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: kopps@who.int. 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: schmidth@who.int; fax: (+41 22) 791 4730) by 16 September 2016.

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Working document QAS/15.606/Rev 2

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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

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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

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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.

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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.

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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

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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.

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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

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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.

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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

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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

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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

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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

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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

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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

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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

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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

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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