DRAFT NOTE for GUIDANCE on ORGANIC IMPURITIES in 3 ACTIVE PHARMACEUTICAL INGREDIENTS and FINISHED 4 PHARMACEUTICAL PRODUCTS 5 (July 2016)

Working document QAS/15.606/Rev2 July 2016 Draft document for comment

2 DRAFT NOTE FOR GUIDANCE ON ORGANIC IMPURITIES IN 3 ACTIVE PHARMACEUTICAL INGREDIENTS AND FINISHED 4 PHARMACEUTICAL PRODUCTS 5 (July 2016)

7 DRAFT FOR COMMENT

Should you have any comments on the attached text, please send these to Dr Herbert Schmidt, Medicines Quality Assurance, Technologies, Standards and Norms, World Health Organization, 1211 Geneva 27, Switzerland; email: [email protected]; fax: (+41 22) 791 4730) by 16 September 2016.

In order to speed up the process for receiving draft monographs and for sending comments, please let us have your email address (to [email protected]) and we will add it to our electronic mailing list. Please specify if you wish to receive monographs. 9 10 ______11 © World Health Organization 2016 12 All rights reserved. 13 This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The 14 draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, 15 in any form or by any means outside these individuals and organizations (including the organizations' concerned staff and 16 member organizations) without the permission of the World Health Organization. The draft should not be displayed on any 17 website. 18 Please send any request for permission to: 19 Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies, Standards and Norms, Department of Essential 20 Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland. 21 Fax: (41-22) 791 4730; email: [email protected]. 22 The designations employed and the presentation of the material in this draft do not imply the expression of any opinion 23 whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or 24 of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate 25 border lines for which there may not yet be full agreement. 26 The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or 27 recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors 28 and omissions excepted, the names of proprietary products are distinguished by initial capital letters. 29 All reasonable precautions have been taken by the World Health Organization to verify the information contained in this 30 draft. However, the printed material is being distributed without warranty of any kind, either expressed or implied. The 31 responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health 32 Organization be liable for damages arising from its use. 33 This draft does not necessarily represent the decisions or the stated policy of the World Health Organization. 34 Working document QAS/15.606/Rev 2 page 2

35 SCHEDULE FOR THE ADOPTION PROCESS OF DOCUMENT QAS/15.606

36 DRAFT NOTE FOR GUIDANCE ON ORGANIC IMPURITIES IN ACTIVE 37 PHARMACEUTICAL INGREDIENTS AND FINISHED PHARMACEUTICAL 38 PRODUCTS 39

Date

First draft prepared by the Secretariat of January–March 2015 The International Pharmacopeia with feedback from a group of experts

Discussion at consultation on new 13–15 April 2015 medicines, quality control and laboratory standards

First draft sent out for public consultation April 2015

Review of comments received by the August 2015 Secretariat of The International Pharmacopoeia and a group of experts; possible revision of the text

Presentation to WHO Expert Committee on October 2015 Specifications for Pharmaceutical Preparations for adoption

Preparation of the first revised draft (Rev.1) November 2015–March 2016 by Dr M. Brits, considering the feedback received from the members of the Subgroup and the members of the Expert Committee during the 51st meeting

First draft sent out for comments to April 2016 Working group as recommended during the 50th meeting of the WHO Expert Committee on Specifications for Pharmaceutical Preparations

Discussion at consultation on quality 9–11 May 2016 control laboratory tools and specifications for medicines

Preparation of second revised draft (Rev.2), June–July 2016

Working document QAS/15.606/Rev2 page 3

considering comments received from the working group.

Draft (Rev.2) sent out for public July 2016 consultation

Review of comments received September 2016

Presentation to WHO Expert Committee on October 2016 Specifications for Pharmaceutical Preparations for adoption

Further follow-up action as required 40

3 Working document QAS/15.606/Rev 2 page 4

42 DRAFT NOTE FOR GUIDANCE ON ORGANIC IMPURITIES IN 43 ACTIVE PHARMACEUTICAL INGREDIENTS AND FINISHED 44 PHARMACEUTICAL PRODUCTS 45

46 [Note from the Secretariat. Considering current practices in use for The International 47 Pharmacopoeia and available guidance on how to establish limits for impurities, the 48 following note for guidance on organic impurities in active pharmaceutical substances and 49 finished pharmaceutical products was drafted.

50 It is intended to replace the text on Related substances in finished pharmaceutical product 51 monographs in the folder Notes for guidance, Supplementary information section with the 52 following chapter.]

54 1. SCOPE

55 Purity is a critical attribute of active pharmaceutical ingredients (APIs) and finished 56 pharmaceutical products (FPPs), which potentially affects their safety and efficacy. 57 Therefore, API and FPP monographs in The International Pharmacopoeia (Ph.Int.) shall 58 contain specifications for purity which include requirements for the control of impurities, 59 wherever possible.

60 Impurities in APIs and FPPs may include starting materials, by-products, intermediates, 61 degradation products, reagents, ligands, residual catalysts and residual solvents. They can be 62 classified as either organic, inorganic or biological.

63 This guidance note covers requirements for controlling organic process-related impurities and 64 degradation products in APIs and FPPs, and provides guidance on how to assess compliance 65 with Ph.Int. requirements.

66 Statements in this document are applicable to monographs included in the Ph.Int. after the 67 publication of this guidance note. Compliance with monographs published before this 68 updated guidance shall be evaluated against the previous text Related substances in dosage 69 form monographs1 unless required otherwise by the competent authority. A list of all 70 monographs included in the Ph.Int. before the publication of this guidance note is presented 71 in the document titled Monographs to be evaluated against the text Related substances in 72 dosage form monographs which can be found in The International Pharmacopoeia under 73 Supplementary information. [Note from the Secretariat. The mentioned list is attached at the 74 end of this document.]

1 Once this new guidance note is adopted by the Expert Committee on Specifications for Pharmaceutical Substances, the replaced text can be found on the homepage of The International Pharmacopoeia under Omitted texts.

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75 Excluded from this guidance note are biological/biotechnological products, peptides, 76 oligonucleotides, radiopharmaceuticals, herbal products and crude products of animal and 77 plant origin.

78 Further excluded are the following:

79  extraneous contaminants that should not occur in APIs and FPPs and are more 80 appropriately addressed as good manufacturing practices (GMP) issues; 81  crystallographic modifications (“polymorphic forms”); 82  residual solvents resulting from API or FPP manufacture; 83  impurities that arise from printing inks or excipients (reaction products between 84 excipients and APIs are not excluded); 85  organic impurities that are leached from container-closure systems; 86  fermentation products and semisynthetic products derived therefrom; 87  highly toxic (e.g. genotoxic) impurities or degradation products and residual solvents 88 (volatile organic impurities) are addressed using separate applicable guidance.

89 2. DEFINING THE PURITY OF APIS AND FPPS

90 To control relevant organic impurities individual monographs will contain a stability- 91 indicating test entitled Related substances. This test may be supplemented by a specific test 92 where a given impurity is not adequately controlled by the related substances test or where 93 there are particular reasons (for example, safety reasons a genotoxic/mutagenic or an 94 enantiomeric impurity) requiring specific control.

95 Monographs of APIs shall include specification limits for all impurities (i.e. process-related 96 impurities that result from the manufacturing process and degradation products) observed at 97 levels above the identification threshold. Monographs on FPPs must include appropriate 98 limits for degradation products and, if possible to be detected by the method, impurities from 99 the manufacturing process. This approach provides, in conjunction with the monograph on 100 the API, the means for an independent control laboratory without access to manufacturer’s 101 data to establish whether or not an API of pharmacopoeial quality has been used to 102 manufacture the FPP under examination.2

103 Instruction for control of impurities may also be included in the manufacture section of a 104 monograph, for example, where the only analytical method appropriate for the control of a 105 given impurity is to be performed by the manufacturer since the method is technically too 106 complex for general use. The production process (including the purification steps) should be 107 validated to give sufficient control so that the product, if tested, would comply with the 108 specified limits using a suitable analytical method.

2 It is recognized that limits for degradation impurities given in FPP monographs may need to be higher than the limits for the same impurities that appear in the monograph for the corresponding API to take into account any degradation which may occur during the manufacture and/or storage of the FPP. If the test for impurities in the FPP also limits impurities arising during the API synthesis, the reporting threshold as normally determined for the dosage form degradation products (not as for the API) will apply.

5 Working document QAS/15.606/Rev 2 page 6

109 Under the section on Impurities in the monographs for APIs and FPPs, known impurities are 110 listed (transparency list) that are able to be separated and detected by the described test 111 method(s). In FPPs monographs reference may also be made to the list in the monograph of 112 the corresponding API if the test is able to detect these known impurities. Whenever possible, 113 the impurities are identified as degradation products and/or synthesis-related impurities.

114 Tests for related substances are intended to provide control of known potential or actual 115 impurities rather than to control all possible impurities. The tests are not designed to detect 116 any adventitious contaminants or adulteration. APIs or FPPs found to contain an impurity not 117 detectable by means of the prescribed tests are not of pharmaceutical quality if the nature or 118 amount of the impurity found is incompatible with GMP or applicable regulatory standards.

119 3. GLOSSARY

120 degradation product. An impurity resulting from a chemical change in the active 121 pharmaceutical ingredient (API) brought about during manufacture and/or storage of the API 122 or the dosage form by the effect of, for example, light, oxygen, temperature, pH, water or by 123 reaction with an excipient or another API (in fixed-dose combination dosage form) and/or the 124 immediate container-closure system.

125 extraneous contaminant. An impurity arising from any source extraneous to the 126 manufacturing process.

127 identification threshold. A limit above (>) which an impurity should be identified, 128 based on the applicable regulatory standards.

129 identified impurity. An impurity for which a structural characterization has been 130 achieved.

131 impurity (API). Any component of an API that is not the chemical entity defined as 132 the API.

133 impurity (FPP). Any component of the FPP that is not the API or an excipient in the 134 FPP.

135 independent control laboratory. [Note by the Secretariat. Definition is under 136 preparation.]

137 intermediate. A material produced during steps of the synthesis of an API that 138 undergoes further chemical transformation before it becomes an active pharmaceutical 139 ingredient.

140 ligand. An agent with a strong affinity to a metal ion.

141 polymorphic forms. Different crystalline forms of the active pharmaceutical 142 ingredient. These can include solvation or hydration products (also known as pseudo- 143 polymorphs) and amorphous forms.

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144 qualification threshold. A limit above (>) which an impurity should be qualified.

145 reporting threshold. a limit above which an impurity is to be reported. 146 147 specified impurity. An impurity that is individually listed and limited with a specific 148 acceptance criterion in the monograph. A specified impurity can be either identified or 149 unidentified.

150 starting material. A material used in the synthesis of an active pharmaceutical 151 ingredient (API) that is incorporated as an element into the structure of an intermediate and/or 152 of the API. Starting materials are normally commercially available and of defined chemical 153 and physical properties and structure.

154 unidentified impurity. An impurity for which a structural characterization has not 155 been achieved and that is defined solely by qualitative analytical properties (e.g. 156 chromatographic retention time).

157 unspecified impurity. An impurity that is limited by a general acceptance criterion, 158 but not individually listed with its own specific acceptance criterion (e.g. relative retention 159 time).

160 4. SETTING ACCEPTANCE CRITERIA FOR ORGANIC IMPURITIES

161 Limits in the Ph.Int. are usually set based on:

162  the evaluation of information, provided by manufacturers, concerning the nature of 163 impurities, the reason for their presence, the concentrations that may be encountered 164 in material produced under GMP, the manner in which the API or FPP may change 165 during storage and when subjected to stress conditions (e.g. light, heat, moisture, acid, 166 base or oxygen) and information on the toxicity of any organic impurity in relation to 167 that of the substance itself; 168  justified limits accepted when the marketing authorization was granted or when the 169 product was included in the WHO list of prequalified APIs or prequalified FPPs. Such 170 acceptance included establishing the qualification of the limits by scientific principles 171 inter alia ICH Q3 guidelines; 172  limits published by other pharmacopoeias applying good pharmacopoeial practices 173 (GPhP);3 174  principles published in current regulatory guidance documents, such as those 175 published by the International Council on Harmonisation of Technical Requirements 176 for Registration of Pharmaceuticals for Human Use (ICH).

3 At the time this note for guidance was drafted the draft proposal for GPhP (QAS/13.526/Rev.5) was sent out for public consultation (see http://www.who.int/medicines/areas/quality_safety/quality_assurance/GPhP-Rev5- QAS13-526.pdf?ua=1 ). The statement made thus refers to the future, i.e. to a time when GPhP have been implemented and put into practice by pharmacopoeias.

7 Working document QAS/15.606/Rev 2 page 8

177 Safety considerations are of particular importance in establishing acceptance criteria for 178 impurities.

179 The historical safety record, the route of administration, the type of dosage form, the 180 maximum daily dose, the duration of treatment, the need for and the availability of the 181 medicine are also to be taken into consideration when setting limits for impurities.

182 Also, comments received on the draft monographs from Member States, stakeholders and 183 other interested parties during the public consultation phase are reviewed and considered.

184 5. CLAIMING COMPLIANCE WITH THE REQUIREMENTS BY A 185 MANUFACTURER 186 187 In the event of monographs that were published prior to the publication of this guidance note 188 which have no related substances test (or equivalent) or where the existing test does not 189 comply with the requirements of the applicable regulatory standards the manufacturer shall 190 nevertheless ensure that there is suitable control of organic impurities.

191 When an API contains impurities other than those mentioned in the Impurities section (for 192 example, because it was manufactured using an alternative method of synthesis) the 193 manufacturer must ascertain that these impurities can be controlled by the method(s) and 194 limits described in the monograph; otherwise a new method and specifications shall be 195 developed and submitted to the competent authority for approval, while a revision of the 196 monograph of The International Pharmacopoeia shall be proposed by the manufacturer.

197 When a chromatographic peak (at a level greater than the applicable identification threshold) 198 cannot be assigned unambiguously to an impurity in the transparency list using the means 199 described in the monograph (e.g. by means of retention times, relative retentions or 200 comparison to reference substances mentioned in the monograph) the manufacturer has to 201 apply additional measures in order to identify the impurity. These measures may include, for 202 example, ensuring that the response is not due to the chromatographic solvent system or 203 excipients used in the formulation and the identification of potential impurities not referred to 204 in the monograph by the use of additional analytical techniques, e.g. so-called hyphenated 205 analytical techniques, e.g. gas chromatography- or liquid chromatography-mass spectrometric 206 methods. If identification by structure is initially not possible the impurity could be listed as 207 an unidentified specified impurity until identification has been achieved.

208 When a related substance not listed in the transparency list is found in an API or in an FPP (at 209 a level above the identification threshold) it is the responsibility of the manufacturer to 210 demonstrate that it is identified and a qualified limit is set, in accordance with the applicable 211 regulatory standards, and to communicate this to The International Pharmacopoeia.

212

213

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214 Monographs to be evaluated against the text Related substances in 215 dosage form monographs

216 A list of all monographs included in The International Pharmacopoeia before the publication 217 of the guidance note: Guidance on organic impurities in active pharmaceutical ingredients 218 and finished pharmaceutical products is presented in this document. Compliance of the 219 monographs listed hereunder shall be evaluated against the previous text Related substances 220 in dosage form monographs4 unless required otherwise by the competent authority.

221 In the event that a revision of any of the specified text is to be published in The International 222 Pharmacopoeia, the revised text will be removed from this list and compliance of the revised 223 text will be evaluated against the Guidance on organic impurities in active pharmaceutical 224 ingredients and finished pharmaceutical products guidance note.

225 Pharmaceutical substances monographs

226 Abacavir sulfate 227 Acacia 228 Acetazolamide 229 Acetic acid 230 Acetylsalicylic acid 231 Aciclovir 232 Albendazole 233 Alcohol 234 Alcuronium chloride 235 Alginic acid 236 Allopurinol 237 Aluminium hydroxide 238 Aluminium magnesium silicate 239 Aluminium sulfate 240 Amidotrizoic acid 241 Amikacin sulfate 242 Amikacin 243 Amiloride hydrochloride 244 Aminophylline 245 Amitriptyline hydrochloride 246 Amodiaquine 247 Amodiaquine hydrochloride 248 Amoxicillin trihydrate 249 Amphotericin B 250 Ampicillin 251 Ampicillin sodium 252 Anaesthetic Ether

4 Once the new guidance note Guidance on organic impurities in active pharmaceutical ingredients and finished pharmaceutical products is adopted by the Expert Committee on Specifications for Pharmaceutical Substances, the replaced text can be found in The International Pharmacopoeia under Omitted texts.

9 Working document QAS/15.606/Rev 2 page 10

253 Antimony sodium tartrate 254 Arachis oil 255 Artemether 256 Artemisinin 257 Artemotil 258 Artenimol 259 Artesunate 260 Ascorbic acid 261 Atazanavir sulfate 262 Atenolol 263 Atropine sulfate 264 Azathioprine 265 Bacitracin 266 Bacitracin zinc 267 Barium sulfate 268 Beclometasone dipropionate 269 Bentonite 270 Benzalkonium chloride 271 Benzathine benzylpenicillin 272 Benznidazole 273 Benzocaine 274 Benzoic acid 275 Benzyl alcohol 276 Benzyl benzoate 277 Benzyl hydroxybenzoate 278 Benzylpenicillin potassium 279 Benzylpenicillin sodium 280 Bephenium hydroxynaphthoate 281 Betamethasone 282 Betamethasone valerate 283 Biperiden 284 Biperiden hydrochloride 285 Bleomycin hydrochloride 286 Bleomycin sulfate 287 Bupivacaine hydrochloride 288 Busulfan 289 Butylated hydroxyanisole 290 Butylated hydroxytoluene 291 Caffeine 292 Calamine 293 Calcium carbonate 294 Calcium folinate 295 Calcium gluconate 296 Calcium hydrogen phosphate 297 Calcium phosphate 298 Calcium stearate 299 Calcium sulfate

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300 Capreomycin sulfate 301 Captopril 302 Carbamazepine 303 Carbidopa 304 Carbomer 305 Carmellose sodium 306 Carnauba wax 307 Cellacefate 308 Cetomacrogol 1000 309 Cetostearyl alcohol 310 Cetrimide 311 Cetyl alcohol 312 Cetyl esters wax 313 Charcoal, activated 314 Chloral hydrate 315 Chlorambucil 316 Chloramphenicol 317 Chloramphenicol palmitate 318 Chloramphenicol sodium succinate 319 Chlorhexidine diacetate 320 Chlorhexidine dihydrochloride 321 Chlormethine hydrochloride 322 Chlorobutanol 323 Chlorocresol 324 Chloroquine phosphate 325 Chloroquine sulfate 326 Chlorphenamine hydrogen maleate 327 Chlorpromazine hydrochloride 328 Chlortalidone 329 Chlortetracycline hydrochloride 330 Ciclosporin 331 Cimetidine 332 Ciprofloxacin 333 Ciprofloxacin hydrochloride 334 Cisplatin 335 Citric acid 336 Clindamycin phosphate 337 Clofazimine 338 Clomifene citrate 339 Cloxacillin sodium 340 Coal tar 341 Codeine monohydrate 342 Codeine phosphate 343 Colchicine 344 Colecalciferol 345 Cyanocobalamin

11 Working document QAS/15.606/Rev 2 page 12

346 Cyclophosphamide 347 Cycloserine 348 Cytarabine 349 Dacarbazine 350 Dactinomycin 351 Dapsone 352 Deferoxamine mesilate 353 Dehydroemetine dihydrochloride 354 Dexamethasone 355 Dexamethasone acetate 356 Dexamethasone sodium phosphate 357 Dextromethorphan hydrobromide 358 Diazepam 359 Diazoxide 360 Dicloxacillin sodium 361 Dicoumarol 362 Didanosine 363 Diethylcarbamazine dihydrogen citrate 364 Diethyltoluamide 365 Digitoxin 366 Digoxin 367 Diloxanide furoate 368 Dilute hydrochloric acid 369 Diluted Isosorbide dinitrate 370 Dimercaprol 371 Dinitrogen oxide 372 Diphenoxylate hydrochloride 373 Disodium edetate 374 Dithranol 375 Dopamine hydrochloride 376 Doxorubicin hydrochloride 377 Doxycycline hyclate 378 Edrophonium chloride 379 Efavirenz 380 Emetine hydrochloride 381 Emtricitabine 382 Ephedrine 383 Ephedrine hydrochloride 384 Ephedrine sulfate 385 Epinephrine 386 Epinephrine hydrogen tartrate 387 Ergocalciferol 388 Ergometrine hydrogen maleate 389 Ergotamine tartrate 390 Erythromycin 391 Erythromycin ethylsuccinate 392 Erythromycin lactobionate

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393 Erythromycin stearate 394 Ethambutol hydrochloride 395 Ethanol 396 Ethinylestradiol 397 Ethionamide 398 Ethosuximide 399 Ethyl hydroxybenzoate 400 Ethylcellulose 401 Etoposide 402 Ferrous fumarate 403 Ferrous sulfate 404 Fluconazole 405 Flucytosine 406 Fludrocortisone acetate 407 Fluorescein sodium 408 Fluorouracil 409 Fluphenazine decanoate 410 Fluphenazine enantate 411 Fluphenazine hydrochloride 412 Folic acid 413 Furosemide 414 Gallamine triethiodide 415 Gelatin 416 Gentamicin sulfate 417 Glibenclamide 418 Glucose 419 Glycerol 420 Glycerol 85% m/m 421 Glyceryl monostearate 422 Griseofulvin 423 Haloperidol 424 Halothane 425 Hard fat 426 Hard paraffin 427 Heparin calcium 428 Heparin sodium 429 Homatropine hydrobromide 430 Homatropine methylbromide 431 Hydralazine hydrochloride 432 Hydrochloric acid 433 Hydrochlorothiazide 434 Hydrocortisone 435 Hydrocortisone acetate 436 Hydrocortisone sodium succinate 437 Hydrous Benzoyl peroxide 438 Hydroxocobalamin

13 Working document QAS/15.606/Rev 2 page 14

439 Hydroxocobalamin chloride - Hydroxocobalamini sulfas - Hydroxocobalamin sulfate 440 Hydroxyethylcellulose 441 Hydroxypropylcellulose 442 Hypromellose 443 Ibuprofen 444 Idoxuridine 445 Imipramine hydrochloride 446 Indinavir sulfate 447 Indometacin 448 Insulin 449 Iodine 450 Iohexol 451 Iopanoic acid 452 Iotroxic acid 453 Ipecacuanha root 454 Isoniazid 455 Isoprenaline hydrochloride 456 Isoprenaline sulfate 457 Kanamycin acid sulfate 458 Kanamycin monosulfate 459 Kaolin 460 Ketamine hydrochloride 461 Ketoconazole 462 Lactic acid 463 Lactose 464 Lamivudine 465 Levamisole hydrochloride 466 Levodopa 467 Levonorgestrel 468 Levothyroxine sodium 469 Lidocaine 470 Lidocaine hydrochloride 471 Lindane 472 Lithium carbonate 473 Loperamide hydrochloride 474 Lopinavir 475 Lumefantrine 476 Magnesium hydroxide 477 Magnesium oxide 478 Magnesium stearate 479 Magnesium sulfate heptahydrate 480 Mannitol 481 Mebendazole 482 Medroxyprogesterone acetate 483 Mefloquine hydrochloride 484 Meglumine 485 Mercaptopurine

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486 Mercuric oxycyanide 487 DL-Methionine 488 Methotrexate 489 Methyl hydroxybenzoate 490 Methylcellulose 491 Methyldopa 492 Methylrosanilinium chloride 493 Methyltestosterone 494 Methylthioninium chloride 495 Metoclopramide hydrochloride 496 Metrifonate 497 Metronidazole 498 Metronidazole benzoate 499 Miconazole nitrate 500 Microcrystalline cellulose 501 Morphine hydrochloride 502 Morphine sulfate 503 Naloxone hydrochloride 504 Nelfinavir mesilate 505 Neomycin sulfate 506 Neostigmine bromide 507 Neostigmine metilsulfate 508 Nevirapine 509 Niclosamide 510 Nicotinamide 511 Nicotinic acid 512 Nifedipine 513 Nifurtimox 514 Niridazole 515 Nitrazepam 516 Nitrofurantoin 517 Nonoxinol 9 518 Norethisterone acetate 519 Norethisterone 520 Norethisterone enantate 521 Noscapine 522 Noscapine hydrochloride 523 Nystatin 524 Oseltamivir phosphate 525 Oxamniquine 526 Oxygen 527 Oxytetracycline dihydrate 528 Oxytetracycline hydrochloride 529 Oxytocin 530 Papaverine hydrochloride 531 Paracetamol

15 Working document QAS/15.606/Rev 2 page 16

532 Paromomycin sulfate 533 Penicillamine 534 Pentamidine isetionate 535 Pentamidine mesilate 536 Pethidine hydrochloride 537 Phenobarbital 538 Phenobarbital sodium 539 Phenoxymethylpenicillin 540 Phenoxymethylpenicillin calcium 541 Phenoxymethylpenicillin potassium 542 Phenylmercuric nitrate 543 Phenytoin 544 Phenytoin sodium 545 Physostigmine salicylate 546 Phytomenadione 547 Pilocarpine hydrochloride 548 Pilocarpine nitrate 549 Piperazine adipate 550 Piperazine citrate 551 Podophyllum resin 552 Polysorbates 20, 60, 80 553 Potassium chloride 554 Potassium citrate 555 Potassium iodide 556 Povidone 557 Praziquantel 558 Prednisolone 559 Prednisolone acetate 560 Prednisolone sodium phosphate 561 Primaquine diphosphate 562 Probenecid 563 Procainamide hydrochloride 564 Procaine benzylpenicillin 565 Procaine hydrochloride 566 Procarbazine hydrochloride 567 Progesterone 568 Proguanil hydrochloride 569 Promethazine hydrochloride 570 2-Propanol 571 Propranolol hydrochloride 572 Propylene glycol 573 Propyliodone 574 Propyl hydroxybenzoate 575 Propylthiouracil 576 Protamine sulfate 577 Protionamide 578 Purified water

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579 Pyrantel embonate 580 Pyrazinamide 581 Pyridostigmine bromide 582 Pyridoxine hydrochloride 583 Pyrimethamine 584 Quinidine sulfate 585 Quinine bisulfate 586 Quinine dihydrochloride 587 Quinine hydrochloride 588 Quinine sulfate 589 Reserpine 590 Retinol concentrate, oily form 591 Riboflavin 592 Rifampicin 593 Ritonavir 594 Saccharin sodium 595 Salbutamol 596 Salbutamol sulfate 597 Salicylic acid 598 Saquinavir mesilate 599 Saquinavir 600 Selenium disulfide 601 Senna fruit 602 Senna leaf 603 Silver nitrate 604 Sodium amidotrizoate 605 Sodium calcium edetate 606 Sodium chloride 607 Sodium citrate 608 Sodium cromoglicate 609 Sodium fluoride 610 Sodium hydrogen carbonate 611 Sodium hydroxide 612 Sodium nitrite 613 Sodium nitroprusside 614 Sodium salicylate 615 Sodium stibogluconate 616 Sodium sulfate 617 Sodium sulfate, anhydrous 618 Sodium thiosulfate 619 Sodium valproate 620 Spectinomycin hydrochloride 621 Spironolactone 622 Starches 623 Stavudine 624 Sterile water for injections

17 Working document QAS/15.606/Rev 2 page 18

625 Streptomycin sulfate 626 Sulfacetamide 627 Sulfacetamide sodium 628 Sulfadiazine silver 629 Sulfadimidine 630 Sulfadimidine sodium 631 Sulfadoxine 632 Sulfamethoxazole 633 Sulfamethoxypyridazine 634 Sulfasalazine 635 Suramin sodium 636 Suxamethonium chloride 637 Talc 638 Tamoxifen citrate 639 Tenofovir disoproxil fumarate 640 Testosterone enantate 641 Testosterone propionate 642 Tetracaine hydrochloride 643 Tetracycline hydrochloride 644 Thiamine hydrobromide 645 Thiamine hydrochloride 646 Thiamine mononitrate 647 Thioacetazone 648 Thiopental sodium 649 Tiabendazole 650 Timolol maleate 651 Tolbutamide 652 Trihexyphenidyl hydrochloride 653 Trimethadione 654 Trimethoprim 655 Tropicamide 656 Tubocurarine chloride 657 Verapamil hydrochloride 658 Vinblastine sulfate 659 Vincristine sulfate 660 Warfarin sodium 661 Water for injections 662 White, soft paraffin; Yellow soft paraffin 663 Wool fat 664 Zidovudine 665 Zinc acetate 666 Zinc gluconate 667 Zinc oxide 668 Zinc sulfate 669

670

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671 Dosage form monographs

672 Abacavir oral solution 673 Abacavir tablets 674 Acetylsalicylic acid tablets 675 Aciclovir for injection 676 Aciclovir tablets 677 Albendazole chewable tablets 678 Allopurinol tablets 679 Amikacin for injection 680 Amodiaquine tablets 681 Amoxicillin oral suspension 682 Amphotericin B for injection 683 Ampicillin capsules 684 Ampicillin sodium for injection 685 Artemether and lumefantrine oral suspension 686 Artemether and lumefantrine tablets 687 Artemether capsules 688 Artemether injection 689 Artemether tablets 690 Artemotil injection 691 Artenimol tablets 692 Artesunate for injection 693 Artesunate tablets 694 Atazanavir capsules 695 Atropine sulfate tablets 696 Benzylpenicillin potassium for injection 697 Capreomycin for injection 698 Carbamazepine tablets 699 Chewable mebendazole tablets 700 Chloroquine phosphate tablets 701 Chloroquine sulfate oral solution 702 Chloroquine sulfate tablets 703 Chlorphenamine hydrogen maleate tablets 704 Cloxacillin sodium capsules 705 Cloxacillin sodium for injection 706 Codeine phosphate tablets 707 Colchicine tablets 708 Cycloserine capsules 709 Dapsone tablets 710 Dexamethasone phosphate injection 711 Dexamethasone tablets 712 Didanosine oral powder 713 Didanosine tablets 714 Diethylcarbamazine dihydrogen citrate tablets 715 Diloxanide furoate tablets 716 Doxycycline capsules

19 Working document QAS/15.606/Rev 2 page 20

717 Doxycycline tablets 718 Efavirenz capsules 719 Efavirenz oral solution 720 Efavirenz tablets 721 Efavirenz, emtricitabine and tenofovir tablets 722 Emtricitabine and tenofovir tablets 723 Emtricitabine capsules 724 Ephedrine sulfate injection 725 Ergometrine hydrogen maleate tablets 726 Ergometrine injection 727 Erythromycin ethylsuccinate tablets 728 Erythromycin stearate tablets 729 Ethambutol hydrochloride tablets 730 Fluconazole capsules 731 Fluconazole injection 732 Glyceryl trinitrate tablets 733 Griseofulvin tablets 734 Ibuprofen tablets 735 Indinavir capsules 736 Indometacin tablets 737 Isoniazid and ethambutol hydrochloride tablets 738 Isoniazid tablets 739 Kanamycin for injection 740 Lamivudine oral solution 741 Lamivudine tablets 742 Levamisole tablets 743 Levonorgestrel and ethinylestradiol tablets 744 Levonorgestrel tablets 745 Lopinavir and ritonavir tablets 746 Magnesium sulfate injection 747 Medroxyprogesterone injection 748 Mefloquine tablets 749 Melarsoprol injection 750 Metronidazole injection 751 Metronidazole oral suspension 752 Metronidazole tablets 753 Morphine sulfate tablets 754 Nelfinavir mesilate oral powder 755 Nelfinavir mesilate tablets 756 Nevirapine oral suspension 757 Nevirapine tablets 758 Niclosamide tablets 759 Nitrofurantoin tablets 760 Nystatin tablets 761 Oral rehydration salts 762 Oseltamivir capsules 763 Oxytocin injection

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764 Paediatric didanosine liquid for oral use 765 Paediatric zinc sulfate oral solution 766 Paediatric zinc sulfate tablets 767 Paracetamol oral solution 768 Paracetamol oral suspension 769 Paracetamol tablets 770 Pentamidine isetionate for injection 771 Pethidine hydrochloride tablets 772 Phenobarbital tablets 773 Phenoxymethylpenicillin potassium tablets 774 Phenytoin sodium tablets 775 Piperazine adipate tablets 776 Piperazine citrate tablets 777 Praziquantel tablets 778 Prednisolone phosphate injection 779 Prednisolone sodium succinate for injection 780 Prednisolone tablets 781 Primaquine diphosphate tablets 782 Probenecid tablets 783 Procaine benzylpenicillin for injection 784 Pyrantel chewable tablets 785 Pyrantel oral suspension 786 Pyrantel tablets 787 Pyrazinamide tablets 788 Quinine bisulfate tablets 789 Quinine dihydrochloride injection 790 Quinine sulfate tablets 791 Retinol oral solution 792 Rifampicin and isoniazid dispersible tablets 793 Rifampicin and isoniazid tablets 794 Rifampicin capsules 795 Rifampicin tablets 796 Rifampicin, isoniazid and ethambutol hydrochloride tablets 797 Rifampicin, isoniazid and pyrazinamide dispersible tablets 798 Rifampicin, isoniazid and pyrazinamide tablets 799 Rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride tablets 800 Ritonavir tablets 801 Saquinavir mesilate capsules 802 Saquinavir tablets 803 Sodium bicarbonate intravenous infusion 804 Stavudine capsules 805 Streptomycin for injection 806 Sulfadoxine and pyrimethamine tablets 807 Sulfamethoxazole and trimethoprim intravenous infusion 808 Sulfamethoxazole and trimethoprim oral suspension 809 Sulfamethoxazole and trimethoprim tablets

21 Working document QAS/15.606/Rev 2 page 22

810 Tenofovir tablets 811 Zidovudine and lamivudine tablets 812 Zidovudine capsules 813 Zidovudine intravenous infusion 814 Zidovudine, lamivudine and abacavir tablets 815 Zidovudine, lamivudine and nevirapine tablets 816 Zidovudine oral solution 817

818 ***