV PLRHETHGGE DVAVFSKGPM 450 AHLLHGVHEQ NYVPHVMAYA ACIGANLGHC APASSLKDKT HTCPPCPAPE 500 LLGGPSVFLF PPKPKDTLMI SRTPEVTCVV VDVSHEDPEV KFNWYVDGVE 550 VHNAKTKPRE EQYNSTYRVV SVLTVLHQDW LNGKEYKCKV SNKALPAPIE 600 KTISKAKGQP REPQVYTLPP SREEMTKNQV SLTCLVKGFY PSDIAVEWES 650 NGQPENNYKT TPPVLDSDGS FFLYSKLTVD KSRWQQGNVF SCSVMHEALH 700 NHYTQKSLSL SPGKDIDDDD DDDDDD 726 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro 122-184 122'-184' 472-480 472'-480' 528-588 528'-588' 634-692 634'-692' 493-493' 496-496'

Glycosylation sites (N) / Sites de glycosylation (N) / Posiciones de glicosilación (N) Asn-123 Asn-123' Asn-213 Asn-213' Asn-254 Asn-254' Asn-286 Asn-286' Asn-413 Asn-413' Asn-564 Asn-564'

atinumabum # atinumab immunoglobulin G4-kappa, anti-[Homo sapiens RTN4 (reticulon 4, neurite outgrowth inhibitor, NOGO), isoform A], Homo sapiens monoclonal antibody; gamma4 heavy chain (1-441) [Homo sapiens VH (IGHV3-7*01 (93.80%) -(IGHD)-IGHJ2*01 T122>S) [8.8.7] (1-114) -IGHG4*01 (115-441)], (128-214')-disulfide with kappa light chain (1'-214') [Homo sapiens V-KAPPA (IGKV3-11*01 (100.00%) -IGKJ5*01 R123>K) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; (220-220'':223- 223'')-bisdisulfide dimer

atinumab immunoglobuline G4-kappa, anti-[Homo sapiens RTN4 (réticulon 4, inhibiteur de la croissance des neurites, NOGO), isoforme A], Homo sapiens anticorps monoclonal;chaîne lourde gamma4 (1-441) [Homo sapiens VH (IGHV3-7*01 (93.80%) -(IGHD)-IGHJ2*01 T122>S) [8.8.7] (1-114) -IGHG4*01 (115-441)], (128-214')-disulfure avec la chaîne légère kappa (1'-214') [Homo sapiens V-KAPPA (IGKV3- 11*01 (100.00%) -IGKJ5*01 R123>K) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dimère (220-220'':223-223'')-bisdisulfure

atinumab inmunoglobulina G4-kappa, anti-[ RTN4 de Homo sapiens (reticulón 4, inhibidor del crecimiento de las neuritas, NOGO), isoforma A], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma4 (1-441) [VH de Homo sapiens (IGHV3-7*01 (93.80%) -(IGHD)-IGHJ2*01 T122>S) [8.8.7] (1-114) -IGHG4*01 (115-441)], (128-214')-disulfuro con la cadena ligera kappa (1'-214') [Homo sapiens V-KAPPA (IGKV3-11*01 (100.00%) -IGKJ5*01 R123>K) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dímero (220- 220'':223-223'')-bisdisulfuro

300 WHO Drug Information Vol. 25, No. 3, 2011 Recommended INN: List 66

Heavy chain / Chaîne lourde / Cadena pesada EVQLVESGGG LVQPGGSLRL SCAASGFTFS NYWMSWVRQA PGKGLEWVAT 50 IKQDGSQKNY VDSVKGRFTI SRDNAKNSLY LRLNSLRAED TAVYYCATEL 100 FDLWGRGSLV TVSSASTKGP SVFPLAPCSR STSESTAALG CLVKDYFPEP 150 VTVSWNSGAL TSGVHTFPAV LQSSGLYSLS SVVTVPSSSL GTKTYTCNVD 200 HKPSNTKVDK RVESKYGPPC PSCPAPEFLG GPSVFLFPPK PKDTLMISRT 250 PEVTCVVVDV SQEDPEVQFN WYVDGVEVHN AKTKPREEQF NSTYRVVSVL 300 TVLHQDWLNG KEYKCKVSNK GLPSSIEKTI SKAKGQPREP QVYTLPPSQE 350 EMTKNQVSLT CLVKGFYPSD IAVEWESNGQ PENNYKTTPP VLDSDGSFFL 400 YSRLTVDKSR WQEGNVFSCS VMHEALHNHY TQKSLSLSLG K 441 Light chain / Chaîne légère / Cadena ligera EIVLTQSPAT LSLSPGERAT LSCRASQSVS SYLAWYQQKP GQAPRLLIYD 50 ASNRATGIPA RFSGSGSGTD FTLTISSLEP EDFAVYYCQQ RSNWPITFGQ 100 GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150 DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200 LSSPVTKSFN RGEC 214 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 141-197 255-315 361-419 22''-96'' 141''-197'' 255''-315'' 361''-419'' Intra-L 23'-88' 134'-194' 23'''-88''' 134'''-194''' Inter-H-L 128-214' 128''-214''' Inter-H-H 220-220'' 223-223''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 291, 291''

atopaxarum atopaxar 2-(5,6-diethoxy-7-fluoro-1-imino-1,3-dihydro-2H-isoindol-2-yl)- 1-[3-tert-butyl-4-methoxy-5-(morpholin-4-yl)phenyl]ethan-1-one

atopaxar 2-(5,6-diéthoxy-7-fluoro-1-imino-1,3-dihydro-2H-isoindol-2-yl)- 1-[3-tert-butyl-4-méthoxy-5-(morpholin-4-yl)phényl]éthanone

atopaxar 2-(5,6-dietoxi-7-fluoro-1-imino-1,3-dihidro-2H-isoindol-2-il)-1-[3-terc- butil-4-metoxi-5-(morfolin-4-il)fenil]etan-1-ona

C29H38FN3O5

F NH H3C CH3 H3C O CH N 3 OCH H3C O 3 O N

O

bisegliptinum bisegliptin ethyl 4-({2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]- 2-oxoethyl}amino)bicyclo[2.2.2]octane-1-carboxylate

biségliptine 4-({2-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]- 2-oxoéthyl}amino)bicyclo[2.2.2]octane-1-carboxylate d'éthyle

bisegliptina 4-({2-[(2S,4S)-2-ciano-4-fluoropirrolidin-1-il]- 2-oxoetil}amino)biciclo[2.2.2]octano-1-carboxilato de etilo

C18H26FN3O3

O H H CN N N

H3C O H F O

301 Recommended INN: List 66 WHO Drug Information Vol. 25, No. 3, 2011

burixaforum burixafor (2-{4-[6-amino-2-({[(1r,4r)-4-({[3- (cyclohexylamino)propyl]amino}methyl)cyclohexyl]methyl}amino) pyrimidin-4-yl]piperazin-1-yl}ethyl)phosphonic acid

burixafor acide (2-{4-[6-amino-2-({[(1r,4r)-4-({[3- (cyclohexylamino)propyl]amino}méthyl)cyclohexyl]méthyl}amino) pyrimidin-4-yl]pipérazin-1-yl}éthyl)phosphonique

burixafor ácido (2-{4-[6-amino-2-({[(1r,4r)-4-({[3- (ciclohexilamino)propil]amino}metil)ciclohexil]metil}amino)pirimidin- 4-il]piperazin-1-il}etil)fosfónico

C27H51N8O3P

O P OH N N N H H H OH N N N

N

NH2

cadazolidum cadazolid 1-cyclopropyl-6-fluoro-7-[4-({2-fluoro-4-[(5R)-5-(hydroxymethyl)- 2-oxo-1,3-oxazolidin-3-yl]phenoxy}methyl)-4-hydroxypiperidin-1-yl]- 4-oxo-1,4-dihydroquinolin-3-carboxylic acid

cadazolid acide 1-cyclopropyl-6-fluoro-7-[4-({2-fluoro-4-[(5R)-5- (hydroxyméthyl)-2-oxo-1,3-oxazolidin-3-yl]phénoxy}méthyl)- 4-hydroxypipéridin-1-yl]-4-oxo-1,4-dihydroquinoléine-3-carboxylique

cadazolid ácido 1-ciclopropil-6-fluoro-7-[4-({2-fluoro-4-[(5R)-5-(hidroximetil)- 2-oxo-1,3-oxazolidin-3-il]fenoxi}metil)-4-hidroxipiperidin-1-il]-4-oxo- 1,4-dihidroquinolin-3-carboxílico

C29H29F2N3O8

O O H HO N OH O F N N

F CO2H O carlumabum # carlumab immunoglobulin G1-kappa, anti-[Homo sapiens CCL2 (chemokine (C-C motif) ligand 2, C-C motif chemokine 2, monocyte chemoattractant protein-1, MCP-1, monocyte chemotactic and activating factor, MCAF, small inducible cytokine A2, SCYA2, HC11)], Homo sapiens monoclonal antibody; gamma1 heavy chain (1-449) [Homo sapiens VH (IGHV1-69*01 (99.00%) -(IGHD)-IGHJ4*01 [8.8.12] (1-119) -IGHG1*01 (120-449)), (222-216')-disulfide with kappa light chain (1'-216') [Homo sapiens V-KAPPA (IGKV3-11*01 (94.50%) -IGKJ1*01) [7.3.10] (1'-109') - IGKC*01 (110'-216')]; (228-228'':231-231'')-bisdisulfide dimer

302 WHO Drug Information Vol. 25, No. 3, 2011 Recommended INN: List 66

carlumab immunoglobuline G1-kappa, anti-[Homo sapiens CCL2 (chimiokine (C-C motif) ligand 2, C-C motif chimiokine 2, protéine 1 chimioattractante du monocyte, MCP-1, facteur activateur et chimiotactique du monocyte, MCAF, SCYA2, HC11)], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-449) [Homo sapiens VH (IGHV1-69*01 (99.00%) -(IGHD)-IGHJ4*01 [8.8.12] (1-119) -IGHG1*01 (120-449)), (222-216')-disulfure avec la chaîne légère kappa (1'-216') [Homo sapiens V-KAPPA (IGKV3-11*01 (94.50%) -IGKJ1*01) [7.3.10] (1'-109') -IGKC*01 (110'-216')]; dimère (228-228'':231-231'')- bisdisulfure

carlumab inmunoglobulina G1-kappa, anti-[Homo sapiens CCL2 (quimiokina (C-C motif) ligando 2, C-C motif quimiokina 2, proteìna 1 quimiotàctica de monocito, MCP-1, factor activador y quimiotàctico de monocito, MCAF, SCYA2, HC11)], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma1 (1-449) [Homo sapiens VH (IGHV1-69*01 (99.00%) -(IGHD)-IGHJ4*01 [8.8.12] (1-119) -IGHG1*01 (120-449)), (222-216')-disulfuro con la cadena ligera kappa (1'-216') [Homo sapiens V-KAPPA (IGKV3-11*01 (94.50%) -IGKJ1*01) [7.3.10] (1'-109') -IGKC*01 (110'-216')]; dìmero (228-228'':231-231'')- bisdisulfuro

Heavy chain / Chaîne lourde / Cadena pesada QVQLVQSGAE VKKPGSSVKV SCKASGGTFS SYGISWVRQA PGQGLEWMGG 50 IIPIFGTANY AQKFQGRVTI TADESTSTAY MELSSLRSED TAVYYCARYD 100 GIYGELDFWG QGTLVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD 150 YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY 200 ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK 250 DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS 300 TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV 350 YTLPPSRDEL TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL 400 DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK 449 Light chain / Chaîne légère / Cadena ligera EIVLTQSPAT LSLSPGERAT LSCRASQSVS DAYLAWYQQK PGQAPRLLIY 50 DASSRATGVP ARFSGSGSGT DFTLTISSLE PEDFAVYYCH QYIQLHSFTF 100 GQGTKVEIKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW 150 KVDNALQSGN SQESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH 200 QGLSSPVTKS FNRGEC 216 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 146-202 263-323 369-427 22''-96'' 146''-202'' 263''-323'' 369''-427'' Intra-L 23'-89' 136'-196' 23'''-89''' 136'''-196''' Inter-H-L 222-216' 222''-216''' Inter-H-H 228-228'' 231-231''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 299, 299''

cenisertibum cenisertib (1S,2S,3R,4R)-3-{[5-fluoro-2-({3-methyl-4-(4-methylpiperazin- 1-yl)phenyl}amino)pyrimidin-4-yl]amino}bicyclo[2.2.1]hept-5-ene- 2-carboxamide

cénisertib (1S,2S,3R,4R)-3-[(5-fluoro-2-{[3-méthyl-4-(4-méthylpipérazin- 1-yl)phényl]amino}pyrimidin-4-yl)amino]bicyclo[2.2.1]hept-5-ène- 2-carboxamide

cenisertib (1S,2S,3R,4R)-3-{[5-fluoro-2-({3-metil-4-(4-metilpiperazin- 1-il)fenil}amino)pirimidin-4-il]amino}biciclo[2.2.1]hept-5-eno- 2-carboxamida

303 Recommended INN: List 66 WHO Drug Information Vol. 25, No. 3, 2011

C24H30FN7O CH3 CH3 N F N N O H HN N N H H H2N H H

crolibulinum crolibulin (4R)-2,7,8-triamino-4-(3-bromo-4,5-dimethoxyphenyl)-4H-chromene- 3-carbonitrile

crolibuline (4R)-2,7,8-triamino-4-(3-bromo-4,5-diméthoxyphényl)-4H-chromène- 3-carbonitrile

crolibulina (4R)-2,7,8-triamino-4-(3-bromo-4,5-dimetoxifenil)-4H-cromeno- 3-carbonitrilo

C18H17BrN4O3

NH2

NH2

O H H3CO NH2 CN H3CO Br

darexabanum darexaban N-[2-hydroxy-6-(4-methoxybenzamido)phenyl]-4-(4-methyl- 1,4-diazepan-1-yl)benzamide

darexaban N-[2-hydroxy-6-(4-méthoxybenzamido)phényl]-4-(4-méthyl- 1,4-diazépan-1-yl)benzamide

darexabán N-[2-hidroxi-6-(4-metoxibenzamido)fenil]-4-(4-metil-1,4-diazepan- 1-il)benzamida

C27H30N4O4

HO O

OCH3 N H HN N O N H3C

304 WHO Drug Information Vol. 25, No. 3, 2011 Recommended INN: List 66

delamanidum delamanid (2R)-2-methyl-6-nitro-2-[(4-{4-[4-(trifluoromethoxy)phenoxy]piperidin- 1-yl}phenoxy)methyl]-2,3-dihydroimidazo[2,1-b][1,3]oxazole

délamanid (2R)-2-méthyl-6-nitro-2-[(4-{4-[4-(trifluorométhoxy)phénoxy]pipéridin- 1-yl}phénoxy)méthyl]-2,3-dihydroimidazo[2,1-b]oxazole

delamanid (2R)-2-metil-6-nitro-2-[(4-{4-[4-(trifluorometoxi)fenoxi]piperidin- 1-il}fenoxi)metil]-2,3-dihidroimidazo[2,1-b][1,3]oxazol

C25H25F3N4O6

O

N OCF3 N O

O2N O N CH3

edivoxetinum edivoxetine (1R)-2-(5-fluoro-2-methoxyphenyl)-1-[(2S)-morpholin-2-yl]-1-(oxan- 4-yl)ethan-1-ol

édivoxétine (1R)-2-(5-fluoro-2-méthoxyphényl)-1-[(2S)-morpholin-2-yl]-1-(oxan- 4-yl)éthan-1-ol

edivoxetina (1R)-2-(5-fluoro-2-metoxifenil)-1-[(2S)-morfolin-2-il]-1-(oxan-4-il)etan- 1-ol

C18H26FNO4

F O

HO H

ONH OCH3

efinaconazolum efinaconazole (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)- 1-(1H-1,2,4-triazin-1-yl)butan-2-ol

éfinaconazole (2R,3R)-2-(2,4-difluorophényl)-3-(4-méthylènepipéridin-1-yl)- 1-(1H-1,2,4-triazol-1-yl)butan-2-ol

efinaconazol (2R,3R)-2-(2,4-difluorofenil)-3-(4-metilenopiperidin-1-il)- 1-(1H-1,2,4-triazin-1-il)butan-2-ol

C18H22F2N4O

F

F H2C HO N

HCH3 N N N

305 Recommended INN: List 66 WHO Drug Information Vol. 25, No. 3, 2011

egaptivonum pegolum egaptivon pegol a pegylated aptamer which binds von Willebrand factor; 5'-O-{[6-(carboxyamino)hexyl]hydroxyphosphoryl}-2'-O- methylguanylyl-(3'→5')-2'-O-methylcytidylyl-(3'→5')-2'-O- methylguanylyl-(3'→5')-2'-O-methyluridylyl-(3'→5')-2'-deoxyguanylyl- (3'→5')-2'-deoxycytidylyl-(3'→5')-2'-deoxyadenylyl-(3'→5')-2'-O- methylguanylyl-(3'→5')-2'-O-methyluridylyl-(3'→5')-2'-O- methylguanylyl-(3'→5')-2'-O-methylcytidylyl-(3'→5')-2'-O- methylcytidylyl-(3'→5')-2'-O-methyluridylyl-(3'→5')-2'-O- methyluridylyl-(3'→5')-2'-O-methylcytidylyl-(3'→5')-2'-O- methylguanylyl-(3'→5')-2'-O-methylguanylyl-(3'→5')-2'-O- methylcytidylyl-(3'→5')-2'-deoxycytidylyl-(3'→5')-2'-O-methyl-P- thioguanylyl-(3'→5')-thymidylyl-(3'→5')-2'-O-methylguanylyl-(3'→5')- 2'-deoxycytidylyl-(3'→5')-2'-deoxyguanylyl-(3'→5')-2'-deoxyguanylyl- (3'→5')-thymidylyl-(3'→5')-2'-O-methylguanylyl-(3'→5')-2'-O- methylcytidylyl-(3'→5')-2'-deoxycytidylyl-(3'→5')-2'-O-methyluridylyl- (3'→5')-2'-deoxycytidylyl-(3'→5')-2'-deoxycytidylyl-(3'→5')-2'-O- methylguanylyl-(3'→5')-2'-O-methyluridylyl-(3'→5')-2'-deoxycytidylyl- (3'→5')-2'-O-methyladenylyl-(3'→5')-2'-O-methylcytidylyl-(3'→5')-2'- O-methylguanylyl-(3'→5')-2'-O-methylcytidylyl-(3'→3')-thymidine, carbamate ester with monomethyl ether of polyethylene gycol (20 kDa)

egaptivon pégol aptamère pégylé qui se lie au facteur de von Willebrand; ester carbamique entre l'éther monométhylique du polyéthylèneglycol (macrogol 20 kDa) et le 5'-O-{[6- (carboxyamino)hexyl]hydroxyphosphoryl}-2'-O-méthylguanylyl- (3'→5')-2'-O-méthylcytidylyl-(3'→5')-2'-O-méthylguanylyl-(3'→5')-2'- O-méthyluridylyl-(3'→5')-2'-désoxyguanylyl-(3'→5')-2'- désoxycytidylyl-(3'→5')-2'-désoxyadénylyl-(3'→5')-2'-O- méthylguanylyl-(3'→5')-2'-O-méthyluridylyl-(3'→5')-2'-O- méthylguanylyl-(3'→5')-2'-O-méthylcytidylyl-(3'→5')-2'-O- méthylcytidylyl-(3'→5')-2'-O-méthyluridylyl-(3'→5')-2'-O- méthyluridylyl-(3'→5')-2'-O-méthylcytidylyl-(3'→5')-2'-O- méthylguanylyl-(3'→5')-2'-O-méthylguanylyl-(3'→5')-2'-O- méthylcytidylyl-(3'→5')-2'-désoxycytidylyl-(3'→5')-2'-O-méthyl-P- thioguanylyl-(3'→5')-thymidylyl-(3'→5')-2'-O-méthylguanylyl-(3'→5')- 2'-désoxycytidylyl-(3'→5')-2'-désoxyguanylyl-(3'→5')-2'- désoxyguanylyl-(3'→5')-thymidylyl-(3'→5')-2'-O-méthylguanylyl- (3'→5')-2'-O-méthylcytidylyl-(3'→5')-2'-désoxycytidylyl-(3'→5')-2'-O- méthyluridylyl-(3'→5')-2'-désoxycytidylyl-(3'→5')-2'-désoxycytidylyl- (3'→5')-2'-O-méthylguanylyl-(3'→5')-2'-O-méthyluridylyl-(3'→5')-2'- désoxycytidylyl-(3'→5')-2'-O-méthyladénylyl-(3'→5')-2'-O- méthylcytidylyl-(3'→5')-2'-O-méthylguanylyl-(3'→5')-2'-O- méthylcytidylyl-(3'→3')-thymidine

306 WHO Drug Information Vol. 25, No. 3, 2011 Recommended INN: List 66

egaptivón pegol aptámero pegilado que se une al factor de von Willebrand; éster carbámico entre el éter monometílico del polietilenglicol (macrogol 20 kDa) y el 5'-O-{[6-(carboxiamino)hexil]hidroxifosforil}- 2'-O-metilguanilil-(3'→5')-2'-O-metilcitidilil-(3'→5')-2'-O-metilguanilil- (3'→5')-2'-O-metiluridilil-(3'→5')-2'-desoxiguanilil-(3'→5')-2'- desoxicitidilil-(3'→5')-2'-desoxiadenilil-(3'→5')-2'-O-metilguanilil- (3'→5')-2'-O-metiluridilil-(3'→5')-2'-O-metilguanilil-(3'→5')-2'-O- metilcitidilil-(3'→5')-2'-O-metilcitidilil-(3'→5')-2'-O-metiluridilil-(3'→5')- 2'-O-metiluridilil-(3'→5')-2'-O-metilcitidilil-(3'→5')-2'-O-metilguanilil- (3'→5')-2'-O-metilguanilil-(3'→5')-2'-O-metilcitidilil-(3'→5')-2'- desoxicitidilil-(3'→5')-2'-O-metil-P-tioguanilil-(3'→5')-timidilil-(3'→5')- 2'-O-metilguanilil-(3'→5')-2'-desoxicitidilil-(3'→5')-2'-desoxiguanilil- (3'→5')-2'-desoxiguanilil-(3'→5')-timidilil-(3'→5')-2'-O-metilguanilil- (3'→5')-2'-O-metilcitidilil-(3'→5')-2'-desoxicitidilil-(3'→5')-2'-O- metiluridilil-(3'→5')-2'-desoxicitidilil-(3'→5')-2'-desoxicitidilil-(3'→5')-2'- O-metilguanilil-(3'→5')-2'-O-metiluridilil-(3'→5')-2'-desoxicitidilil- (3'→5')-2'-O-mtiladenilil-(3'→5')-2'-O-metilcitidilil-(3'→5')-2'-O- metilguanilil-(3'→5')-2'-O-metilcitidilil-(3'→3')-timidina

C413H546N144O275P40S (C2H4O)n

H N O CH3 O n O (3'-5')( pGmCm Gm Um dG dC dA Gm Um Gm Cm Cm

Um Cm Gm Gm Cm dC Gm sp dT Gm dC dG dG dT Gm Gm Cm dC Um dC dC Gm Um dC Am Cm Gm Cm3' 3'dT)

elobixibatum elobixibat [(2R)-2-(2-{[3,3-dibutyl-7-(methylsulfanyl)-1,1-dioxo-5-phenyl- 2,3,4,5-tetrahydro-1H-1λ6,5-benzothiazepin-8-yl]oxy}acetamido)- 2-phenylacetamido]acetic acid

élobixibat acide [(2R)-2-(2-{[3,3-dibutyl-7-(méthylsulfanyl)-1,1-dioxo-5-phényl- 2,3,4,5-tétrahydro-1H-1λ6,5-benzothiazépin-8-yl]oxy}acétamido)- 2-phénylacétamido]acétique

elobixibat ácido [(2R)-2-(2-{[3,3-dibutil-5-fenil-7-(metilsulfanil)-1,1-dioxo- 2,3,4,5-tetrahidro-1H-1λ6,5-benzotiazepin-8-il]oxi}acetamido)- 2-fenilacetamido]acético

C36H45N3O7S2

CH3

CH3 N S O H3C H N S O N CO2H H O O O H

307 Recommended INN: List 66 WHO Drug Information Vol. 25, No. 3, 2011

elsiglutidum elsiglutide [2-glycine(A>G),3-glutamic acid(D>E),8-serine(D>S),10- leucine(M>L),11-serine(N>S),16-alanine(N>A),24-alanine(N>A),28- alanine(Q>A)]human glucagon-like peptide 2 (GLP-2) fusion protein with hexalysinamide

elsiglutide [2-glycine(A>G),3-acide glutamique(D>E),8-sérine(D>S),10- leucine(M>L),11-sérine(N>S),16-alanine(N>A),24-alanine(N>A),28- alanine(Q>A)]peptide 2 semblable au glucagon humain (GLP-2) protéine de fusion avec l'hexalysinamide

elsiglutida [2-glicina(A>G),3-acide glutámico(D>E), 8-serina(D>S),10- leucina(M>L),11-serina(N>S),16-alanina(N>A),24-alanina(N>A),28- alanina(Q>A)]péptido 2 similar al glucagón humano(GLP-2) proteína de fusión con hexalisinamida

C196H323N53O56

HGEGSFSSEL STILDALAAR DFIAWLIATK ITDKKKKKK 39

Modified residue / Résidu modifié / Residuo modificado K lysinamide

empagliflozinum empagliflozin (1S)-1,5-anhydro-1-C-{4-chloro-3-[(4-{[(3S)-oxolan- 3-yl]oxy}phenyl)methyl]phenyl}-D-glucitol

empagliflozine (1S)-1,5-anhydro-1-C-{4-chloro-3-[(4-{[(3S)-oxolan- 3-yl]oxy]}phényl)méthyl]phényl}-D-glucitol

empagliflozina (1S)-1,5-anhidro-1-C-{4-cloro-3-[(4-{[(3S)-oxolan- 3-il]oxi}fenil)metil]fenil}-D-glucitol

C23H27ClO7

H O O

Cl

HO

O OH HO OH

308 WHO Drug Information Vol. 25, No. 3, 2011 Recommended INN: List 66

enavatuzumabum # enavatuzumab immunoglobulin G1-kappa, anti-[Homo sapiens TNFRSF12A (tumor necrosis factor receptor superfamily member 12A, fibroblast growth factor (FGF)-inducible 14 kDa protein, Fn14, TNF-like weak inducer of apoptosis (Tweak) receptor, Tweak receptor, TweakR, CD266], humanized monoclonal antibody; gamma1 heavy chain (1-449) [humanized VH (Homo sapiens IGHV3-7*01 (86.70%) -(IGHD)-IGHJ6*01 T123>L (114)) [8.10.10] (1-119) -Homo sapiens IGHG1*01 CH3 D12>E (358), L14>M (360) (120-449)], (222-218')-disulfide with kappa light chain (1'-218') [humanized V-KAPPA (Homo sapiens IGKV1-39*01 (84.80%) - IGKJ4*01) [10.3.9] (1'-111') -Homo sapiens IGKC*01 (112'-218')]; (228-228":231-231")-bisdisulfide dimer

énavatuzumab immunoglobuline G1-kappa, anti-[Homo sapiens TNFRSF12A (membre 12A de la superfamille des récepteurs du facteur de nécrose tumorale, protéine de 14 kDa induite par le facteur de croissance du fibroblaste (FGF), Fn14, TNF-like faible inducteur d'apoptose (Tweak), récepteur de Tweak, CD266], anticorps monoclonal humanisé; chaîne lourde gamma1 (1-449) [VH humanisé (Homo sapiens IGHV3-7*01 (86.70%) -(IGHD)-IGHJ6*01 T123>L (114)) [8.10.10] (1-119) -Homo sapiens IGHG1*01 CH3 D12>E (358), L14>M (360) (120-449)], (222-218')-disulfure avec la chaîne légère kappa (1'-218') [V-KAPPA humanisé (Homo sapiens IGKV1-39*01 (84.80%) - IGKJ4*01) [10.3.9] (1'-111') -Homo sapiens IGKC*01 (112'-218')]; dimère (228-228":231-231")-bisdisulfure

enavatuzumab inmunoglobulina G1-kappa, anti-[TNFRSF12A de Homo sapiens (miembro 12A de la superfamilia de receptores del factor de necrosis tumoral, proteína de 14 kDa inducida por el factor de crecimiento de fibroblastos (FGF), Fn14, TNF-like débil inductor de apoptosis (Tweak), receptor de Tweak, CD266], anticuerpo monoclonal humanizado; cadena pesada gamma1 (1-449) [VH humanizada (Homo sapiens IGHV3-7*01 (86.70%) -(IGHD)-IGHJ6*01 T123>L (114)) [8.10.10] (1-119) -Homo sapiens IGHG1*01 CH3 D12>E (358), L14>M (360) (120-449)], (222-218')-disulfuro con la cadena ligera kappa (1'-218') [V-KAPPA humanizada (Homo sapiens IGKV1-39*01 (84.80%) - IGKJ4*01) [10.3.9] (1'-111') -Homo sapiens IGKC*01 (112'-218')]; dímero (228-228":231-231")-bisdisulfuro

Heavy chain / Chaîne lourde / Cadena pesada EVQLVESGGG LVQPGGSLRL SCAASGFTFS SYWMSWVRQA PGKGLEWVAE 50 IRLKSDNYAT HYAESVKGRF TISRDDSKNS LYLQMNSLRA EDTAVYYCTG 100 YYADAMDYWG QGTLVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD 150 YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY 200 ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK 250 DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS 300 TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV 350 YTLPPSREEM TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL 400 DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK 449 Light chain / Chaîne légère / Cadena ligera DIQMTQSPSS LSASVGDRVT ITCRASQSVS TSSYSYMHWY QQKPGKAPKL 50 LIKYASNLES GVPSRFSGSG SGTDFTLTIS SLQPEDFATY YCQHSWEIPY 100 TFGGGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKV 150 QWKVDNALQS GNSQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEV 200 THQGLSSPVT KSFNRGEC 218 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-98 146-202 263-323 369-427 22''-98'' 146''-202'' 263''-323'' 369''-427'' Intra-L 23'-92' 138'-198' 23'''-92''' 138'''-198''' Inter-H-L 222-218' 222''-218''' Inter-H-H 228-228'' 231-231''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 299, 299''

309 Recommended INN: List 66 WHO Drug Information Vol. 25, No. 3, 2011

enokizumabum # enokizumab immunoglobulin G1-kappa, anti-[Homo sapiens IL9 (interleukin 9, IL-9, T cell growth factor p40)], humanized monoclonal antibody; gamma1 heavy chain (1-452) [humanized VH (Homo sapiens IGHV1-69*11 (87.80%) -(IGHD)-IGHJ4*01) [8.8.15] (1-122) -Homo sapiens IGHG1*03 (123-452)], (225-214')-disulfide with kappa light chain (1'-214') [humanized V-KAPPA (Homo sapiens IGKV1-39*01 (83.20%) -IGKJ4*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'- 214')]; (231-231":234-234")-bisdisulfide dimer

énokizumab immunoglobuline G1-kappa, anti-[Homo sapiens IL9 (interleukine 9, IL-9, facteur de croissance p40 des cellules T)], anticorps monoclonal humanisé; chaîne lourde gamma1 (1-452) [VH humanisé (Homo sapiens IGHV1-69*11 (87.80%) -(IGHD)-IGHJ4*01) [8.8.15] (1-122) -Homo sapiens IGHG1*03 (123-452)], (225-214')-disulfure avec la chaîne légère kappa (1'-214') [V-KAPPA humanisé (Homo sapiens IGKV1- 39*01 (83.20%) -IGKJ4*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dimère (231-231":234-234")-bisdisulfure

enokizumab inmunoglobulina G1-kappa, anti-[IL9 de Homo sapiens (interleukina 9, IL-9, factor de crecimiento p40 de células T)], anticuerpo monoclonal humanizado; cadena pesada gamma1 (1-452) [VH humanizada (Homo sapiens IGHV1-69*11 (87.80%) -(IGHD)-IGHJ4*01) [8.8.15] (1-122) -Homo sapiens IGHG1*03 (123-452)], (225-214')-disulfuro con la cadena ligera kappa (1'-214') [V-KAPPA humanizada (Homo sapiens IGKV1- 39*01 (83.20%) -IGKJ4*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dímero (231-231":234-234")-bisdisulfuro

Heavy chain / Chaîne lourde / Cadena pesada QVQLVQSGAE VKKPGSSVKV SCKASGGTFS YYWIEWVRQA PGQGLEWMGE 50 ILPGSGTTNP NEKFKGRVTI TADESTSTAY MELSSLRSED TAVYYCARAD 100 YYGSDYVKFD YWGQGTLVTV SSASTKGPSV FPLAPSSKST SGGTAALGCL 150 VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT 200 QTYICNVNHK PSNTKVDKRV EPKSCDKTHT CPPCPAPELL GGPSVFLFPP 250 KPKDTLMISR TPEVTCVVVD VSHEDPEVKF NWYVDGVEVH NAKTKPREEQ 300 YNSTYRVVSV LTVLHQDWLN GKEYKCKVSN KALPAPIEKT ISKAKGQPRE 350 PQVYTLPPSR EEMTKNQVSL TCLVKGFYPS DIAVEWESNG QPENNYKTTP 400 PVLDSDGSFF LYSKLTVDKS RWQQGNVFSC SVMHEALHNH YTQKSLSLSP 450 GK 452 Light chain / Chaîne légère / Cadena ligera DIQMTQSPSS LSASVGDRVT ITCKASQHVI THVTWYQQKP GKAPKLLIYG 50 TSYSYSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQQ FYEYPLTFGG 100 GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150 DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200 LSSPVTKSFN RGEC 214

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 149-205 266-326 372-430 22''-96'' 149''-205'' 266''-326'' 372''-430'' Intra-L 23'-88' 134'-194' 23'''-88''' 134'''-194''' Inter-H-L 225-214' 225''-214''' Inter-H-H 231-231'' 234-234''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 302, 302''

erteberelum erteberel (3aS,4R,9bR)-4-(4-hydroxyphenyl)-1,2,3,3a,4,9b- hexahydrocyclopenta[c]chromen-8-ol

ertébérel (3aS,4R,9bR)-4(4-hydroxyphényl)-1,2,3,3a,4,9b- hexahydrocyclopenta[c][1]chromén-8-ol

310 WHO Drug Information Vol. 25, No. 3, 2011 Recommended INN: List 66

erteberel (3aS,4R,9bR)-4-(4-hidroxifenil)-1,2,3,3a,4,9b- hexahidrociclopenta[c]cromen-8-ol

C18H18O3

H H OH H O

HO

etrolizumabum # etrolizumab immunoglobulin G1-kappa, anti-[Homo sapiens integrins ITGA4_ITGB7 (integrin alpha4 (CD49d)_beta7, integrin α4β7, lymphocyte Peyer's patch adhesion molecule 1, LPAM-1) and ITGAE_ITGB7 (integrin alphaE (CD103, alphaIEL)_beta7, integrin αEβ7, HML-1], humanized monoclonal antibody; gamma1 heavy chain (1-446) [humanized VH (Homo sapiens IGHV3-66*01 (81.40%) -(IGHD)-IGHJ4*01) [8.7.11] (1-117) -Homo sapiens IGHG1*01 CH3 D12>E (356), L14>M (358), K130>del (118- 446)], (220-214')-disulfide with kappa light chain (1'-214') [humanized V-KAPPA (Homo sapiens IGKV1-39*01 (85.30%) -IGKJ1*01) [6.4.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; (226-226":229-229")- bisdisulfide dimer

étrolizumab immunoglobuline G1-kappa, anti-[Homo sapiens intégrines ITGA4_ITGB7 (intégrine alpha4 (CD49d)_bêta7, intégrine α4β7, récepteur d'adressage spécifique des plaques de Peyer, LPAM-1) et ITGAE_ITGB7 (intégrine alphaE (CD103, alphaIEL)_bêta7, intégrine αEβ7, HML1)], anticorps monoclonal humanisé; chaîne lourde gamma1 (1-446) [VH humanisé (Homo sapiens IGHV3-66*01 (81.40%) -(IGHD)-IGHJ4*01) [8.7.11] (1-117) -Homo sapiens IGHG1*01 CH3 D12>E (356), L14>M (358), K130>del (118- 446)], (220-214')-disulfure avec la chaîne légère kappa (1'-214') [V-KAPPA humanisé (Homo sapiens IGKV1-39*01 (85.30%) - IGKJ1*01) [6.4.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dimère (226-226":229-229")-bisdisulfure

etrolizumab immunoglobuline G1-kappa, anti-[integrinas ITGA4_ITGB7 de Homo sapiens (integrina alfa4 (CD49d)_beta7, integrina α4β7, molécula de adhesión específica de linfocitos de las placas de Peyer, LPAM-1) e ITGAE_ITGB7 (integrina alfaE (CD103, alfaIEL)_beta7, integrina αEβ7, HML1)], anticuerpo monoclonal humanizado; cadena pesada gamma1 (1-446) [VH humanizada (Homo sapiens IGHV3-66*01 (81.40%) -(IGHD)-IGHJ4*01) [8.7.11] (1-117) -Homo sapiens IGHG1*01 CH3 D12>E (356), L14>M (358), K130>del (118- 446)], (220-214')-disulfuro con la cadena ligera kappa (1'-214') [V-KAPPA humanizado (Homo sapiens IGKV1-39*01 (85.30%) - IGKJ1*01) [6.4.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dímero (226-226":229-229")-bisdisulfuro

311 Recommended INN: List 66 WHO Drug Information Vol. 25, No. 3, 2011

Heavy chain / Chaîne lourde / Cadena pesada EVQLVESGGG LVQPGGSLRL SCAASGFFIT NNYWGWVRQA PGKGLEWVGY 50 ISYSGSTSYN PSLKSRFTIS RDTSKNTFYL QMNSLRAEDT AVYYCARTGS 100 SGYFDFWGQG TLVTVSSAST KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF 150 PEPVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSVVTVPS SSLGTQTYIC 200 NVNHKPSNTK VDKKVEPKSC DKTHTCPPCP APELLGGPSV FLFPPKPKDT 250 LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY 300 RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK GQPREPQVYT 350 LPPSREEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS 400 DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPG 446 Light chain / Chaîne légère / Cadena ligera DIQMTQSPSS LSASVGDRVT ITCRASESVD DLLHWYQQKP GKAPKLLIKY 50 ASQSISGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQQ GNSLPNTFGQ 100 GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150 DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200 LSSPVTKSFN RGEC 214

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-95 144-200 261-321 367-425 22''-95'' 144''-200'' 261''-321'' 367''-425'' Intra-L 23'-88' 134'-194' 23'''-88''' 134'''-194''' Inter-H-L 220-214' 220''-214''' Inter-H-H 226-226'' 229-229''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 297, 297''

florbenazinum (18F) florbenazine (18F) (2R,3R,11bR)-9-(3-[18F]fluoropropoxy)-10-methoxy- 3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinolin-2-ol

florbénazine (18F) (2R,3R,11bR)-9-(3-[18F]fluoropropoxy)-10-méthoxy- 3-(2-méthylpropyl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinoléin-2-ol

florbenazina (18F) (2R,3R,11bR)-9-(3-[18F]fluoropropoxi)-3-(2-metilpropil)-10-metoxi- 1,3,4,6,7,11b-hexahidro-2H-pirido[2,1-a]isoquinolin-2-ol

18 C21H32 FNO3

H OH

CH3 H H H3CO CH3 N

18 [ F] O

forigerimodum forigerimod O3,140-phosphono(human U1 small nuclear ribonucleoprotein 70 kDa (snRNP70))-(131-151)-peptide

forigérimod O3,140-phosphono(petite ribonucléoprotéine nucléaire U1 humaine de 70 kDa (snRNP70))-(131-151)-peptide

forigerimod O3,140-fosfono(pequeña ribonucleoproteína nuclear U1 humana de 70 kDa (snRNP70))-(131-151)-péptido

312 WHO Drug Information Vol. 25, No. 3, 2011 Recommended INN: List 66

C117H181N34O32PS

RIHMVYSKRS GKPRGYAFIE Y 21

Modified residues / Résidus modifiés / Residuos modificados OH S OH 10 O P O3,10-phosphono O H (phosphoserine) N C H O fulranumabum # fulranumab immunoglobulin G2-kappa, anti-[Homo sapiens NGF (nerve growth factor, nerve growth factor beta polypeptide, NGFB, beta-NGF)], Homo sapiens monoclonal antibody; gamma2 heavy chain (1-449) [Homo sapiens VH (IGHV3-48*02 (92.90%) -(IGHD)-IGHJ4*01) [8.8.16] (1-123) -IGHG2*01 (124-449)], (137-214')-disulfide with kappa light chain (1'-214') [Homo sapiens V-KAPPA (IGKV1-13*02 (100.00%) -IGKJ4*01) [6.3.9] (1'-107') - IGKC*01 (108'-214')]; (225-225'':226-226':229-229'':232-232''')- tetrakisdisulfide dimer

fulranumab immunoglobuline G2-kappa, anti-[Homo sapiens NGF (facteur de croissance du nerf, facteur de croissance du nerf polypeptide bêta, NGFB, bêta-NGF)], Homo sapiens anticorps monoclonal; chaîne lourde gamma2 (1-449) [Homo sapiens VH (IGHV3-48*02 (92.90%) -(IGHD)-IGHJ4*01) [8.8.16] (1-123) -IGHG2*01 (124-449)], (137-214')-disulfure avec la chaîne légère kappa (1'-214') [Homo sapiens V-KAPPA (IGKV1-13*02 (100.00%) -IGKJ4*01) [6.3.9] (1'- 107') -IGKC*01 (108'-214')]; dimère (225-225'':226-226':229- 229'':232-232''')-tétrakisdisulfure

fulranumab inmunoglobulina G2-kappa, anti-[NGF de Homo sapiens (factor de crecimiento de nervios, factor de crecimiento de nervios polipétido beta, NGFB, beta-NGF)], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma2 (1-449) [Homo sapiens VH (IGHV3-48*02 (92.90%) -(IGHD)-IGHJ4*01) [8.8.16] (1-123) -IGHG2*01 (124-449)], (137-214')-disulfuro con la cadena ligera kappa (1'-214') [Homo sapiens V-KAPPA (IGKV1-13*02 (100.00%) -IGKJ4*01) [6.3.9] (1'- 107') -IGKC*01 (108'-214')]; dímero (225-225'':226-226':229- 229'':232-232''')-tetrakisdisulfuro

Heavy chain / Chaîne lourde / Cadena pesada EVQLVESGGG LVQPGGSLRL SCAASGFTLR SYSMNWVRQA PGKGLEWVSY 50 ISRSSHTIFY ADSVKGRFTI SRDNAKNSLY LQMDSLRDED TAMYYCARVY 100 SSGWHVSDYF DYWGQGILVT VSSASTKGPS VFPLAPCSRS TSESTAALGC 150 LVKDYFPEPV TVSWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSNFG 200 TQTYTCNVDH KPSNTKVDKT VERKCCVECP PCPAPPVAGP SVFLFPPKPK 250 DTLMISRTPE VTCVVVDVSH EDPEVQFNWY VDGVEVHNAK TKPREEQFNS 300 TFRVVSVLTV VHQDWLNGKE YKCKVSNKGL PAPIEKTISK TKGQPREPQV 350 YTLPPSREEM TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPML 400 DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK 449 Light chain / Chaîne légère / Cadena ligera AIQLTQSPSS LSASVGDRVT ITCRASQGIS SALAWYQQKP GKAPKLLIYD 50 ASSLESGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQQ FNSYPLTFGG 100 GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150 DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200 LSSPVTKSFN RGEC 214 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 150-206 263-323 369-427 22''-96'' 150''-206'' 263''-323'' 369''-427'' Intra-L 23'-88' 134'-194' 23'''-88''' 134'''-194''' Inter-H-L 137-214' 137''-214''' Inter-H-H 225-225'' 226-226'' 229-229'' 232-232''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 299, 299''

313 Recommended INN: List 66 WHO Drug Information Vol. 25, No. 3, 2011

gaxilosum gaxilose 4-O-β-D-galactopyranosyl-D-xylose

gaxilose 4-O-β-D-galactopyranosyl-D-xylose

gaxilosa 4-O-β-D-galactopiranosil-D-xilosa

C11H20O10

O HO OH OH HO O O OH OH

OH

gevokizumabum # gevokizumab immunoglobulin G2-kappa, anti-[Homo sapiens IL1B (interleukin 1 beta, 1L1F2, IL-1B)], humanized monoclonal antibody; gamma2 heavy chain (1-445) [humanized VH (Homo sapiens IGHV2-5*10 (72.70%) -(IGHD)-IGHJ5*01) [10.7.12] (1-120) -Homo sapiens IGHG2*02 CH3 K130>del (121-445)], (134-214')-disulfide with kappa light chain (1'-214') [humanized V-KAPPA (Homo sapiens IGKV1-39*01 (82.10%) -IGKJ1*01 V124>L (104')) [6.3.9] (1'-107') - Homo sapiens IGKC*01 (108'-214')]; (222-222":223-223":226- 226":229-229")-tetrakisdisulfide dimer

gévokizumab immunoglobuline G2-kappa, anti-[Homo sapiens IL1B (interleukine 1 bêta, 1L1F2, IL-1B)], anticorps monoclonal humanisé; chaîne lourde gamma2 (1-445) [VH humanisé (Homo sapiens IGHV2-5*10 (72.70%) -(IGHD)-IGHJ5*01) [10.7.12] (1-120) -Homo sapiens IGHG2*02 CH3 K130>del (121-445)], (134-214')-disulfure avec la chaîne légère kappa (1'-214') [V-KAPPA humanisé (Homo sapiens IGKV1-39*01 (82.10%) -IGKJ1*01 V124>L (104')) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dimère (222- 222":223-223":226-226":229-229")-tétrakisdisulfure

gevokizumab inmunoglobulina G2-kappa, anti-[IL1B de Homo sapiens (interleukina 1 beta, 1L1F2, IL-1B)], anticuerpo monoclonal humanizado; cadena pesada gamma2 (1-445) [VH humanizada (Homo sapiens IGHV2-5*10 (72.70%) -(IGHD)-IGHJ5*01) [10.7.12] (1-120) -Homo sapiens IGHG2*02 CH3 K130>del (121-445)], (134-214')-disulfuro con la cadena ligera kappa (1'-214') [V-KAPPA humanizado (Homo sapiens IGKV1-39*01 (82.10%) -IGKJ1*01 V124>L (104')) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dímero (222- 222":223-223":226-226":229-229")-tetrakisdisulfuro

314 WHO Drug Information Vol. 25, No. 3, 2011 Recommended INN: List 66

Heavy chain / Chaîne lourde / Cadena pesada QVQLQESGPG LVKPSQTLSL TCSFSGFSLS TSGMGVGWIR QPSGKGLEWL 50 AHIWWDGDES YNPSLKSRLT ISKDTSKNQV SLKITSVTAA DTAVYFCARN 100 RYDPPWFVDW GQGTLVTVSS ASTKGPSVFP LAPCSRSTSE STAALGCLVK 150 DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VTSSNFGTQT 200 YTCNVDHKPS NTKVDKTVER KCCVECPPCP APPVAGPSVF LFPPKPKDTL 250 MISRTPEVTC VVVDVSHEDP EVQFNWYVDG MEVHNAKTKP REEQFNSTFR 300 VVSVLTVVHQ DWLNGKEYKC KVSNKGLPAP IEKTISKTKG QPREPQVYTL 350 PPSREEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPMLDSD 400 GSFFLYSKLT VDKSRWQQGN VFSCSVMHEA LHNHYTQKSL SLSPG 445 Light chain / Chaîne légère / Cadena ligera DIQMTQSTSS LSASVGDRVT ITCRASQDIS NYLSWYQQKP GKAVKLLIYY 50 TSKLHSGVPS RFSGSGSGTD YTLTISSLQQ EDFATYFCLQ GKMLPWTFGQ 100 GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150 DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200 LSSPVTKSFN RGEC 214

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-97 147-203 260-320 366-424 22''-97'' 147''-203'' 260''-320'' 366''-424'' Intra-L 23'-88' 134'-194' 23'''-88''' 134'''-194''' Inter-H-L 134-214' 134''-214''' Inter-H-H 222-222'' 223-223'' 226-226'' 229-229''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 296, 296''

granotapidum granotapide diethyl 2-({2-[3-(dimethylcarbamoyl)-4-{4'-(trifluoromethyl)- [1,1'-biphenyl]-2-carboxamido}phenyl]acetyloxy}methyl)- 2-phenylpropanedioate

granotapide 2-[({2-[3-(diméthylcarbamoyl)-4-({[4'-(trifluorométhyl)-[1,1'-biphényl]- 2-yl-carboxamido)phényl]acétyl}oxy)méthyl]-2-phénylpropanedioate de diéthyle

granotapida 2-({2-[3-(dimetilcarbamoil)-4-{4'-(trifluorometil)-[1,1'-bifenil]- 2-carboxamido}fenil]acetiloxi}metil)-2-fenilpropanodioato de dietilo

C39H37F3N2O8

CF3 H C CH 3 O O 3

O O O O O N H CH3 O N

CH3

icrucumabum # icrucumab immunoglobulin G1-kappa, anti-[Homo sapiens FLT1 (fms-related tyrosine kinase 1, vascular endothelial growth factor receptor 1, VEGFR-1, VEGFR, FLT, FRT, vascular permeability factor receptor)], Homo sapiens monoclonal antibody; gamma1 heavy chain (1-456) [Homo sapiens VH (IGHV3-33*01 (93.90%) -(IGHD)-IGHJ6*01 [8.8.19] (1-126) -IGHG1*03 (127-456)], (229-215')-disulfide with kappa light chain (1'-215') [Homo sapiens V-KAPPA (IGKV3-20*01 (100.00%) -IGKJ4*01) [7.3.9] (1'-108') - IGKC1*01 (109'-215')]; (235-235'':238-238'')-bisdisulfide dimer

315 Recommended INN: List 66 WHO Drug Information Vol. 25, No. 3, 2011

icrucumab immunoglobuline G1 kappa, anti-[Homo sapiens FLT1 (tyrosine kinase 1 apparentée au fms, récepteur 1 du facteur de croissance endothélial vasculaire, VEGFR-1, VEGFR, FLT, FRT, récepteur du facteur de perméabilité vasculaire)], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-456) [Homo sapiens VH (IGHV3-33*01 (93.90%) -(IGHD)-IGHJ6*01 [8.8.19] (1-126) -IGHG1*03 (127-456)), (229-215')-disulfure avec la chaîne légère kappa (1'-215') [Homo sapiens V-KAPPA (IGKV3-20*01 (100.00%) -IGKJ4*01) [7.3.9] (1'-108') -IGKC1*01 (109'-215')]; dimère (235-235'':238-238'')- bisdisulfure

icrucumab inmunoglobulina G1 kappa, anti-[Homo sapiens FLT1 (tirosin kinasa 1 emparentada con el fms, receptor 1 del factor de crecimiento endotelial vascular, VEGFR-1, VEGFR, FLT, FRT, receptor del factor de permeabilidad vascular)], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma1 (1-456) [Homo sapiens VH (IGHV3-33*01 (93.90%) -(IGHD)-IGHJ6*01 [8.8.19] (1-126) -IGHG1*03 (127-456)), (229-215')-disulfuro con la cadena ligera kappa (1'-215') [Homo sapiens V-KAPPA (IGKV3-20*01 (100.00%) -IGKJ4*01) [7.3.9] (1'-108') -IGKC1*01 (109'-215')]; dímero (235-235'':238-238'')- bisdisulfuro

Heavy chain / Chaîne lourde / Cadena pesada QAQVVESGGG VVQSGRSLRL SCAASGFAFS SYGMHWVRQA PGKGLEWVAV 50 IWYDGSNKYY ADSVRGRFTI SRDNSENTLY LQMNSLRAED TAVYYCARDH 100 YGSGVHHYFY YGLDVWGQGT TVTVSSASTK GPSVFPLAPS SKSTSGGTAA 150 LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS 200 SLGTQTYICN VNHKPSNTKV DKRVEPKSCD KTHTCPPCPA PELLGGPSVF 250 LFPPKPKDTL MISRTPEVTC VVVDVSHEDP EVKFNWYVDG VEVHNAKTKP 300 REEQYNSTYR VVSVLTVLHQ DWLNGKEYKC KVSNKALPAP IEKTISKAKG 350 QPREPQVYTL PPSREEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY 400 KTTPPVLDSD GSFFLYSKLT VDKSRWQQGN VFSCSVMHEA LHNHYTQKSL 450 SLSPGK 456 Light chain / Chaîne légère / Cadena ligera EIVLTQSPGT LSLSPGERAT LSCRASQSVS SSYLAWYQQK PGQAPRLLIY 50 GASSRATGIP DRFSGSGSGT DFTLTISRLE PEDFAVYYCQ QYGSSPLTFG 100 GGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK 150 VDNALQSGNS QESVTEQDSK DSTYSLSSTL TLSKADYEKH KVYACEVTHQ 200 GLSSPVTKSF NRGEC 215 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 153-209 270-330 376-434 22''-96'' 153''-209'' 270''-330'' 376''-434'' Intra-L 23'-89' 135'-195' 23'''-89''' 135'''-195''' Inter-H-L 229-215' 229''-215''' Inter-H-H 235-235'' 238-238''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 306, 306''

irosustatum irosustat 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta[c]chromen-3-yl sulfamate

irosustat sulfamate de 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta[c]chromèn- 3-yle

irosustat sulfamato de 6-oxo-6,7,8,9,10,11-hexahidrociclohepta[c]cromen-3-ilo

316 WHO Drug Information Vol. 25, No. 3, 2011 Recommended INN: List 66

C14H15NO5S

O NH2 S OO

O

O

ivacaftorum ivacaftor N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline- 3-carboxamide

ivacaftor N-[2,4-di-tert-butyl-5-hydroxyphényl]-4-oxo-1,4-dihydroquinoléine- 3-carboxamide

ivacaftor N-(2,4-di-terc-butil-5-hidroxifenil)-4-oxo-1,4-dihidroquinolina- 3-carboxamida

C24H28N2O3

H CH3 N H3C CH3 H N CH O O 3 CH3 OH CH3

ixazomibum ixazomib {(1R)-1-[(2,5-dichlorobenzamido)acetamido]-3-methylbutyl}boronic acid

ixazomib acide [(1R)-1-{[N-(2,5-dichlorobenzoyl)glycyl]amino}- 3-méthylbutyl]boronique

ixazomib acido {(1R)-1-[(2,5-diclorobenzamido)acetamido]- 3-metilbutil]borónico

C14H19BCl2N2O4

O OH H Cl N B N OH H H O CH3 Cl

CH3

lenvatinibum lenvatinib 4-{3-chloro-4-[(cyclopropylcarbamoyl)amino]phenoxy}- 7-methoxyquinoline-6-carboxamide

lenvatinib 4-{3-chloro-4-[(cyclopropylcarbamoyl)amino]phénoxy}- 7-méthoxyquinoléine-6-carboxamide

lenvatinib 4-{3-cloro-4-[(ciclopropilcarbamoil)amino]fenoxi}-7-metoxiquinolina- 6-carboxamida

317 Recommended INN: List 66 WHO Drug Information Vol. 25, No. 3, 2011

C21H19ClN4O4

H3CO N

H2N

O O O

N N H H Cl

letaxabanum letaxaban 1-(1-{(2S)-3-[(6-chloronaphthalen-2-yl)sulfonyl]- 2-hydroxypropanoyl}piperidin-4-yl)tetrahydropyrimidin-2(1H)-one

létaxaban 1-(1-{(2S)-3-[(6-chloronaphtalén-2-yl)sulfonyl]- 2-hydroxypropanoyl}pipéridin-4-yl)tétrahydropyrimidin-2(1H)-one

letaxabán 1-(1-{(2S)-3-[(6-cloronaftalen-2-il)sulfonil]- 2-hidroxipropanoil}piperidin-4-il)tetrahidropirimidin-2(1H)-ona

C22H26ClN3O5S

Cl O

N S HO H OO N

N O H

letermovirum letermovir (4S)-2-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy- 5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid

létermovir acide {(4S)-8-fluoro-2-[4-(3-méthoxyphényl)pipérazin-1-yl]- 3-[2-méthoxy-5-(trifluorométhyl)phényl]-3,4-dihydroquinazolin- 4-yl}acétique

letermovir ácido (4S)-2-{8-fluoro-2-[4-(3-metoxifenil)piperazin-1-il]-3-[2-metoxi- 5-(trifluorometil)fenil]-3,4-dihidroquinazolin-4-il}acético

C29H28F4N4O4

F3C

H3CO N OCH3 H N N

N CO2H

F

318 WHO Drug Information Vol. 25, No. 3, 2011 Recommended INN: List 66

levoglucosum levoglucose L-glucose

lévoglucose L-glucose

levoglucosa L-glucosa

C6H12O6

HO O HO OH HO

OH

linsitinibum linsitinib (1s,3r)-3-[8-amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin- 3-yl]-1-methylcyclobutan-1-ol

linsitinib (1s,3r)-3-[8-amino-1-(2-phénylquinoléin-7-yl)imidazo[1,5-a]pyrazin- 3-yl]-1-méthylcyclobutan-1-ol

linsitinib (1s,3r)-3-[8-amino-1-(2-fenilquinolin-7-il)imidazo[1,5-a]pirazin-3-il]- 1-metilciclobutan-1-ol

C26H23N5O

N OH NH H3C N 2

N H N

luseogliflozinum luseogliflozin (2S,3R,4R,5S,6R)-2-{5-[(4-ethoxyphenyl)methyl]-2-methoxy- 4-methylphenyl}-6-(hydroxymethyl)thiane-3,4,5-triol

luséogliflozine (2S,3R,4R,5S,6R)-2-{5-[(4-éthoxyphényl)méthyl]-2-méthoxy- 4-méthylphényl}-6-(hydroxyméthyl)thiane-3,4,5-triol

luseogliflozina (2S,3R,4R,5S,6R)-2-{5-[(4-etoxifenil)metil]-4-metilfenil-2-metoxi}- 6-(hidroximetil)tiano-3,4,5-triol

C23H30O6S

O CH3

CH3

HO

S OCH3 OH HO OH

319 Recommended INN: List 66 WHO Drug Information Vol. 25, No. 3, 2011

lusutrombopagum lusutrombopag (2E)-3-{2,6-dichloro-4-[(4-{3-[(1S)-1-(hexyloxy)ethyl]- 2-methoxyphenyl}-1,3-thiazol-2-yl)carbamoyl]phenyl}-2-methylprop- 2-enoic acid

lusutrombopag acide (2E)-3-{2,6-dichloro-4-[(4-{3-[(1S)-1-(hexyloxy)éthyl]- 2-méthoxyphényl}-1,3-thiazol-2-yl)carbamoyl]phényl}-2-méthylprop- 2-énoïque

lusutrombopag ácido (2E)-3-{2,6-dicloro-4-[(4-{3-[(1S)-1-(hexiloxi)etil]-2-metoxifenil}- 1,3-tiazol-2-il)carbamoil]fenil}-2-metilprop-2-enoico

C29H32Cl2N2O5S

S O Cl N N CH3 H

OCH3 CO2H

CH3 Cl H3C O H

mavoglurantum mavoglurant methyl (3aR,4S,7aR)-4-hydroxy- 4-[2-(3-methylphenyl)ethynyl]octahydro-1H-indole-1-carboxylate

mavoglurant (3aR,4S,7aR)-4-hydroxy-4-[2-(3-méthylphényl)éthynyl]octahydro- 1H-indole-1-carboxylate de méthyle

mavoglurant (3aR,4S,7aR)-4-hidroxi-4-[2-(3-metilfenil)etinil]octahidro-1H-indol- 1-carboxilato de metil

C19H23NO3

H H O

HO N O CH3 H3C

mogamulizumabum # mogamulizumab immunoglobulin G1-kappa, anti-[Homo sapiens CCR4 (chemokine (C-C motif) receptor 4, CC chemokine receptor 4, CCR-4, CKR4, k5-5, CD194)], humanized monoclonal antibody; gamma1 heavy chain (1-449) [humanized VH (Homo sapiens IGHV3-21*01 (83.70%) -(IGHD)-IGHJ4*01) [8.8.12] (1-119) -Homo sapiens IGHG1*01 (120-449)], (222-219')-disulfide with kappa light chain (1'-219') [humanized V-KAPPA (Homo sapiens IGKV2-29*02 (81.00%) -IGKJ1*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; (228-228":231-231")-bisdisulfide dimer

mogamulizumab immunoglobuline G1-kappa, anti-[Homo sapiens CCR4 (récepteur 4 de chimiokine (C-C motif), récepteur 4 de chimiokine CC, CCR-4, CKR4, k5-5, CD194)], anticorps monoclonal humanisé; chaîne lourde gamma1 (1-449) [VH humanisé (Homo sapiens IGHV3-21*01 (83.70%) -(IGHD)-IGHJ4*01) [8.8.12] (1-119) -Homo sapiens IGHG1*01 (120-449)], (222-219')-disulfure avec la chaîne légère kappa (1'-219') [V-KAPPA humanisé (Homo sapiens IGKV2- 29*02 (81.00%) -IGKJ1*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; dimère (228-228":231-231")-bisdisulfure

320 WHO Drug Information Vol. 25, No. 3, 2011 Recommended INN: List 66

mogamulizumab inmunoglobulina G1-kappa, anti-[CCR4 de Homo sapiens (receptor 4 de quimiokina (C-C motif), receptor 4 de quimiokina CC, CCR-4, CKR4, k5-5, CD194)], anticuerpo monoclonal humanizado; cadena pesada gamma1 (1-449) [VH humanizada (Homo sapiens IGHV3-21*01 (83.70%) -(IGHD)-IGHJ4*01) [8.8.12] (1-119) -Homo sapiens IGHG1*01 (120-449)], (222-219')-disulfuro con la cadena ligera kappa (1'-219') [V-KAPPA humanizada (Homo sapiens IGKV2- 29*02 (81.00%) -IGKJ1*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; dímero (228-228":231-231")-bisdisulfuro

Heavy chain / Chaîne lourde / Cadena pesada EVQLVESGGD LVQPGRSLRL SCAASGFIFS NYGMSWVRQA PGKGLEWVAT 50 ISSASTYSYY PDSVKGRFTI SRDNAKNSLY LQMNSLRVED TALYYCGRHS 100 DGNFAFGYWG QGTLVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD 150 YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY 200 ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK 250 DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS 300 TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV 350 YTLPPSRDEL TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL 400 DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK 449 Light chain / Chaîne légère / Cadena ligera DVLMTQSPLS LPVTPGEPAS ISCRSSRNIV HINGDTYLEW YLQKPGQSPQ 50 LLIYKVSNRF SGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCFQGSLLP 100 WTFGQGTKVE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK 150 VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE 200 VTHQGLSSPV TKSFNRGEC 219 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 146-202 263-323 369-427 22''-96'' 146''-202'' 263''-323'' 369''-427'' Intra-L 23'-93' 139'-199' 23'''-93''' 139'''-199''' Inter-H-L 222-219' 222''-219''' Inter-H-H 228-228'' 231-231''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 299, 299''

namilumabum # namilumab immunoglobulin G1-kappa, anti-[Homo sapiens CSF2 (Homo sapiens colony stimulating factor 2 (granulocyte-macrophage), granulocyte-macrophage colony stimulating factor, GM-CSF)], Homo sapiens monoclonal antibody; gamma1 heavy chain (1-449) [Homo sapiens VH (IGHV1-2*02 (89.80%) -(IGHD)-IGHJ4*01 L123>M (114)) [8.8.12] (1-119) - IGHG1*01 (120-449)], (222-214')-disulfide with kappa light chain (1'-214') [Homo sapiens V-KAPPA (IGKV1-39*01 (88.40%) - IGKJ4*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; (228-228'':231- 231'')-bisdisulfide dimer

namilumab immunoglobuline G1-kappa, anti-[Homo sapiens CSF2 (Homo sapiens facteur 2 stimulant de colonies (granulocyte-macrophage), facteur stimulant des colonies de granulocytes et macrophages, GM-CSF)], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-449) [Homo sapiens VH (IGHV1-2*02 (89.80%) -(IGHD)-IGHJ4*01 L123>M (114)) [8.8.12] (1-119) - IGHG1*01 (120-449)], (222-214')-disulfure avec la chaîne légère kappa (1'-214') [Homo sapiens V-KAPPA (IGKV1-39*01 (88.40%) - IGKJ4*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dimère (228- 228'':231-231'')-bisdisulfure

321 Recommended INN: List 66 WHO Drug Information Vol. 25, No. 3, 2011

namilumab inmunoglobulina G1-kappa, anti-[CSF2 de Homo sapiens (Homo sapiens factor 2 estimulante de colonias (granulocito-macrófago), factor estimulante de colonias de granulocitos y macrófagos, GM-CSF)], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma1 (1-449) [Homo sapiens VH (IGHV1-2*02 (89.80%) -(IGHD)-IGHJ4*01 L123>M (114)) [8.8.12] (1-119) - IGHG1*01 (120-449)], (222-214')-disulfuro con la cadena ligera kappa (1'-214') [Homo sapiens V-KAPPA (IGKV1-39*01 (88.40%) - IGKJ4*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dímero (228- 228'':231-231'')-bisdisulfuro

Heavy chain / Chaîne lourde / Cadena pesada QVQLVQSGAE VKKPGASVKV SCKAFGYPFT DYLLHWVRQA PGQGLEWVGW 50 LNPYSGDTNY AQKFQGRVTM TRDTSISTAY MELSRLRSDD TAVYYCTRTT 100 LISVYFDYWG QGTMVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD 150 YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY 200 ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK 250 DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS 300 TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV 350 YTLPPSRDEL TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL 400 DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK 449 Light chain / Chaîne légère / Cadena ligera DIQMTQSPSS VSASVGDRVT IACRASQNIR NILNWYQQRP GKAPQLLIYA 50 ASNLQSGVPS RFSGSGSGTD FTLTINSLQP EDFATYYCQQ SYSMPRTFGG 100 GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150 DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200 LSSPVTKSFN RGEC 214 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 146-202 263-323 369-427 22''-96'' 146''-202'' 263''-323'' 369''-427'' Intra-L 23'-88' 134'-194' 23'''-88''' 134'''-194''' Inter-H-L 222-214' 222''-214''' Inter-H-H 228-228'' 231-231''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 299, 299''

naronapridum naronapride (3R)-1-azabicyclo[2.2.2]octan-3-yl 6-[(3S,4R)-4-(4-amino-5-chloro- 2-methoxybenzamido)-3-methoxypiperidin-1-yl]hexanoate

naronapride 6-{(3S,4R)-4-(4-amino-5-chloro-2-méthoxybenzamido)- 3-méthoxypipéridin-1-yl}hexanoate de (3R)-1-azabicyclo[2.2.2]oct- 3-yl

naronaprida 6-[(3S,4R)-4-(4-amino-5-cloro-2-metoxibenzamido)- 3-metoxipiperidin-1-il]hexanoato de (3R)-1-azabiciclo[2.2.2]octan- 3-ilo

C27H41ClN4O5

O O N H H Cl O N N H HOCH3 H2N OCH3

322 WHO Drug Information Vol. 25, No. 3, 2011 Recommended INN: List 66

onartuzumabum # onartuzumab immunoglobulin G1-kappa monovalent Fab-Fc, anti-[Homo sapiens MET (met proto-oncogene, hepatocyte growth factor receptor, HGFR, scatter factor receptor, HGF/SF receptor, receptor tyrosine- protein kinase c-Met, papillary renal cell carcinoma 2, RCCP2)], humanized monoclonal antibody; gamma1 heavy chain (1-449) [humanized VH (Homo sapiens IGHV3-74*01 (77.30%) -(IGHD)-IGHJ4*01) [8.8.12] (1-119) -Homo sapiens IGHG1*01 CH3 D12>E (358), L14>M (360), T22>S (368), L24>A (370), Y86>V (409) (120-449)], (222-220')-disulfide with kappa light chain (1'-220') [humanized V-KAPPA (Homo sapiens IGKV4-1*01 (80.20%) -IGKJ1*01) [12.3.9] (1'-113') -Homo sapiens IGKC*01 (114'-220')], (228-6'':231-9'')-bisdisulfide with truncated gamma1 chain consisting of partial hinge-CH2-CH3 (1"-227") [Homo sapiens IGHG1*01 hinge 6-15(1"-10")-CH2(11"-120")-CH3(121"- 227") CH3 D12>E (136"), L14>M (138"), T22>W (146")]

onartuzumab immunoglobuline G1-kappa monovalent Fab-Fc, anti-[Homo sapiens MET (proto-oncogène met, récepteur du facteur de croissance hépatocytaire, HGFR, récepteur du facteur de dispersion, récepteur de l'HGF/SF, récepteur protéine-tyrosine kinase c-Met, carcinome papillaire à cellules rénales 2, RCCP2)], anticorps monoclonal humanisé; chaîne lourde gamma1 (1-449) [VH humanisé (Homo sapiens IGHV3-74*01 (77.30%) -(IGHD)-IGHJ4*01) [8.8.12] (1-119) -Homo sapiens IGHG1*01 CH3 D12>E (358), L14>M (360), T22>S (368), L24>A (370), Y86>V (409) (120-449)], (222-220')-disulfure avec la chaîne légère kappa (1'-220') [V-KAPPA humanisé (Homo sapiens IGKV4-1*01 (80.20%) -IGKJ1*01) [12.3.9] (1'-113') -Homo sapiens IGKC*01 (114'-220')], (228-6'':231-9'')-bisdisulfure avec la chaîne gamma1 tronquée comprenant charnière partielle-CH2-CH3 (1"- 227") [Homo sapiens IGHG1*01 charnière 6-15(1"-10")-CH2(11"- 120")-CH3(121"-227") CH3 D12>E (136"), L14>M (138"), T22>W (146")]

onartuzumab inmunoglobulina G1-kappa monovalente Fab-Fc, anti-[Homo sapiens MET (protooncogén met, receptor del factor de crecimiento hepatocitario, HGFR, receptor del factor de dispersión, receptor de l'HGF/SF, receptor de tirosina proteín-kinasa c-Met, carcinoma papilar de cèlulas renales 2, RCCP2)], anticuerpo monoclonal humanizado; cadena pesada gamma1 (1-449) [VH humanizada (Homo sapiens IGHV3-74*01 (77.30%) -(IGHD)-IGHJ4*01) [8.8.12] (1-119) -Homo sapiens IGHG1*01 CH3 D12>E (358), L14>M (360), T22>S (368), L24>A (370), Y86>V (409) (120-449)], (222-220')-disulfuro con la cadena ligera kappa (1'-220') [V-KAPPA humanizada (Homo sapiens IGKV4-1*01 (80.20%) -IGKJ1*01) [12.3.9] (1'-113') -Homo sapiens IGKC*01 (114'-220')], (228-6'':231-9'')-bisdisulfuro con la cadena gamma1 truncada que comprende parte de la bisagra-CH2-CH3 (1"-227") [Homo sapiens IGHG1*01 bisagra 6-15(1"-10")-CH2(11"- 120")-CH3(121"-227") CH3 D12>E (136"), L14>M (138"), T22>W (146")]

323 Recommended INN: List 66 WHO Drug Information Vol. 25, No. 3, 2011

Heavy chain / Chaîne lourde / Cadena pesada (H) EVQLVESGGG LVQPGGSLRL SCAASGYTFT SYWLHWVRQA PGKGLEWVGM 50 IDPSNSDTRF NPNFKDRFTI SADTSKNTAY LQMNSLRAED TAVYYCATYR 100 SYVTPLDYWG QGTLVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD 150 YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY 200 ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK 250 DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS 300 TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV 350 YTLPPSREEM TKNQVSLSCA VKGFYPSDIA VEWESNGQPE NNYKTTPPVL 400 DSDGSFFLVS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK 449 Light chain / Chaîne légère / Cadena ligera (L) DIQMTQSPSS LSASVGDRVT ITCKSSQSLL YTSSQKNYLA WYQQKPGKAP 50 KLLIYWASTR ESGVPSRFSG SGSGTDFTLT ISSLQPEDFA TYYCQQYYAY 100 PWTFGQGTKV EIKRTVAAPS VFIFPPSDEQ LKSGTASVVC LLNNFYPREA 150 KVQWKVDNAL QSGNSQESVT EQDSKDSTYS LSSTLTLSKA DYEKHKVYAC 200 EVTHQGLSSP VTKSFNRGEC 220 Hinge-CH2-CH3 / Charnière-CH2-CH3/ Bisagra-CH2-CH3 (H'') DKTHTCPPCP APELLGGPSV FLFPPKPKDT LMISRTPEVT CVVVDVSHED 50 PEVKFNWYVD GVEVHNAKTK PREEQYNSTY RVVSVLTVLH QDWLNGKEYK 100 CKVSNKALPA PIEKTISKAK GQPREPQVYT LPPSREEMTK NQVSLWCLVK 150 GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSKL TVDKSRWQQG 200 NVFSCSVMHE ALHNHYTQKS LSLSPGK 227 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 146-202 263-323 369-427 Intra-H'' 41''-101'' 147''-205'' Intra-L 23'-94' 140'-200' Inter-H-L 222-220' Inter-H-H'' 228-6'' 231-9''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 299, 77'' unglycosylated as expressed in Escherichia coli

orteronelum orteronel 6-[(7S)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl]- N-methylnaphthalene-2-carboxamide

ortéronel 6-[(7S)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl]- N-méthylnaphtalène-2-carboxamide

orteronel 6-[(7S)-7-hidroxi-6,7-dihidro-5H-pirrolo[1,2-c]imidazol-7-il]- N-metilnaftaleno-2-carboxamida

C18H17N3O2

N

HO N

H N H3C O

pacritinibum pacritinib ((2E,16E)-11-[2-(pyrrolidin-1-yl)ethoxy]-14,19-dioxa- 5,7,27-triazatetracyclo[19.3.1.12,6.18,12]heptacosa- 1(25),2,4,6,8,10,12(26),16,21,23-decaene

pacritinib (16E)-11-[2-(pyrrolidin-1-yl)éthoxy]-14,19-dioxa- 5,7,27-triazatétracyclo[19.3.1.12,6.18,12]heptacosa- 1(24),2,4,6,8,10,12(26),16,21(25),22-décaène

pacritinib ((2E,16E)-11-[2-(pirrolidin-1-il)etoxi]-14,19-dioxa- 5,7,27-triazatetraciclo[19.3.1. 12,6.18,12]heptacosa 1(25),2,4,6,8,10,12(26),16,21,23-decaeno

324 WHO Drug Information Vol. 25, No. 3, 2011 Recommended INN: List 66

C28H32N4O3

O

HN N

N O N O

plecanatidum plecanatide [3-glutamic acid(D>E)]human uroguanylin (UGN)

plécanatide [3-acide glutamique(D>E)]uroguanyline humaine (UGN)

plecanatida [3-ácido glutámico(D>E)]uroguanilina humana (UGN)

C65H104N18O26S4

NDECELCVNV ACTGCL 16

Disulfide bridges location / Position des ponts disulfure/ Posiciones de los puentes disulfuros 4-12 7-15

pomaglumetadum methionilum 6 pomaglumetad methionil (1R,4S,5S,6S)-4-(L-methionylamino)-2,2-dioxo-2λ - thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid

6 pomaglumétad méthionil acide (1R,4S,5S,6S)-4-(L-méthionylamino)-2,2-dioxo-2λ - thiabicyclo[3.1.0]hexane-4,6-dicarboxylique

6 pomaglumetad metionilo ácido (1R,4S,5S,6S)-4-(L-metionilamino)-2,2-dioxo-2λ - tiabiciclo[3.1.0]hexano-4,6-dicarboxílico

C12H18N2O7S2

O H CO2H O S H O H S H3C N CO2H H HNH 2

ponatinibum ponatinib 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4- methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide

ponatinib 3-[2-(imidazo[1,2-b]pyridazin-3-yl)éthynyl]-4-méthyl-N-{4-[(4- méthylpipérazin-1-yl)méthyl]-3-(trifluorométhyl)phényl}benzamide

ponatinib 3-[2-(imidazo[1,2-b]piridazin-3-il)etinil]-4-metil-N-{4-[(4- metilpiperazin-1-il)metil]-3-(trifluorometil)fenil}benzamida

325 Recommended INN: List 66 WHO Drug Information Vol. 25, No. 3, 2011

C29H27F3N6O

H3C H N CF3 CH3 N O N N N N

ponezumabum # ponezumab immunoglobulin G2-kappa, anti-[Homo sapiens amyloid beta (A beta) peptide Aβ40], humanized monoclonal antibody; gamma2 heavy chain (1-442) [humanized VH (Homo sapiens IGHV1-46*02 (84.50%) -(IGHD)-IGHJ6*01) [8.8.9] (1-116) -Homo sapiens IGHG2*01 CH2 A115>S (325), P116>S (326) (117-442)], (130-219')-disulfide with kappa light chain (1'-219') [humanized V-KAPPA (Homo sapiens IGKV2-30*01 (89.00%) -IGKJ5*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; (218- 218":219-219":222-222":225-225")-tetrakisdisulfide dimer

ponezumab immunoglobuline G2-kappa, anti-[Homo sapiens peptide amyloïde bêta (A bêta) Aβ40], anticorps monoclonal humanisé; chaîne lourde gamma2 (1-442) [VH humanisé (Homo sapiens IGHV1-46*02 (84.50%) -(IGHD)-IGHJ6*01) [8.8.9] (1-116) -Homo sapiens IGHG2*01 CH2 A115>S (325), P116>S (326) (117-442)], (130-219')-disulfure avec la chaîne légère kappa (1'-219') [V-KAPPA humanisé (Homo sapiens IGKV2-30*01 (89.00%) -IGKJ5*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; dimère (218- 218":219-219":222-222":225-225")-tétrakisdisulfure

ponezumab inmunoglobulina G2-kappa, anti-[péptido amiloide beta de Homo sapiens (A beta) Aβ40], anticuerpo monoclonal humanizado; cadena pesada gamma2 (1-442) [VH humanizada (Homo sapiens IGHV1-46*02 (84.50%) -(IGHD)-IGHJ6*01) [8.8.9] (1-116) -Homo sapiens IGHG2*01 CH2 A115>S (325), P116>S (326) (117-442)], (130-219')-disulfuro con la cadena ligera kappa (1'-219') [V-KAPPA humanizada (Homo sapiens IGKV2-30*01 (89.00%) -IGKJ5*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; dímer (218- 218":219-219":222-222":225-225")-tetrakisdisulfuro

Heavy chain / Chaîne lourde / Cadena pesada QVQLVQSGAE VKKPGASVKV SCKASGYYTE AYYIHWVRQA PGQGLEWMGR 50 IDPATGNTKY APRLQDRVTM TRDTSTSTVY MELSSLRSED TAVYYCASLY 100 SLPVYWGQGT TVTVSSASTK GPSVFPLAPC SRSTSESTAA LGCLVKDYFP 150 EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS NFGTQTYTCN 200 VDHKPSNTKV DKTVERKCCV ECPPCPAPPV AGPSVFLFPP KPKDTLMISR 250 TPEVTCVVVD VSHEDPEVQF NWYVDGVEVH NAKTKPREEQ FNSTFRVVSV 300 LTVVHQDWLN GKEYKCKVSN KGLPSSIEKT ISKTKGQPRE PQVYTLPPSR 350 EEMTKNQVSL TCLVKGFYPS DIAVEWESNG QPENNYKTTP PMLDSDGSFF 400 LYSKLTVDKS RWQQGNVFSC SVMHEALHNH YTQKSLSLSP GK 442 Light chain / Chaîne légère / Cadena ligera DVVMTQSPLS LPVTLGQPAS ISCKSSQSLL YSDAKTYLNW FQQRPGQSPR 50 RLIYQISRLD PGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCLQGTHYP 100 VLFGQGTRLE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK 150 VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE 200 VTHQGLSSPV TKSFNRGEC 219

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 143-199 256-316 362-420 22''-96'' 143''-199'' 256''-316'' 362''-420'' Intra-L 23'-93' 139'-199' 23'''-93''' 139'''-199''' Inter-H-L 130-219' 130''-219''' Inter-H-H 218-218'' 219-219'' 222-222'' 225-225''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 292, 292''

326 WHO Drug Information Vol. 25, No. 3, 2011 Recommended INN: List 66

pracinostatum pracinostat (2E)-3-{2-butyl-1-[2-(dimethylamino)ethyl]-1H-benzimidazol-5-yl}- N-hydroxyprop-2-enamide

pracinostat (2E)-3-{2-butyl-1-[2-(diéthylamino)éthyl]-1H-benzimidazol-5-yl]- N-hydroxyprop-2-énamide

pracinostat (2E)-3-{2-butil-1-[2-(dimetilamino)etil]-1H-bencimidazol-5-il}- N-hidroxyprop-2-enamida

C20H30N4O2

H3C N N

H3C N H N OH H3C O

quizartinibum quizartinib 1-(5-tert-butyl-1,2-oxazol-3-yl)-3-(4-{7-[2-(morpholin- 4-yl)ethoxy]imidazo[2,1-b][1,3]benzothiazol-2-yl}phenyl)urea

quizartinib N-[5-tert-butyl-1,2-oxazol-3-yl]-N'-(4-{7-[2-(morpholin- 4-yl)éthoxy]imidazo[2,1-b][1,3]benzothiazol-2-yl}phényl)urée

quizartinib 1-(5-terc-butil-1,2-oxazol-3-il)-3-(4-{7-[2-(morfolin- 4-il)etoxi]imidazo[2,1-b][1,3]benzotiazol-2-il}fenil)urea

C29H32N6O4S

O S N H3C CH O N 3 N CH3 O O N N N H H

radotinibum radotinib 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]- 3-{[4-(pyrazin-2-yl)pyrimidin-2-yl]amino}benzamide

radotinib 4-méthyl-N-[3-(4-méthyl-1H-imidazol-1-yl)-5-(trifluorométhyl)phényl]- 3-{[4-(pyrazin-2-yl)pyrimidin-2-yl]amino}benzamide

radotinib 4-metil-N-[3-(4-metil-1H-imidazol-1-il)-5-(trifluorometil)fenil]- 3-{[4-(pirazin-2-il)pirimidin-2-il]amino}benzamida

C27H21F3N8O

H3C N N H CH3 N N N N N H O N

CF3

327 Recommended INN: List 66 WHO Drug Information Vol. 25, No. 3, 2011

radretumabum # radretumab immunoglobulin scFv-CH dimer, anti-[Homo sapiens fibronectin extra domain B (ED-B)], Homo sapiens monoclonal antibody fragment dimer of single chain (scFv) fused with the IGHE CH4; scFv-CH (1-357) [Homo sapiens VH (IGHV3-23*01 (94.90%) - (IGHD)-IGHJ4*01) [8.8.14] (1-116)-12-mer linker (117-128)- Homo sapiens V-KAPPA (IGKV3-20*01 (94.80%) -IGKJ1*01) [7.3.9] (129- 236)-5-mer linker (237-241)- Homo sapiens IGHE*01 CH4 (242- 349)-8-mer linker (350-357)]; (357:357') disulfide dimer

radrétumab immunoglobuline scFv-CH dimère, anti-[Homo sapiens extra domaine B (ED-B) de la fibronectine], Homo sapiens anticorps monoclonal fragment dimère de scFv fusionné au CH4 de l'IGHE; scFv-CH (1-357) [Homo sapiens VH (IGHV3-23*01 (94.90%) - (IGHD)-IGHJ4*01) [8.8.14] (1-116)-12-mer linker (117-128)- Homo sapiens V-KAPPA (IGKV3-20*01 (94.80%) -IGKJ1*01) [7.3.9] (129- 236)-5-mer linker (237-241)- Homo sapiens IGHE*01 CH4 (242- 349)-8-mer linker (350-357)]; dimère (357:357')

radretumab inmunoglobulina scFv-CH dímero, anti-[Homo sapiens extra dominio B (ED-B) de la fibronectina], fragmento de anticuerpo monoclonal de Homo sapiens dímero de scFv fusionado con el CH4 del IGHE; scFv-CH (1-357) [Homo sapiens VH (IGHV3-23*01 (94.90%) - (IGHD)-IGHJ4*01) [8.8.14] (1-116)-dodecámero de conexión (117- 128)- Homo sapiens V-KAPPA (IGKV3-20*01 (94.80%) -IGKJ1*01) [7.3.9] (129-236)-pentámero de conexión (237-241)- Homo sapiens IGHE*01 CH4 (242-349)-octámero de conexión (350-357)]; dímero (357:357') disulfuro

scFv-CH chain / Chaîne scFv-CH / Cadena scFv-CH EVQLLESGGG LVQPGGSLRL SCAASGFTFS SFSMSWVRQA PGKGLEWVSS 50 ISGSSGTTYY ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCAKPF 100 PYFDYWGQGT LVTVSSGDGS SGGSGGASEI VLTQSPGTLS LSPGERATLS 150 CRASQSVSSS FLAWYQQKPG QAPRLLIYYA SSRATGIPDR FSGSGSGTDF 200 TLTISRLEPE DFAVYYCQQT GRIPPTFGQG TKVEIKSGGS GGPRAAPEVY 250 AFATPEWPGS RDKRTLACLI QNFMPEDISV QWLHNEVQLP DARHSTTQPR 300 KTKGSGFFVF SRLEVTRAEW EQKDEFICRA VHEAASPSQT VQRAVSVNPE 350 SSRRGGC 357 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-chain 22-96 151-217 268-328 22'-96' 151'-217' 268'-328' Inter-chain 357-357'

selurampanelum selurampanel N-[6-(1-methyl-1H-pyrazol-5-yl)-7-(propan-2-yl)-2,4-dioxo- 1,4-dihydroquinazolin-3(2H)-yl]methanesulfonamide

sélurampanel N-[6-(1-méthyl-1H-pyrazol-5-yl)-7-(propan-2-yl)-2,4-dioxo- 1,4-dihydroquinazolin-3(2H)-yl]méthanesulfonamide

selurampanel N-[6-(1-metil-1H-pirazol-5-il)-7-(propan-2-il)-2,4-dioxo- 1,4-dihidroquinazolin-3(2H)-il]metanosulfonamida

C16H19N5O4S

CH3 H N O H3C O O N S N CH3 H N N O CH3

328 WHO Drug Information Vol. 25, No. 3, 2011 Recommended INN: List 66

setipiprantum setipiprant [8-fluoro-2-(naphthalene-1-carbonyl)-1,2,3,4-tetrahydro- 5H-pyrido[4,3-b]indol-5-yl]acetic acid

sétipiprant acide 2-[8-fluoro-2-(naphtalén-1-ylcarbonyl)-1,2,3,4-tétrahydro- 5H-pyrido[4,3-b]indol-5-yl]acétique

setipiprant ácido {8-fluoro-2-(naftalen-1-carbonil)-1,2,3,4-tetrahidro- 5H-pirido[4,3-b]indol-5-il}acético

C24H19FN2O3

CO2H N

N

O F

silmitasertibum silmitasertib 5-[(3-chlorophenyl)amino]benzo[c][2,6]naphthyridine-8-carboxylic acid

silmitasertib acide 5-[(3-chlorophényl)amino]benzo[c][2,6]naphtyridine- 8-carboxylique

silmitasertib ácido 5-[(3-clorofenil)amino]benzo[c][2,6]naftiridina-8-carboxílico

C19H12ClN3O2

H N N CO2H

Cl N

simoctocogum alfa # simoctocog alfa B-domain deleted human coagulation factor VIII; [749-glutamine,750-alanine-751-tyrosine-753-tyrosine-754-arginine- 755-arginine-756-glycine]human coagulation factor VIIIa heavy chain-(1-756)-peptide (containing F5/8 type A 1 and A 2 domains) fusion protein with human coagulation factor VIIIa light chain, glycosylated

simoctocog alfa facteur VIII de coagulation humain dont le domaine B a été supprimé; [749-glutamine,750-alanine-751-tyrosine-753-tyrosine-754-arginine- 755-arginine-756-glycine]chaîne lourde du facteur VIIIa de coagulation humain-(1-756)-peptide (contenant les domaines F5/8 type A 1 and A 2) protéine de fusion avec la chaîne légère du facteur VIIIa de coagulation humain glycosylé

simoctocog alfa factor VIII de coagulación humano cuyo dominio B se ha suprimido; [749-glutamina,750-alanina-751-tirosina-753-tirosina-754-arginina- 755-arginina-756-glicina]cadena pesada del factor VIIIa de coagulación humano-(1-756)-péptido (contiene los dominios F5/8 tipo A 1 y A 2) proteína de fusión con la cadena ligera del factor VIIIa de coagulación humano glicosilado

329 Recommended INN: List 66 WHO Drug Information Vol. 25, No. 3, 2011

C7459H11338N1992O2188S68 (peptide)

ATRRYYLGAV ELSWDYMQSD LGELPVDARF PPRVPKSFPF NTSVVYKKTL 50 FVEFTDHLFN IAKPRPPWMG LLGPTIQAEV YDTVVITLKN MASHPVSLHA 100 VGVSYWKASE GAEYDDQTSQ REKEDDKVFP GGSHTYVWQV LKENGPMASD 150 PLCLTYSYLS HVDLVKDLNS GLIGALLVCR EGSLAKEKTQ TLHKFILLFA 200 VFDEGKSWHS ETKNSLMQDR DAASARAWPK MHTVNGYVNR SLPGLIGCHR 250 KSVYWHVIGM GTTPEVHSIF LEGHTFLVRN HRQASLEISP ITFLTAQTLL 300 MDLGQFLLFC HISSHQHDGM EAYVKVDSCP EEPQLRMKNN EEAEDYDDDL 350 TDSEMDVVRF DDDNSPSFIQ IRSVAKKHPK TWVHYIAAEE EDWDYAPLVL 400 APDDRSYKSQ YLNNGPQRIG RKYKKVRFMA YTDETFKTRE AIQHESGILG 450 PLLYGEVGDT LLIIFKNQAS RPYNIYPHGI TDVRPLYSRR LPKGVKHLKD 500 FPILPGEIFK YKWTVTVEDG PTKSDPRCLT RYYSSFVNME RDLASGLIGP 550 LLICYKESVD QRGNQIMSDK RNVILFSVFD ENRSWYLTEN IQRFLPNPAG 600 VQLEDPEFQA SNIMHSINGY VFDSLQLSVC LHEVAYWYIL SIGAQTDFLS 650 VFFSGYTFKH KMVYEDTLTL FPFSGETVFM SMENPGLWIL GCHNSDFRNR 700 GMTALLKVSS CDKNTGDYYE DSYEDISAYL LSKNNAIEPR SFSQNSRHQA 750 YRYRRGEITR TTLQSDQEEI DYDDTISVEM KKEDFDIYDE DENQSPRSFQ 800 KKTRHYFIAA VERLWDYGMS SSPHVLRNRA QSGSVPQFKK VVFQEFTDGS 850 FTQPLYRGEL NEHLGLLGPY IRAEVEDNIM VTFRNQASRP YSFYSSLISY 900 EEDQRQGAEP RKNFVKPNET KTYFWKVQHH MAPTKDEFDC KAWAYFSDVD 950 LEKDVHSGLI GPLLVCHTNT LNPAHGRQVT VQEFALFFTI FDETKSWYFT 1000 ENMERNCRAP CNIQMEDPTF KENYRFHAIN GYIMDTLPGL VMAQDQRIRW 1050 YLLSMGSNEN IHSIHFSGHV FTVRKKEEYK MALYNLYPGV FETVEMLPSK 1100 AGIWRVECLI GEHLHAGMST LFLVYSNKCQ TPLGMASGHI RDFQITASGQ 1150 YGQWAPKLAR LHYSGSINAW STKEPFSWIK VDLLAPMIIH GIKTQGARQK 1200 FSSLYISQFI IMYSLDGKKW QTYRGNSTGT LMVFFGNVDS SGIKHNIFNP 1250 PIIARYIRLH PTHYSIRSTL RMELMGCDLN SCSMPLGMES KAISDAQITA 1300 SSYFTNMFAT WSPSKARLHL QGRSNAWRPQ VNNPKEWLQV DFQKTMKVTG 1350 VTTQGVKSLL TSMYVKEFLI SSSQDGHQWT LFFQNGKVKV FQGNQDSFTP 1400 VVNSLDPPLL TRYLRIHPQS WVHQIALRME VLGCEAQDLY 1440 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro 153-179 248-329 528-554 630-711 940-966 1007-1011 1129-1277 1282-1434

Sulfated residues (Y) / Résidus sulfatés (Y) / Reioduos sulfatados (Y) Tyr-346 Tyr-718 Tyr-719 Tyr-723 Tyr-772 Tyr-788

Glycosylation sites (N) / Sites de glycosylation (N) / Posiciones de glicosilación (N) Asn-41 Asn-239 Asn-918 Asn-1226

talimogenum laherparepvecum # talimogene laherparepvec recombinant replicating Herpes simplex type -1 virus vector, with ICP47 and both copies of ICP34.5 genes deleted, expressing human granulocyte macrophage colony stimulating factor (hGM-CSF) in the ICP34.5 loci

talimogène laherparépvec vecteur viral Herpes simplex type 1 répliquant avec délétion du gène ICP47 et des deux copies du gène ICP34.5, exprimant le facteur humain de développement des polynucléaires et des macrophages (hGM-CSF) dans les loci ICP34.5

talimogén laherparepvec vector virus del Herpes simplex tipo-1 replicante recombinante con delección del gen ICP47 y las dos copias del gen ICP34.5, que expresa el factor humano estimulante de colonias de granulocitos y macrógafos (hGM-CSF) in los loci ICP34.5

tedizolidum tedizolid (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl]phenyl}- 5-(hydroxymethyl)-1,3-oxazolidin-2-one

tédizolid (5R)-3-{3-fluoro-4-[6-(2-méthyl-2H-tétrazol-5-yl)pyridin-3-yl]phényl}- 5-(hydroxyméthyl)-1,3-oxazolidin-2-one

tedizolid (5R)-3-{3-fluoro-4-[6-(2-metil-2H-tetrazol-5-il)piridin-3-il]fenil}- 5-(hidroximetil)-1,3-oxazolidina-2-ona

330 WHO Drug Information Vol. 25, No. 3, 2011 Recommended INN: List 66

C17H15FN6O3

O O H HO N F

N N N CH3 N N

telotristatum telotristat 4-(2-amino-6-{(1R -1-[4-chloro-2-(3-methyl-1H-pyrazol-1-yl) phenyl])- 2,2,2-trifluoroethoxy}pyrimidin-4-yl)-L-phenylalanine

télotristat 4-(2-amino-6-{(1R)-1-[4-chloro-2-(3-méthyl-1H-pyrazol-1-yl)phényl]- 2,2,2-trifluoroéthoxy}pryrimidin-4-yl)-L-phénylalanine

telotristat 4-(2-amino-6-{(1R -1-[4-cloro-2-(3-metil-1H-pirazol-1-il)fenil])- 2,2,2-trifluoroetoxi}pirimidin-4-il)-L-fenilalanina

C25H22ClF3N6O3

NH2

N N H CF3

O H NH2 N Cl N CO2H CH3

tregalizumabum # tregalizumab immunoglobulin G1-kappa, anti-[Homo sapiens CD4 (T cell surface antigen T4/Leu-3, p55)], humanized monoclonal antibody; gamma1 heavy chain (1-454) [humanized VH (Homo sapiens IGHV3-15*06 (77.80%) -(IGHD)-IGHJ5*01) [8.10.15] (1-124) -Homo sapiens IGHG1*01 (125-454)], (227-218')-disulfide with kappa light chain (1'-218') [humanized V-KAPPA (Homo sapiens IGKV4-1*01 (80.20%) -IGKJ1*01) [10.3.9] (1'-111') -Homo sapiens IGKC*01 (112'-218')]; (233-233":236-236")-bisdisulfide dimer

trégalizumab immunoglobuline G1-kappa, anti-[Homo sapiens CD4 (antigène de surface T4/Leu-3 de cellule T, p55)], anticorps monoclonal humanisé; chaîne lourde gamma1(1-454) [VH humanisé (Homo sapiens IGHV3-15*06 (77.80%) -(IGHD)-IGHJ5*01) [8.10.15] (1-124) -Homo sapiens IGHG1*01 (125-454)], (227-218')-disulfure avec la chaîne légère kappa (1'-218') [V-KAPPA humanisé (Homo sapiens IGKV4- 1*01 (80.20%) -IGKJ1*01) [10.3.9] (1'-111') -Homo sapiens IGKC*01 (112'-218')]; dimère (233-233":236-236")-bisdisulfure

tregalizumab inmunoglobulina G1-kappa, anti-[CD4 de Homo sapiens (antígeno de superficie T4/Leu-3 de célula T, p55)], anticuerpo monoclonal humanizado; cadena pesada gamma1(1-454) [VH humanizada (Homo sapiens IGHV3-15*06 (77.80%) -(IGHD)-IGHJ5*01) [8.10.15] (1-124) -Homo sapiens IGHG1*01 (125-454)], (227-218')-disulfuro con la cadena ligera kappa (1'-218') [V-KAPPA humanizada (Homo sapiens IGKV4- 1*01 (80.20%) -IGKJ1*01) [10.3.9] (1'-111') -Homo sapiens IGKC*01 (112'-218')]; dimero (233-233":236-236")-bisdisulfuro

331 Recommended INN: List 66 WHO Drug Information Vol. 25, No. 3, 2011

Heavy chain / Chaîne lourde / Cadena pesada EEQLVESGGG LVKPGGSLRL SCAASGFSFS DCRMYWLRQA PGKGLEWIGV 50 ISVKSENYGA NYAESVRGRF TISRDDSKNT VYLQMNSLKT EDTAVYYCSA 100 SYYRYDVGAW FAYWGQGTLV TVSSASTKGP SVFPLAPSSK STSGGTAALG 150 CLVKDYFPEP VTVSWNSGAL TSGVHTFPAV LQSSGLYSLS SVVTVPSSSL 200 GTQTYICNVN HKPSNTKVDK KVEPKSCDKT HTCPPCPAPE LLGGPSVFLF 250 PPKPKDTLMI SRTPEVTCVV VDVSHEDPEV KFNWYVDGVE VHNAKTKPRE 300 EQYNSTYRVV SVLTVLHQDW LNGKEYKCKV SNKALPAPIE KTISKAKGQP 350 REPQVYTLPP SRDELTKNQV SLTCLVKGFY PSDIAVEWES NGQPENNYKT 400 TPPVLDSDGS FFLYSKLTVD KSRWQQGNVF SCSVMHEALH NHYTQKSLSL 450 SPGK 454 Light chain / Chaîne légère / Cadena ligera DIVMTQSPDS LAVSLGERAT INCRASKSVS TSGYSYIYWY QQKPGQPPKL 50 LIYLASILES GVPDRFSGSG SGTDFTLTIS SLQAEDVAVY YCQHSRELPW 100 TFGQGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKV 150 QWKVDNALQS GNSQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEV 200 THQGLSSPVT KSFNRGEC 218 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-98 151-207 268-328 374-432 22''-98'' 151''-207'' 268''-328'' 374''-432'' Intra-L 23'-92' 138'-198' 23'''-92''' 138'''-198''' Inter-H-L 227-218' 227''-218''' Inter-H-H 233-233'' 236-236''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 304, 304''

turoctocogum alfa # turoctocog alfa human coagulation factor VIII-(1-750)-(1638-2332)-peptide, glycosylated

turoctocog alfa facteur VIII de coagulation humain-(1-750)-(1638-2332)-peptide glycosylé

turoctocog alfa factor VIII de coagulación humano-(1-750)-(1638-2332)-péptido glicosilado

C7480H11379N1999O2194S68 (peptide)

ATRRYYLGAV ELSWDYMQSD LGELPVDARF PPRVPKSFPF NTSVVYKKTL 50 FVEFTDHLFN IAKPRPPWMG LLGPTIQAEV YDTVVITLKN MASHPVSLHA 100 VGVSYWKASE GAEYDDQTSQ REKEDDKVFP GGSHTYVWQV LKENGPMASD 150 PLCLTYSYLS HVDLVKDLNS GLIGALLVCR EGSLAKEKTQ TLHKFILLFA 200 VFDEGKSWHS ETKNSLMQDR DAASARAWPK MHTVNGYVNR SLPGLIGCHR 250 KSVYWHVIGM GTTPEVHSIF LEGHTFLVRN HRQASLEISP ITFLTAQTLL 300 MDLGQFLLFC HISSHQHDGM EAYVKVDSCP EEPQLRMKNN EEAEDYDDDL 350 TDSEMDVVRF DDDNSPSFIQ IRSVAKKHPK TWVHYIAAEE EDWDYAPLVL 400 APDDRSYKSQ YLNNGPQRIG RKYKKVRFMA YTDETFKTRE AIQHESGILG 450 PLLYGEVGDT LLIIFKNQAS RPYNIYPHGI TDVRPLYSRR LPKGVKHLKD 500 FPILPGEIFK YKWTVTVEDG PTKSDPRCLT RYYSSFVNME RDLASGLIGP 550 LLICYKESVD QRGNQIMSDK RNVILFSVFD ENRSWYLTEN IQRFLPNPAG 600 VQLEDPEFQA SNIMHSINGY VFDSLQLSVC LHEVAYWYIL SIGAQTDFLS 650 VFFSGYTFKH KMVYEDTLTL FPFSGETVFM SMENPGLWIL GCHNSDFRNR 700 GMTALLKVSS CDKNTGDYYE DSYEDISAYL LSKNNAIEPR SFSQNSRHPS 750 QNPPVLKRHQ REITRTTLQS DQEEIDYDDT ISVEMKKEDF DIYDEDENQS 800 PRSFQKKTRH YFIAAVERLW DYGMSSSPHV LRNRAQSGSV PQFKKVVFQE 850 FTDGSFTQPL YRGELNEHLG LLGPYIRAEV EDNIMVTFRN QASRPYSFYS 900 SLISYEEDQR QGAEPRKNFV KPNETKTYFW KVQHHMAPTK DEFDCKAWAY 950 FSDVDLEKDV HSGLIGPLLV CHTNTLNPAH GRQVTVQEFA LFFTIFDETK 1000 SWYFTENMER NCRAPCNIQM EDPTFKENYR FHAINGYIMD TLPGLVMAQD 1050 QRIRWYLLSM GSNENIHSIH FSGHVFTVRK KEEYKMALYN LYPGVFETVE 1100 MLPSKAGIWR VECLIGEHLH AGMSTLFLVY SNKCQTPLGM ASGHIRDFQI 1150 TASGQYGQWA PKLARLHYSG SINAWSTKEP FSWIKVDLLA PMIIHGIKTQ 1200 GARQKFSSLY ISQFIIMYSL DGKKWQTYRG NSTGTLMVFF GNVDSSGIKH 1250 NIFNPPIIAR YIRLHPTHYS IRSTLRMELM GCDLNSCSMP LGMESKAISD 1300 AQITASSYFT NMFATWSPSK ARLHLQGRSN AWRPQVNNPK EWLQVDFQKT 1350 MKVTGVTTQG VKSLLTSMYV KEFLISSSQD GHQWTLFFQN GKVKVFQGNQ 1400 DSFTPVVNSL DPPLLTRYLR IHPQSWVHQI ALRMEVLGCE AQDLY 1445 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro 153-179 248-329 528-554 630-711 945-971 1012-1016 1134-1282 1287-1439

Sulfated residues (Y) / Résidus sulfatés (Y) / Residuos sulfatados(Y) Tyr-346 Tyr-718 Tyr-719 Tyr-723 Tyr-777 Tyr-793

Glycosylation sites (N) / Sites de glycosylation (N) / Posiciones de glicosilación (N) Asn-41 Asn-239 Asn-923 Asn-1231

332 WHO Drug Information Vol. 25, No. 3, 2011 Recommended INN: List 66

ublituximabum # ublituximab immunoglobulin G1-kappa, anti-[Homo sapiens MS4A1 (membrane- spanning 4-domains subfamily A member 1, B lymphocyte surface antigen B1, leukocyte surface antigen Leu-16, Bp35, CD20), chimeric monoclonal antibody; gamma1 heavy chain (1-448) [Mus musculus VH (IGHV1-12*01 - (IGHD)-IGHJ4*01) [8.8.11] (1-118) -Homo sapiens IGHG1*01 (119- 448)], (221-213')-disulfide with kappa light chain (1'-213') [Mus musculus V-KAPPA (IGKV4-72*01 -IGKJ1*01) [5.3.9] (1'-106') - Homo sapiens IGKC*01 (107'-213')]; (227-227'':230-230'')- bisdisulfide dimer

ublituximab immunoglobuline G1-kappa, anti-[Homo sapiens MS4A1 (membre 1 de la sous-famille A avec 4 transmembrane regions, antigène de surface B1 des lymphocytes B, antigène de surface Leu-16 des leucocytes, Bp35, CD20), anticorps monoclonal chimérique; chaîne lourde gamma1 (1-448) [Mus musculus VH (IGHV1-12*01 - (IGHD)-IGHJ4*01) [8.8.11] (1-118) -Homo sapiens IGHG1*01 (119- 448)], (221-213')-disulfure avec la chaîne légère kappa (1'-213') [Mus musculus V-KAPPA (IGKV4-72*01 -IGKJ1*01) [5.3.9] (1'-106') -Homo sapiens IGKC*01 (107'-213')]; dimère (227-227'':230-230'')- bisdisulfure

ublituximab inmunoglobulina G1-kappa, anti-[MS4A1 de Homo sapiens (miembro 1 de la subfamilia A con 4 regiones , transmembrana , antígeno de superficie B1 de linfocitos B, antígeno de superficie Leu- 16 de leucocitos, Bp35, CD20), anticuerpo monoclonal quimérico; cadena pesada gamma1 (1-448) [Mus musculus VH(IGHV1-12*01 - (IGHD)-IGHJ4*01) [8.8.11] (1-118) -Homo sapiens IGHG1*01 (119- 448)], (221-213')-disulfuro con la cadena ligera kappa (1'-213') [Mus musculus V-KAPPA (IGKV4-72*01 -IGKJ1*01) [5.3.9] (1'-106') - Homo sapiens IGKC*01 (107'-213')]; dímero (227-227'':230-230'')- bisdisulfuro

Heavy chain / Chaîne lourde / Cadena pesada QAYLQQSGAE LVRPGASVKM SCKASGYTFT SYNMHWVKQT PRQGLEWIGG 50 IYPGNGDTSY NQKFKGKATL TVGKSSSTAY MQLSSLTSED SAVYFCARYD 100 YNYAMDYWGQ GTSVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY 150 FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI 200 CNVNHKPSNT KVDKKVEPKS CDKTHTCPPC PAPELLGGPS VFLFPPKPKD 250 TLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST 300 YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY 350 TLPPSRDELT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD 400 SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPGK 448 Light chain / Chaîne légère / Cadena ligera QIVLSQSPAI LSASPGEKVT MTCRASSSVS YMHWYQQKPG SSPKPWIYAT 50 SNLASGVPAR FSGSGSGTSY SFTISRVEAE DAATYYCQQW TFNPPTFGGG 100 TRLEIKRTVA APSVFIFPPS DEQLKSGTAS VVCLLNNFYP REAKVQWKVD 150 NALQSGNSQE SVTEQDSKDS TYSLSSTLTL SKADYEKHKV YACEVTHQGL 200 SSPVTKSFNR GEC 213

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 145-201 262-322 368-426 22''-96'' 145''-201'' 262''-322'' 368''-426'' Intra-L 23'-87' 133'-193' 23'''-87''' 133'''-193''' Inter-H-L 221-213' 221''-213''' Inter-H-H 227-227'' 230-230''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 298, 298''

333 Recommended INN: List 66 WHO Drug Information Vol. 25, No. 3, 2011

urelumabum # urelumab immunoglobulin G4-kappa, anti-[Homo sapiens TNFRSF9 (tumor necrosis factor receptor superfamily member 9, 4-1BB, T cell antigen ILA, CD137)], Homo sapiens monoclonal antibody; gamma4 heavy chain (1-448) [Homo sapiens VH (IGHV4-34*01 (92.80%) -(IGHD)-IGHJ2*01) [8.7.15] (1-121) -IGHG4*01 hinge S10>P (229) (122-448)], (135-216')-disulfide with kappa light chain (1'-216') [Homo sapiens V-KAPPA (IGKV3-11*01 (100.00%) - IGKJ4*01 G119>C) [6.3.11] (1'-109') -IGKC1*01 (110'-216')]; (227- 227'':230-230'')-bisdisulfide dimer

urélumab immunoglobuline G4-kappa, anti-[Homo sapiens TNFRSF9 (membre 9 de la superfamille des récepteurs du facteur de nécrose tumorale, 4-1BB, antigène ILA de lymphocyte T, CD137)], Homo sapiens anticorps monoclonal; chaîne lourde gamma4 (1-448) [Homo sapiens VH (IGHV4-34*01 (92.80%) -(IGHD)-IGHJ2*01) [8.7.15] (1-121) -IGHG4*01 charnière S10>P (229) (122-448)], (135-216')-disulfure avec la chaîne légère kappa (1'-216') [Homo sapiens V-KAPPA (IGKV3-11*01 (100.00%) - IGKJ4*01 G119>C) [6.3.11] (1'-109') -IGKC1*01 (110'-216')]; dimère (227-227'':230-230'')-bisdisulfure

urelumab inmunoglobulina G4-kappa, anti-[TNFRSF9 de Homo sapiens (miembro 9 de la superfamilia de receptores del factor de necrosis tumoral, 4-1BB, antígeno ILA de linfocito T, CD137)], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma4 (1-448) [Homo sapiens VH (IGHV4-34*01 (92.80%) -(IGHD)-IGHJ2*01) [8.7.15] (1-121) -IGHG4*01 bisagra S10>P (229) (122-448)], (135-216')-disulfuro con la cadena ligera kappa (1'-216') [Homo sapiens V-KAPPA (IGKV3-11*01 (100.00%) - IGKJ4*01 G119>C) [6.3.11] (1'-109') -IGKC1*01 (110'-216')]; dímero (227-227'':230-230'')-bisdisulfuro

Heavy chain / Chaîne lourde / Cadena pesada QVQLQQWGAG LLKPSETLSL TCAVYGGSFS GYYWSWIRQS PEKGLEWIGE 50 INHGGYVTYN PSLESRVTIS VDTSKNQFSL KLSSVTAADT AVYYCARDYG 100 PGNYDWYFDL WGRGTLVTVS SASTKGPSVF PLAPCSRSTS ESTAALGCLV 150 KDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTK 200 TYTCNVDHKP SNTKVDKRVE SKYGPPCPPC PAPEFLGGPS VFLFPPKPKD 250 TLMISRTPEV TCVVVDVSQE DPEVQFNWYV DGVEVHNAKT KPREEQFNST 300 YRVVSVLTVL HQDWLNGKEY KCKVSNKGLP SSIEKTISKA KGQPREPQVY 350 TLPPSQEEMT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD 400 SDGSFFLYSR LTVDKSRWQE GNVFSCSVMH EALHNHYTQK SLSLSLGK 448 Light chain / Chaîne légère / Cadena ligera EIVLTQSPAT LSLSPGERAT LSCRASQSVS SYLAWYQQKP GQAPRLLIYD 50 ASNRATGIPA RFSGSGSGTD FTLTISSLEP EDFAVYYCQQ RSNWPPALTF 100 CGGTKVEIKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW 150 KVDNALQSGN SQESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH 200 QGLSSPVTKS FNRGEC 216 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-95 148-204 262-322 368-426 22''-95'' 148''-204'' 262''-322'' 368''-426'' Intra-L 23'-88' 136'-196' 23'''-88''' 136'''-196''' Inter-H-L 135-216' 135''-216''' Inter-H-H 227-227'' 230-230''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 298, 298''

334 WHO Drug Information Vol. 25, No. 3, 2011 Recommended INN: List 66

usistapidum usistapide methyl (2S)-2-phenyl-2-[4-(4-{4'-(trifluoromethyl)-[1,1'-biphenyl]- 2-carboxamido}phenyl)piperidin-1-yl]acetate

usistapide (+)-(2S)-2-phényl-2-{4-[4-({[4'-(trifluorométhyl)-[1,1'-biphényl]- 2-yl]carbonyl}amino)phényl]pipéridin-1-yl}acétate de méthyle

usistapida (2S)-2-fenil-2-[4-(4-{4'-(trifluorometil)-[1,1'-bifenil]- 2-carboxamido}fenil)piperidin-1-il]acetato de metilo

C34H31F3N2O3

O CH3 CF3 H O

N

O

N H

vesencumabum # vesencumab immunoglobulin G1-kappa, anti-[Homo sapiens NRP1 (neuropilin 1, NRP, vascular endothelial cell growth factor 165 receptor, VEGF165 receptor, VEGF165R, CD304) extracellular domain], Homo sapiens monoclonal antibody; gamma1 heavy chain (1-453) [Homo sapiens VH (IGHV3-23*04 (90.80%) -(IGHD)-IGHJ6*01) [8.8.16] (1-123) -IGHG1*01 CH3 D12>E (362), L14>M (364) (124-453)], (226-214')-disulfide with kappa light chain (1'-214') [Homo sapiens V-KAPPA (IGKV1-39*01 (89.50%) -IGKJ1*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; (232- 232'':235-235'')-bisdisulfide dimer

vésencumab immunoglobuline G1-kappa, anti-[Homo sapiens NRP1 (neuropiline 1, NRP, récepteur de l'isoforme 165 du facteur de croissance des cellules endothéliales vasculaires, récepteur du VEGF165, VEGF165R, CD304) domaine extracellulaire], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-453) [Homo sapiens VH (IGHV3-23*04 (90.80%) -(IGHD)-IGHJ6*01) [8.8.16] (1-123) -IGHG1*01 CH3 D12>E (362), L14>M (364) (124-453)], (226-214')-disulfure avec la chaîne légère kappa (1'-214') [Homo sapiens V-KAPPA (IGKV1- 39*01 (89.50%) -IGKJ1*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dimère (232-232'':235-235'')-bisdisulfure

vesencumab inmunoglobulina G1-kappa, anti-[NRP1 de Homo sapiens (neuropilina 1, NRP, receptor de la isoforma 165 del factor de crecimiento de células endoteliales vasculares, receptor de VEGF165, VEGF165R, CD304) dominio extracelular], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma1 (1-453) [VH de Homo sapiens (IGHV3- 23*04 (90.80%) -(IGHD)-IGHJ6*01) [8.8.16] (1-123) -IGHG1*01 CH3 D12>E (362), L14>M (364) (124-453)], (226-214')-disulfuro con la cadena ligera kappa (1'-214') [Homo sapiens V-KAPPA (IGKV1- 39*01 (89.50%) -IGKJ1*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dímero (232-232'':235-235'')-bisdisulfuro

335 Recommended INN: List 66 WHO Drug Information Vol. 25, No. 3, 2011

Heavy chain / Chaîne lourde / Cadena pesada EVQLVESGGG LVQPGGSLRL SCAASGFTFS SYAMSWVRQA PGKGLEWVSQ 50 ISPAGGYTNY ADSVKGRFTI SADTSKNTAY LQMNSLRAED TAVYYCARGE 100 LPYYRMSKVM DVWGQGTLVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC 150 LVKDYFPEPV TVSWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG 200 TQTYICNVNH KPSNTKVDKK VEPKSCDKTH TCPPCPAPEL LGGPSVFLFP 250 PKPKDTLMIS RTPEVTCVVV DVSHEDPEVK FNWYVDGVEV HNAKTKPREE 300 QYNSTYRVVS VLTVLHQDWL NGKEYKCKVS NKALPAPIEK TISKAKGQPR 350 EPQVYTLPPS REEMTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT 400 PPVLDSDGSF FLYSKLTVDK SRWQQGNVFS CSVMHEALHN HYTQKSLSLS 450 PGK 453 Light chain / Chaîne légère / Cadena ligera DIQMTQSPSS LSASVGDRVT ITCRASQYFS SYLAWYQQKP GKAPKLLIYG 50 ASSRASGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQQ YLGSPPTFGQ 100 GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150 DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200 LSSPVTKSFN RGEC 214 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 150-206 267-327 373-431 22''-96'' 150''-206'' 267''-327'' 373''-431'' Intra-L 23'-88' 134'-194' 23'''-88''' 134'''-194''' Inter-H-L 226-214' 226''-214''' Inter-H-H 232-232'' 235-235''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 303, 303''

vidupiprantum vidupiprant {4-[4-(tert-butylcarbamoyl)-2-(2-chloro- 4-cyclopropylbenzenesulfonamido)phenoxy]-5-chloro- 2-fluorophenyl}acetic acid

vidupiprant acide {4-[4-(tert-butylcarbamoyl)-2-(2-chloro- 4-cyclopropylbenzènesulfonamido)phénoxy]-5-chloro- 2-fluorophényl}acétique

vidupiprant ácido {4-[4-(terc-butilcarbamoil)-2-(2-cloro- 4-ciclopropilbencenosulfonamido)fenoxi]-5-cloro-2-fluorofenil}acético

C28H27Cl2FN2O6S

Cl O

H3C H N CO2H H3C NH

CH3 O S O F O Cl

vosaroxinum vosaroxin 7-[(3S,4S)-3-methoxy-4-(methylamino)pyrrolidin-1-yl]-4-oxo- 1-(1,3-thiazol-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid

vosaroxine acide 7-[(3S,4S)-3-méthoxy-4-(méthylamino)pyrrolidin-1-yl]-4-oxo- 1-(1,3-thiazol-2-yl)-1,4-dihydro-1,8-naphtyridine-3-carboxylique

vosaroxina ácido 7-[(3S,4S)-4-(metilamino)-3-metoxipirrolidin-1-il]-4-oxo- 1-(1,3-tiazol-2-il)-1,4-dihidro-1,8-naftiridina-3-carboxílico

336 WHO Drug Information Vol. 25, No. 3, 2011 Recommended INN: List 66

C18H19N5O4S

CH HN 3 H N S H N N N H3CO

CO2H O

AMENDMENTS TO PREVIOUS LISTS MODIFICATIONS APPORTÉES AUX LISTES ANTÉRIEURES MODIFICACIONES A LAS LISTAS ANTERIORES

Recommended International Non Proprietary Names (Rec. INN): List 51 Dénominations communes internationales proposées (DCI Rec.): Liste 51 Denominaciones Comunes Internacionales Propuestas (DCI Rec.): Lista 51 (WHO Drug Information, Vol. 18, No. 1, 2004)

p. 86 cantuzumabum mertansinum# cantuzumab mertansine replace the description and the structure by the following ones cantuzumab mertansine remplacer la description et la structure par les suivantes cantuzumab mertansina sustitúyase la descripción y la estructura por las siguientes

immunoglobulin G1-kappa, anti-[Homo sapiens MUC1 sialylated carbohydrate, tumour-associated (CA242, cancer antigen 242)], humanized monoclonal antibody conjugated to maytansinoid DM1; gamma1 heavy chain (1-449) [humanized VH (Homo sapiens IGHV7-4-1*02 (76.50%) -(IGHD)-IGHJ2*01 R120>Q (111), L123>T (114)) [8.8.12] (1-119) - Homo sapiens IGHG1*01 (120-449)], (222-219')-disulfide with kappa light chain (1'-219') [humanized V-KAPPA (Homo sapiens IGKV2-28*01 (82.00%) -IGKJ3*01 V124>L (109), D125>E (110), I126>L (111)) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; (228-228":231-231")- bisdisulfide dimer; conjugated, on an average of 4 lysyl, to maytansinoid DM1 [N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytansine] via the reductible SPP linker [N-succinimidyl 4-(2-pyridyldithio)pentanoate] For the mertansine part, please refer to the document "INN for pharmaceutical substances: Names for radicals, groups and others"*

immunoglobuline G1-kappa, anti-[Homo sapiens glycane sialylé de MUC1, associé à des tumeurs (CA242, antigène du cancer 242)], anticorps monoclonal humanisé conjugué au maytansinoïde DM1; chaîne lourde gamma1 (1-449) [VH humanisé (Homo sapiens IGHV7-4- 1*02 (76.50%) -(IGHD)-IGHJ2*01 R120>Q (111), L123>T (114)) [8.8.12] (1- 119) -Homo sapiens IGHG1*01 (120-449)], (222-219')-disulfure avec la chaîne légère kappa (1'-219') [V-KAPPA humanisé (Homo sapiens IGKV2- 28*01 (82.00%) -IGKJ3*01 V124>L (109), D125>E (110), I126>L (111)) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; dimère (228- 228":231-231")-bisdisulfure; conjugué, sur 4 lysyl en moyenne, au maytansinoïde DM1 [N2'-déacétyl-N2'-(3-mercapto-1-oxopropyl)-maytansine] via le linker SPP réductible [4-(2-pyridyldithio)pentanoate de N-succinimidyle] Pour la partie mertansine, veuillez vous référer au document "INN for pharmaceutical substances: Names for radicals, groups and others"*

337 Recommended INN: List 66 WHO Drug Information Vol. 25, No. 3, 2011

inmunoglobulina G1-kappa, anti-[glicano sialilado de MUC1 de Homo sapiens, asociado a tumores (CA242, antígeno del cáncer 242)], anticuerpo monoclonal humanizado conjugado con el maitansinoide DM1; cadena pesada gamma1 (1-449) [VH humanizada (Homo sapiens IGHV7-4- 1*02 (76.50%) -(IGHD)-IGHJ2*01 R120>Q (111), L123>T (114)) [8.8.12] (1- 119) -Homo sapiens IGHG1*01 (120-449)], (222-219')-disulfuro con la cadena ligera kappa (1'-219') [V-KAPPA humanizada (Homo sapiens IGKV2-28*01 (82.00%) -IGKJ3*01 V124>L (109), D125>E (110), I126>L (111)) [11.3.9] (1'- 112') -Homo sapiens IGKC*01 (113'-219')]; dímero (228-228":231-231")- bisdisulfuro; conjugado, por término medio, en 4 grupos lisil, con el maitansinoide DM1 [N2'-desacetil-N2'-(3-mercapto-1-oxopropil)-maitansina] mediante el espaciador SPP reducible [4-(2-piridilditio)pentanoato de N-succinimidilo] Para la mertansina, por favor, consulten el documento "INN for pharmaceutical substances: Names for radicals, groups and others"*.

cantuzumab/ cantuzumab / cantuzumab

Heavy chain / Chaîne lourde / Cadena pesada QVQLVQSGAE VKKPGETVKI SCKASDYTFT YYGMNWVKQA PGQGLKWMGW 50 IDTTTGEPTY AQKFQGRIAF SLETSASTAY LQIKSLKSED TATYFCARRG 100 PYNWYFDVWG QGTTVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD 150 YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY 200 ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK 250 DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS 300 TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV 350 YTLPPSRDEL TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL 400 DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK 449

Light chain / Chaîne légère / Cadena ligera DIVMTQSPLS VPVTPGEPVS ISCRSSKSLL HSNGNTYLYW FLQRPGQSPQ 50 LLIYRMSNLV SGVPDRFSGS GSGTAFTLRI SRVEAEDVGV YYCLQHLEYP 100 FTFGPGTKLE LKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK 150 VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE 200 VTHQGLSSPV TKSFNRGEC 219

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 146-202 263-323 369-427 22''-96'' 146''-202'' 263''-323'' 369''-427'' Intra-L 23'-93' 139'-199' 23'''-93''' 139'''-199''' Inter-H-L 222-219' 222''-219''' Inter-H-H 228-228'' 231-231''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 299, 299'' mertansine / mertansine / mertansina

O O H CH3 S O Ig N S N H CH3 H3C CH3 O CH3 Cl O H H3C N OCH3 H H H O O OH O N H HOCH 3 CH3 4

cantuzumab = Ig(NH2)4

338 WHO Drug Information Vol. 25, No. 3, 2011 Recommended INN: List 66

Recommended International Non Proprietary Names (Rec. INN): List 65 Dénominations communes internationales proposées (DCI Rec.): Liste 65 Denominaciones Comunes Internacionales Propuestas (DCI Rec.): Lista 65 (WHO Drug Information, Vol. 25, No. 1, 2011)

p. 84 samalizumabum # samalizumab replace the description by the following one samalizumab remplacer la description par la suivante samalizumab sustitúyase la descripción por la siguiente

immunoglobulin G2/4-kappa, anti-[Homo sapiens CD200 (OX-2)], humanized monoclonal antibody; gamma2/4 heavy chain (1-442) [humanized VH (Homo sapiens IGHV1-69*01 (73.50%) -(IGHD)-IGHJ4*01 L123>T (112), V124>L (113)) [8.8.10] (1-117) - Homo sapiens IGHG2*01 CH1-hinge-CH2 1.6-1.1 (118-232)- IGHG4*01 CH2 1-125, CH3 1-129 K130>del (233-442)], (131-214')-disulfide with kappa light chain (1'-214') [humanized V-KAPPA (Homo sapiens IGKV1-33*01 (81.10%) - IGKJ2*01 Q120>G (100)) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; (219-219":220-220":223-223":226-226")-tetrakisdisulfide dimer

immunoglobuline G2/4-kappa, anti-[Homo sapiens CD200 (OX-2)], anticorps monoclonal humanisé; chaîne lourde gamma2/4 (1-442) [VH humanisé (Homo sapiens IGHV1-69*01 (73.50%) -(IGHD)-IGHJ4*01 L123>T (112), V124>L (113)) [8.8.10] (1-117) - Homo sapiens IGHG2*01 CH1-charnière-CH2 1.6-1.1 (118-232)- IGHG4*01 CH2 1-125, CH3 1-129 K130>del (233-442)], (131-214')-disulfure avec la chaîne légère kappa (1'-214') [V-KAPPA humanisé (Homo sapiens IGKV1- 33*01 (81.10%) -IGKJ2*01 Q120>G (100)) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dimère (219-219":220-220":223-223":226-226")- tétrakisdisulfure

inmunoglobulina G2/4-kappa, anti-[Homo sapiens CD200 (OX-2)], anticuerpo monoclonal humanizado; cadena pesada gamma2/4 (1-442) [humanizado VH (Homo sapiens IGHV1- 69*01 (73.50%) - (IGHD)-IGHJ4*01 L123>T (112), V124>L (113)) [8.8.10] (1- 117) -Homo sapiens IGHG2*01 CH1-bisagra-CH2 1.6-1.1 (118-232)- IGHG4*01 CH2 1-125, CH3 1-129 K130>del (233-442)], (131-214')-disulfuro con la cadena ligera kappa (1'-214') [V-KAPPA humanizada(Homo sapiens IGKV1-33*01 (81.10%) -IGKJ2*01 Q120>G (100)) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dímero (219-219":220-220":223-223":226-226")-tetrakisdisulfuro

p. 95 vorapaxarum vorapaxar replace the chemical name by the following

ethyl [(1R,3aR,4aR,6R,8aR,9S,9aS)-9-{(1E)-2-[5-(3-fluorophenyl)pyridin- 2-yl]ethen-1-yl}-1-methyl-3-oxododecahydronaphtho[2,3-c]furan-6-yl]carbamate

339 Recommended INN: List 66 WHO Drug Information Vol. 25, No. 3, 2011

* "INN for pharmaceutical substances: Names for radicals, groups & others" document available at / document disponible à / documento disponible en : http://www.who.int/medicines/services/inn/publication/en/index.html

# Electronic structure available on Mednet: http://mednet.who.int/ # Structure électronique disponible sur Mednet: http://mednet.who.int/ # Estructura electrónica disponible en Mednet: http://mednet.who.int/

Procedure and Guiding Principles / Procédure et Directives / Procedimientos y principios generales The text of the Procedures for the Selection of Recommended International Nonproprietary Names for Pharmaceutical Substances and General Principles for Guidance in Devising International Nonproprietary Names for Pharmaceutical Substances will be reproduced in proposed INN lists only. Les textes de la Procédure à suivre en vue du choix de dénominations communes internationales recommandées pour les substances pharmaceutiques et des Directives générales pour la formation de dénominations communes internationales applicables aux substances pharmaceutiques seront publiés seulement dans les listes des DCI proposées. El texto de los Procedimientos de selección de denominaciones comunes internacionales recomendadas para las sustancias farmacéuticas y de los Principios generales de orientación para formar denominaciones comunes internacionales para sustancias farmacéuticas aparece solamente en las listas de DCI propuestas.

340