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Working document QAS/15.606/Rev2
July 2016
Draft document for comment
1
DRAFT NOTE FOR GUIDANCE ON ORGANIC IMPURITIES IN 2
ACTIVE PHARMACEUTICAL INGREDIENTS AND FINISHED 3
PHARMACEUTICAL PRODUCTS 4
(July 2016) 5
6
DRAFT FOR COMMENT 7
8
9
____________________________________________________________________________________________________ 10
© World Health Organization 2016 11
All rights reserved. 12
This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The 13 draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, 14 in any form or by any means outside these individuals and organizations (including the organizations' concerned staff and 15 member organizations) without the permission of the World Health Organization. The draft should not be displayed on any 16 website. 17
Please send any request for permission to: 18
Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies, Standards and Norms, Department of Essential 19 Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland. 20 Fax: (41-22) 791 4730; email: [email protected]. 21
The designations employed and the presentation of the material in this draft do not imply the expression of any opinion 22 whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or 23 of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate 24 border lines for which there may not yet be full agreement. 25
The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or 26 recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors 27 and omissions excepted, the names of proprietary products are distinguished by initial capital letters. 28
All reasonable precautions have been taken by the World Health Organization to verify the information contained in this 29 draft. However, the printed material is being distributed without warranty of any kind, either expressed or implied. The 30 responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health 31 Organization be liable for damages arising from its use. 32
This draft does not necessarily represent the decisions or the stated policy of the World Health Organization. 33 34
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.
Working document QAS/15.606/Rev 2
page 2
2
SCHEDULE FOR THE ADOPTION PROCESS OF DOCUMENT QAS/15.606 35
DRAFT NOTE FOR GUIDANCE ON ORGANIC IMPURITIES IN ACTIVE 36
PHARMACEUTICAL INGREDIENTS AND FINISHED PHARMACEUTICAL 37
PRODUCTS 38
39
Date
First draft prepared by the Secretariat of
The International Pharmacopeia with
feedback from a group of experts
January–March 2015
Discussion at consultation on new
medicines, quality control and laboratory
standards
13–15 April 2015
First draft sent out for public consultation April 2015
Review of comments received by the
Secretariat of The International
Pharmacopoeia and a group of experts;
possible revision of the text
August 2015
Presentation to WHO Expert Committee on
Specifications for Pharmaceutical
Preparations for adoption
October 2015
Preparation of the first revised draft (Rev.1)
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
November 2015–March 2016
First draft sent out for comments to
Working group as recommended during the
50th meeting of the WHO Expert
Committee on Specifications for
Pharmaceutical Preparations
April 2016
Discussion at consultation on quality
control laboratory tools and specifications
for medicines
9–11 May 2016
Preparation of second revised draft (Rev.2), June–July 2016
Working document QAS/15.606/Rev2
page 3
3
considering comments received from the
working group.
Draft (Rev.2) sent out for public
consultation
July 2016
Review of comments received September 2016
Presentation to WHO Expert Committee on
Specifications for Pharmaceutical
Preparations for adoption
October 2016
Further follow-up action as required
40
41
Working document QAS/15.606/Rev 2
page 4
4
DRAFT NOTE FOR GUIDANCE ON ORGANIC IMPURITIES IN 42
ACTIVE PHARMACEUTICAL INGREDIENTS AND FINISHED 43
PHARMACEUTICAL PRODUCTS 44
45
[Note from the Secretariat. Considering current practices in use for The International 46
Pharmacopoeia and available guidance on how to establish limits for impurities, the 47
following note for guidance on organic impurities in active pharmaceutical substances and 48
finished pharmaceutical products was drafted. 49
It is intended to replace the text on Related substances in finished pharmaceutical product 50
monographs in the folder Notes for guidance, Supplementary information section with the 51
following chapter.] 52
53
1. SCOPE 54
Purity is a critical attribute of active pharmaceutical ingredients (APIs) and finished 55
pharmaceutical products (FPPs), which potentially affects their safety and efficacy. 56
Therefore, API and FPP monographs in The International Pharmacopoeia (Ph.Int.) shall 57
contain specifications for purity which include requirements for the control of impurities, 58
wherever possible. 59
Impurities in APIs and FPPs may include starting materials, by-products, intermediates, 60
degradation products, reagents, ligands, residual catalysts and residual solvents. They can be 61
classified as either organic, inorganic or biological. 62
This guidance note covers requirements for controlling organic process-related impurities and 63
degradation products in APIs and FPPs, and provides guidance on how to assess compliance 64
with Ph.Int. requirements. 65
Statements in this document are applicable to monographs included in the Ph.Int. after the 66
publication of this guidance note. Compliance with monographs published before this 67
updated guidance shall be evaluated against the previous text Related substances in dosage 68
form monographs1 unless required otherwise by the competent authority. A list of all 69
monographs included in the Ph.Int. before the publication of this guidance note is presented 70
in the document titled Monographs to be evaluated against the text Related substances in 71
dosage form monographs which can be found in The International Pharmacopoeia under 72
Supplementary information. [Note from the Secretariat. The mentioned list is attached at the 73
end of this document.] 74
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.
Working document QAS/15.606/Rev2
page 5
5
Excluded from this guidance note are biological/biotechnological products, peptides, 75
oligonucleotides, radiopharmaceuticals, herbal products and crude products of animal and 76
plant origin. 77
Further excluded are the following: 78
extraneous contaminants that should not occur in APIs and FPPs and are more 79
appropriately addressed as good manufacturing practices (GMP) issues; 80
crystallographic modifications (“polymorphic forms”); 81
residual solvents resulting from API or FPP manufacture; 82
impurities that arise from printing inks or excipients (reaction products between 83
excipients and APIs are not excluded); 84
organic impurities that are leached from container-closure systems; 85
fermentation products and semisynthetic products derived therefrom; 86
highly toxic (e.g. genotoxic) impurities or degradation products and residual solvents 87
(volatile organic impurities) are addressed using separate applicable guidance. 88
2. DEFINING THE PURITY OF APIS AND FPPS 89
To control relevant organic impurities individual monographs will contain a stability-90
indicating test entitled Related substances. This test may be supplemented by a specific test 91
where a given impurity is not adequately controlled by the related substances test or where 92
there are particular reasons (for example, safety reasons a genotoxic/mutagenic or an 93
enantiomeric impurity) requiring specific control. 94
Monographs of APIs shall include specification limits for all impurities (i.e. process-related 95
impurities that result from the manufacturing process and degradation products) observed at 96
levels above the identification threshold. Monographs on FPPs must include appropriate 97
limits for degradation products and, if possible to be detected by the method, impurities from 98
the manufacturing process. This approach provides, in conjunction with the monograph on 99
the API, the means for an independent control laboratory without access to manufacturer’s 100
data to establish whether or not an API of pharmacopoeial quality has been used to 101
manufacture the FPP under examination.2 102
Instruction for control of impurities may also be included in the manufacture section of a 103
monograph, for example, where the only analytical method appropriate for the control of a 104
given impurity is to be performed by the manufacturer since the method is technically too 105
complex for general use. The production process (including the purification steps) should be 106
validated to give sufficient control so that the product, if tested, would comply with the 107
specified limits using a suitable analytical method. 108
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.
Working document QAS/15.606/Rev 2
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6
Under the section on Impurities in the monographs for APIs and FPPs, known impurities are 109
listed (transparency list) that are able to be separated and detected by the described test 110
method(s). In FPPs monographs reference may also be made to the list in the monograph of 111
the corresponding API if the test is able to detect these known impurities. Whenever possible, 112
the impurities are identified as degradation products and/or synthesis-related impurities. 113
Tests for related substances are intended to provide control of known potential or actual 114
impurities rather than to control all possible impurities. The tests are not designed to detect 115
any adventitious contaminants or adulteration. APIs or FPPs found to contain an impurity not 116
detectable by means of the prescribed tests are not of pharmaceutical quality if the nature or 117
amount of the impurity found is incompatible with GMP or applicable regulatory standards. 118
3. GLOSSARY 119
degradation product. An impurity resulting from a chemical change in the active 120
pharmaceutical ingredient (API) brought about during manufacture and/or storage of the API 121
or the dosage form by the effect of, for example, light, oxygen, temperature, pH, water or by 122
reaction with an excipient or another API (in fixed-dose combination dosage form) and/or the 123
immediate container-closure system. 124
extraneous contaminant. An impurity arising from any source extraneous to the 125
manufacturing process. 126
identification threshold. A limit above (>) which an impurity should be identified, 127
based on the applicable regulatory standards. 128
identified impurity. An impurity for which a structural characterization has been 129
achieved. 130
impurity (API). Any component of an API that is not the chemical entity defined as 131
the API. 132
impurity (FPP). Any component of the FPP that is not the API or an excipient in the 133
FPP. 134
independent control laboratory. [Note by the Secretariat. Definition is under 135
preparation.] 136
intermediate. A material produced during steps of the synthesis of an API that 137
undergoes further chemical transformation before it becomes an active pharmaceutical 138
ingredient. 139
ligand. An agent with a strong affinity to a metal ion. 140
polymorphic forms. Different crystalline forms of the active pharmaceutical 141
ingredient. These can include solvation or hydration products (also known as pseudo-142
polymorphs) and amorphous forms. 143
Working document QAS/15.606/Rev2
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7
qualification threshold. A limit above (>) which an impurity should be qualified. 144
reporting threshold. a limit above which an impurity is to be reported. 145 146
specified impurity. An impurity that is individually listed and limited with a specific 147
acceptance criterion in the monograph. A specified impurity can be either identified or 148
unidentified. 149
starting material. A material used in the synthesis of an active pharmaceutical 150
ingredient (API) that is incorporated as an element into the structure of an intermediate and/or 151
of the API. Starting materials are normally commercially available and of defined chemical 152
and physical properties and structure. 153
unidentified impurity. An impurity for which a structural characterization has not 154
been achieved and that is defined solely by qualitative analytical properties (e.g. 155
chromatographic retention time). 156
unspecified impurity. An impurity that is limited by a general acceptance criterion, 157
but not individually listed with its own specific acceptance criterion (e.g. relative retention 158
time). 159
4. SETTING ACCEPTANCE CRITERIA FOR ORGANIC IMPURITIES 160
Limits in the Ph.Int. are usually set based on: 161
the evaluation of information, provided by manufacturers, concerning the nature of 162
impurities, the reason for their presence, the concentrations that may be encountered 163
in material produced under GMP, the manner in which the API or FPP may change 164
during storage and when subjected to stress conditions (e.g. light, heat, moisture, acid, 165
base or oxygen) and information on the toxicity of any organic impurity in relation to 166
that of the substance itself; 167
justified limits accepted when the marketing authorization was granted or when the 168
product was included in the WHO list of prequalified APIs or prequalified FPPs. Such 169
acceptance included establishing the qualification of the limits by scientific principles 170
inter alia ICH Q3 guidelines; 171
limits published by other pharmacopoeias applying good pharmacopoeial practices 172
(GPhP);3 173
principles published in current regulatory guidance documents, such as those 174
published by the International Council on Harmonisation of Technical Requirements 175
for Registration of Pharmaceuticals for Human Use (ICH). 176
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.
Working document QAS/15.606/Rev 2
page 8
8
Safety considerations are of particular importance in establishing acceptance criteria for 177
impurities. 178
The historical safety record, the route of administration, the type of dosage form, the 179
maximum daily dose, the duration of treatment, the need for and the availability of the 180
medicine are also to be taken into consideration when setting limits for impurities. 181
Also, comments received on the draft monographs from Member States, stakeholders and 182
other interested parties during the public consultation phase are reviewed and considered. 183
5. CLAIMING COMPLIANCE WITH THE REQUIREMENTS BY A 184
MANUFACTURER 185 186 In the event of monographs that were published prior to the publication of this guidance note 187
which have no related substances test (or equivalent) or where the existing test does not 188
comply with the requirements of the applicable regulatory standards the manufacturer shall 189
nevertheless ensure that there is suitable control of organic impurities. 190
When an API contains impurities other than those mentioned in the Impurities section (for 191
example, because it was manufactured using an alternative method of synthesis) the 192
manufacturer must ascertain that these impurities can be controlled by the method(s) and 193
limits described in the monograph; otherwise a new method and specifications shall be 194
developed and submitted to the competent authority for approval, while a revision of the 195
monograph of The International Pharmacopoeia shall be proposed by the manufacturer. 196
When a chromatographic peak (at a level greater than the applicable identification threshold) 197
cannot be assigned unambiguously to an impurity in the transparency list using the means 198
described in the monograph (e.g. by means of retention times, relative retentions or 199
comparison to reference substances mentioned in the monograph) the manufacturer has to 200
apply additional measures in order to identify the impurity. These measures may include, for 201
example, ensuring that the response is not due to the chromatographic solvent system or 202
excipients used in the formulation and the identification of potential impurities not referred to 203
in the monograph by the use of additional analytical techniques, e.g. so-called hyphenated 204
analytical techniques, e.g. gas chromatography- or liquid chromatography-mass spectrometric 205
methods. If identification by structure is initially not possible the impurity could be listed as 206
an unidentified specified impurity until identification has been achieved. 207
When a related substance not listed in the transparency list is found in an API or in an FPP (at 208
a level above the identification threshold) it is the responsibility of the manufacturer to 209
demonstrate that it is identified and a qualified limit is set, in accordance with the applicable 210
regulatory standards, and to communicate this to The International Pharmacopoeia. 211
212
213
Working document QAS/15.606/Rev2
page 9
9
Monographs to be evaluated against the text Related substances in 214
dosage form monographs 215
A list of all monographs included in The International Pharmacopoeia before the publication 216
of the guidance note: Guidance on organic impurities in active pharmaceutical ingredients 217
and finished pharmaceutical products is presented in this document. Compliance of the 218
monographs listed hereunder shall be evaluated against the previous text Related substances 219
in dosage form monographs4 unless required otherwise by the competent authority. 220
In the event that a revision of any of the specified text is to be published in The International 221
Pharmacopoeia, the revised text will be removed from this list and compliance of the revised 222
text will be evaluated against the Guidance on organic impurities in active pharmaceutical 223
ingredients and finished pharmaceutical products guidance note. 224
Pharmaceutical substances monographs 225
Abacavir sulfate 226
Acacia 227
Acetazolamide 228
Acetic acid 229
Acetylsalicylic acid 230
Aciclovir 231
Albendazole 232
Alcohol 233
Alcuronium chloride 234
Alginic acid 235
Allopurinol 236
Aluminium hydroxide 237
Aluminium magnesium silicate 238
Aluminium sulfate 239
Amidotrizoic acid 240
Amikacin sulfate 241
Amikacin 242
Amiloride hydrochloride 243
Aminophylline 244
Amitriptyline hydrochloride 245
Amodiaquine 246
Amodiaquine hydrochloride 247
Amoxicillin trihydrate 248
Amphotericin B 249
Ampicillin 250
Ampicillin sodium 251
Anaesthetic Ether 252
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.
Working document QAS/15.606/Rev 2
page 10
10
Antimony sodium tartrate 253
Arachis oil 254
Artemether 255
Artemisinin 256
Artemotil 257
Artenimol 258
Artesunate 259
Ascorbic acid 260
Atazanavir sulfate 261
Atenolol 262
Atropine sulfate 263
Azathioprine 264
Bacitracin 265
Bacitracin zinc 266
Barium sulfate 267
Beclometasone dipropionate 268
Bentonite 269
Benzalkonium chloride 270
Benzathine benzylpenicillin 271
Benznidazole 272
Benzocaine 273
Benzoic acid 274
Benzyl alcohol 275
Benzyl benzoate 276
Benzyl hydroxybenzoate 277
Benzylpenicillin potassium 278
Benzylpenicillin sodium 279
Bephenium hydroxynaphthoate 280
Betamethasone 281
Betamethasone valerate 282
Biperiden 283
Biperiden hydrochloride 284
Bleomycin hydrochloride 285
Bleomycin sulfate 286
Bupivacaine hydrochloride 287
Busulfan 288
Butylated hydroxyanisole 289
Butylated hydroxytoluene 290
Caffeine 291
Calamine 292
Calcium carbonate 293
Calcium folinate 294
Calcium gluconate 295
Calcium hydrogen phosphate 296
Calcium phosphate 297
Calcium stearate 298
Calcium sulfate 299
Working document QAS/15.606/Rev2
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11
Capreomycin sulfate 300
Captopril 301
Carbamazepine 302
Carbidopa 303
Carbomer 304
Carmellose sodium 305
Carnauba wax 306
Cellacefate 307
Cetomacrogol 1000 308
Cetostearyl alcohol 309
Cetrimide 310
Cetyl alcohol 311
Cetyl esters wax 312
Charcoal, activated 313
Chloral hydrate 314
Chlorambucil 315
Chloramphenicol 316
Chloramphenicol palmitate 317
Chloramphenicol sodium succinate 318
Chlorhexidine diacetate 319
Chlorhexidine dihydrochloride 320
Chlormethine hydrochloride 321
Chlorobutanol 322
Chlorocresol 323
Chloroquine phosphate 324
Chloroquine sulfate 325
Chlorphenamine hydrogen maleate 326
Chlorpromazine hydrochloride 327
Chlortalidone 328
Chlortetracycline hydrochloride 329
Ciclosporin 330
Cimetidine 331
Ciprofloxacin 332
Ciprofloxacin hydrochloride 333
Cisplatin 334
Citric acid 335
Clindamycin phosphate 336
Clofazimine 337
Clomifene citrate 338
Cloxacillin sodium 339
Coal tar 340
Codeine monohydrate 341
Codeine phosphate 342
Colchicine 343
Colecalciferol 344
Cyanocobalamin 345
Working document QAS/15.606/Rev 2
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12
Cyclophosphamide 346
Cycloserine 347
Cytarabine 348
Dacarbazine 349
Dactinomycin 350
Dapsone 351
Deferoxamine mesilate 352
Dehydroemetine dihydrochloride 353
Dexamethasone 354
Dexamethasone acetate 355
Dexamethasone sodium phosphate 356
Dextromethorphan hydrobromide 357
Diazepam 358
Diazoxide 359
Dicloxacillin sodium 360
Dicoumarol 361
Didanosine 362
Diethylcarbamazine dihydrogen citrate 363
Diethyltoluamide 364
Digitoxin 365
Digoxin 366
Diloxanide furoate 367
Dilute hydrochloric acid 368
Diluted Isosorbide dinitrate 369
Dimercaprol 370
Dinitrogen oxide 371
Diphenoxylate hydrochloride 372
Disodium edetate 373
Dithranol 374
Dopamine hydrochloride 375
Doxorubicin hydrochloride 376
Doxycycline hyclate 377
Edrophonium chloride 378
Efavirenz 379
Emetine hydrochloride 380
Emtricitabine 381
Ephedrine 382
Ephedrine hydrochloride 383
Ephedrine sulfate 384
Epinephrine 385
Epinephrine hydrogen tartrate 386
Ergocalciferol 387
Ergometrine hydrogen maleate 388
Ergotamine tartrate 389
Erythromycin 390
Erythromycin ethylsuccinate 391
Erythromycin lactobionate 392
Working document QAS/15.606/Rev2
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13
Erythromycin stearate 393
Ethambutol hydrochloride 394
Ethanol 395
Ethinylestradiol 396
Ethionamide 397
Ethosuximide 398
Ethyl hydroxybenzoate 399
Ethylcellulose 400
Etoposide 401
Ferrous fumarate 402
Ferrous sulfate 403
Fluconazole 404
Flucytosine 405
Fludrocortisone acetate 406
Fluorescein sodium 407
Fluorouracil 408
Fluphenazine decanoate 409
Fluphenazine enantate 410
Fluphenazine hydrochloride 411
Folic acid 412
Furosemide 413
Gallamine triethiodide 414
Gelatin 415
Gentamicin sulfate 416
Glibenclamide 417
Glucose 418
Glycerol 419
Glycerol 85% m/m 420
Glyceryl monostearate 421
Griseofulvin 422
Haloperidol 423
Halothane 424
Hard fat 425
Hard paraffin 426
Heparin calcium 427
Heparin sodium 428
Homatropine hydrobromide 429
Homatropine methylbromide 430
Hydralazine hydrochloride 431
Hydrochloric acid 432
Hydrochlorothiazide 433
Hydrocortisone 434
Hydrocortisone acetate 435
Hydrocortisone sodium succinate 436
Hydrous Benzoyl peroxide 437
Hydroxocobalamin 438
Working document QAS/15.606/Rev 2
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14
Hydroxocobalamin chloride - Hydroxocobalamini sulfas - Hydroxocobalamin sulfate 439
Hydroxyethylcellulose 440
Hydroxypropylcellulose 441
Hypromellose 442
Ibuprofen 443
Idoxuridine 444
Imipramine hydrochloride 445
Indinavir sulfate 446
Indometacin 447
Insulin 448
Iodine 449
Iohexol 450
Iopanoic acid 451
Iotroxic acid 452
Ipecacuanha root 453
Isoniazid 454
Isoprenaline hydrochloride 455
Isoprenaline sulfate 456
Kanamycin acid sulfate 457
Kanamycin monosulfate 458
Kaolin 459
Ketamine hydrochloride 460
Ketoconazole 461
Lactic acid 462
Lactose 463
Lamivudine 464
Levamisole hydrochloride 465
Levodopa 466
Levonorgestrel 467
Levothyroxine sodium 468
Lidocaine 469
Lidocaine hydrochloride 470
Lindane 471
Lithium carbonate 472
Loperamide hydrochloride 473
Lopinavir 474
Lumefantrine 475
Magnesium hydroxide 476
Magnesium oxide 477
Magnesium stearate 478
Magnesium sulfate heptahydrate 479
Mannitol 480
Mebendazole 481
Medroxyprogesterone acetate 482
Mefloquine hydrochloride 483
Meglumine 484
Mercaptopurine 485
Working document QAS/15.606/Rev2
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15
Mercuric oxycyanide 486
DL-Methionine 487
Methotrexate 488
Methyl hydroxybenzoate 489
Methylcellulose 490
Methyldopa 491
Methylrosanilinium chloride 492
Methyltestosterone 493
Methylthioninium chloride 494
Metoclopramide hydrochloride 495
Metrifonate 496
Metronidazole 497
Metronidazole benzoate 498
Miconazole nitrate 499
Microcrystalline cellulose 500
Morphine hydrochloride 501
Morphine sulfate 502
Naloxone hydrochloride 503
Nelfinavir mesilate 504
Neomycin sulfate 505
Neostigmine bromide 506
Neostigmine metilsulfate 507
Nevirapine 508
Niclosamide 509
Nicotinamide 510
Nicotinic acid 511
Nifedipine 512
Nifurtimox 513
Niridazole 514
Nitrazepam 515
Nitrofurantoin 516
Nonoxinol 9 517
Norethisterone acetate 518
Norethisterone 519
Norethisterone enantate 520
Noscapine 521
Noscapine hydrochloride 522
Nystatin 523
Oseltamivir phosphate 524
Oxamniquine 525
Oxygen 526
Oxytetracycline dihydrate 527
Oxytetracycline hydrochloride 528
Oxytocin 529
Papaverine hydrochloride 530
Paracetamol 531
Working document QAS/15.606/Rev 2
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16
Paromomycin sulfate 532
Penicillamine 533
Pentamidine isetionate 534
Pentamidine mesilate 535
Pethidine hydrochloride 536
Phenobarbital 537
Phenobarbital sodium 538
Phenoxymethylpenicillin 539
Phenoxymethylpenicillin calcium 540
Phenoxymethylpenicillin potassium 541
Phenylmercuric nitrate 542
Phenytoin 543
Phenytoin sodium 544
Physostigmine salicylate 545
Phytomenadione 546
Pilocarpine hydrochloride 547
Pilocarpine nitrate 548
Piperazine adipate 549
Piperazine citrate 550
Podophyllum resin 551
Polysorbates 20, 60, 80 552
Potassium chloride 553
Potassium citrate 554
Potassium iodide 555
Povidone 556
Praziquantel 557
Prednisolone 558
Prednisolone acetate 559
Prednisolone sodium phosphate 560
Primaquine diphosphate 561
Probenecid 562
Procainamide hydrochloride 563
Procaine benzylpenicillin 564
Procaine hydrochloride 565
Procarbazine hydrochloride 566
Progesterone 567
Proguanil hydrochloride 568
Promethazine hydrochloride 569
2-Propanol 570
Propranolol hydrochloride 571
Propylene glycol 572
Propyliodone 573
Propyl hydroxybenzoate 574
Propylthiouracil 575
Protamine sulfate 576
Protionamide 577
Purified water 578
Working document QAS/15.606/Rev2
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17
Pyrantel embonate 579
Pyrazinamide 580
Pyridostigmine bromide 581
Pyridoxine hydrochloride 582
Pyrimethamine 583
Quinidine sulfate 584
Quinine bisulfate 585
Quinine dihydrochloride 586
Quinine hydrochloride 587
Quinine sulfate 588
Reserpine 589
Retinol concentrate, oily form 590
Riboflavin 591
Rifampicin 592
Ritonavir 593
Saccharin sodium 594
Salbutamol 595
Salbutamol sulfate 596
Salicylic acid 597
Saquinavir mesilate 598
Saquinavir 599
Selenium disulfide 600
Senna fruit 601
Senna leaf 602
Silver nitrate 603
Sodium amidotrizoate 604
Sodium calcium edetate 605
Sodium chloride 606
Sodium citrate 607
Sodium cromoglicate 608
Sodium fluoride 609
Sodium hydrogen carbonate 610
Sodium hydroxide 611
Sodium nitrite 612
Sodium nitroprusside 613
Sodium salicylate 614
Sodium stibogluconate 615
Sodium sulfate 616
Sodium sulfate, anhydrous 617
Sodium thiosulfate 618
Sodium valproate 619
Spectinomycin hydrochloride 620
Spironolactone 621
Starches 622
Stavudine 623
Sterile water for injections 624
Working document QAS/15.606/Rev 2
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18
Streptomycin sulfate 625
Sulfacetamide 626
Sulfacetamide sodium 627
Sulfadiazine silver 628
Sulfadimidine 629
Sulfadimidine sodium 630
Sulfadoxine 631
Sulfamethoxazole 632
Sulfamethoxypyridazine 633
Sulfasalazine 634
Suramin sodium 635
Suxamethonium chloride 636
Talc 637
Tamoxifen citrate 638
Tenofovir disoproxil fumarate 639
Testosterone enantate 640
Testosterone propionate 641
Tetracaine hydrochloride 642
Tetracycline hydrochloride 643
Thiamine hydrobromide 644
Thiamine hydrochloride 645
Thiamine mononitrate 646
Thioacetazone 647
Thiopental sodium 648
Tiabendazole 649
Timolol maleate 650
Tolbutamide 651
Trihexyphenidyl hydrochloride 652
Trimethadione 653
Trimethoprim 654
Tropicamide 655
Tubocurarine chloride 656
Verapamil hydrochloride 657
Vinblastine sulfate 658
Vincristine sulfate 659
Warfarin sodium 660
Water for injections 661
White, soft paraffin; Yellow soft paraffin 662
Wool fat 663
Zidovudine 664
Zinc acetate 665
Zinc gluconate 666
Zinc oxide 667
Zinc sulfate 668
669
670
Working document QAS/15.606/Rev2
page 19
19
Dosage form monographs 671
Abacavir oral solution 672
Abacavir tablets 673
Acetylsalicylic acid tablets 674
Aciclovir for injection 675
Aciclovir tablets 676
Albendazole chewable tablets 677
Allopurinol tablets 678
Amikacin for injection 679
Amodiaquine tablets 680
Amoxicillin oral suspension 681
Amphotericin B for injection 682
Ampicillin capsules 683
Ampicillin sodium for injection 684
Artemether and lumefantrine oral suspension 685
Artemether and lumefantrine tablets 686
Artemether capsules 687
Artemether injection 688
Artemether tablets 689
Artemotil injection 690
Artenimol tablets 691
Artesunate for injection 692
Artesunate tablets 693
Atazanavir capsules 694
Atropine sulfate tablets 695
Benzylpenicillin potassium for injection 696
Capreomycin for injection 697
Carbamazepine tablets 698
Chewable mebendazole tablets 699
Chloroquine phosphate tablets 700
Chloroquine sulfate oral solution 701
Chloroquine sulfate tablets 702
Chlorphenamine hydrogen maleate tablets 703
Cloxacillin sodium capsules 704
Cloxacillin sodium for injection 705
Codeine phosphate tablets 706
Colchicine tablets 707
Cycloserine capsules 708
Dapsone tablets 709
Dexamethasone phosphate injection 710
Dexamethasone tablets 711
Didanosine oral powder 712
Didanosine tablets 713
Diethylcarbamazine dihydrogen citrate tablets 714
Diloxanide furoate tablets 715
Doxycycline capsules 716
Working document QAS/15.606/Rev 2
page 20
20
Doxycycline tablets 717
Efavirenz capsules 718
Efavirenz oral solution 719
Efavirenz tablets 720
Efavirenz, emtricitabine and tenofovir tablets 721
Emtricitabine and tenofovir tablets 722
Emtricitabine capsules 723
Ephedrine sulfate injection 724
Ergometrine hydrogen maleate tablets 725
Ergometrine injection 726
Erythromycin ethylsuccinate tablets 727
Erythromycin stearate tablets 728
Ethambutol hydrochloride tablets 729
Fluconazole capsules 730
Fluconazole injection 731
Glyceryl trinitrate tablets 732
Griseofulvin tablets 733
Ibuprofen tablets 734
Indinavir capsules 735
Indometacin tablets 736
Isoniazid and ethambutol hydrochloride tablets 737
Isoniazid tablets 738
Kanamycin for injection 739
Lamivudine oral solution 740
Lamivudine tablets 741
Levamisole tablets 742
Levonorgestrel and ethinylestradiol tablets 743
Levonorgestrel tablets 744
Lopinavir and ritonavir tablets 745
Magnesium sulfate injection 746
Medroxyprogesterone injection 747
Mefloquine tablets 748
Melarsoprol injection 749
Metronidazole injection 750
Metronidazole oral suspension 751
Metronidazole tablets 752
Morphine sulfate tablets 753
Nelfinavir mesilate oral powder 754
Nelfinavir mesilate tablets 755
Nevirapine oral suspension 756
Nevirapine tablets 757
Niclosamide tablets 758
Nitrofurantoin tablets 759
Nystatin tablets 760
Oral rehydration salts 761
Oseltamivir capsules 762
Oxytocin injection 763
Working document QAS/15.606/Rev2
page 21
21
Paediatric didanosine liquid for oral use 764
Paediatric zinc sulfate oral solution 765
Paediatric zinc sulfate tablets 766
Paracetamol oral solution 767
Paracetamol oral suspension 768
Paracetamol tablets 769
Pentamidine isetionate for injection 770
Pethidine hydrochloride tablets 771
Phenobarbital tablets 772
Phenoxymethylpenicillin potassium tablets 773
Phenytoin sodium tablets 774
Piperazine adipate tablets 775
Piperazine citrate tablets 776
Praziquantel tablets 777
Prednisolone phosphate injection 778
Prednisolone sodium succinate for injection 779
Prednisolone tablets 780
Primaquine diphosphate tablets 781
Probenecid tablets 782
Procaine benzylpenicillin for injection 783
Pyrantel chewable tablets 784
Pyrantel oral suspension 785
Pyrantel tablets 786
Pyrazinamide tablets 787
Quinine bisulfate tablets 788
Quinine dihydrochloride injection 789
Quinine sulfate tablets 790
Retinol oral solution 791
Rifampicin and isoniazid dispersible tablets 792
Rifampicin and isoniazid tablets 793
Rifampicin capsules 794
Rifampicin tablets 795
Rifampicin, isoniazid and ethambutol hydrochloride tablets 796
Rifampicin, isoniazid and pyrazinamide dispersible tablets 797
Rifampicin, isoniazid and pyrazinamide tablets 798
Rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride tablets 799
Ritonavir tablets 800
Saquinavir mesilate capsules 801
Saquinavir tablets 802
Sodium bicarbonate intravenous infusion 803
Stavudine capsules 804
Streptomycin for injection 805
Sulfadoxine and pyrimethamine tablets 806
Sulfamethoxazole and trimethoprim intravenous infusion 807
Sulfamethoxazole and trimethoprim oral suspension 808
Sulfamethoxazole and trimethoprim tablets 809
Working document QAS/15.606/Rev 2
page 22
22
Tenofovir tablets 810
Zidovudine and lamivudine tablets 811
Zidovudine capsules 812
Zidovudine intravenous infusion 813
Zidovudine, lamivudine and abacavir tablets 814
Zidovudine, lamivudine and nevirapine tablets 815
Zidovudine oral solution 816
817
*** 818