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Working document QAS/14.582

April 2014

Document for comment

1

2

FIP-WHO TECHNICAL GUIDELINES: 3

POINTS TO CONSIDER IN THE 4

PROVISION BY HEALTH-CARE PROFESSIONALS OF 5

CHILDREN-SPECIFIC PREPARATIONS THAT ARE NOT 6

AVAILABLE AS AUTHORIZED PRODUCTS 7

(APRIL 2014) 8

9

DRAFT FOR COMMENT 10

11

12

© World Health Organization 2014 13

All rights reserved. 14

This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The 15

draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, 16

in any form or by any means outside these individuals and organizations (including the organizations' concerned staff and 17

member organizations) without the permission of the World Health Organization. The draft should not be displayed on any 18

website. 19

Please send any request for permission to: 20

Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies, Standards and Norms, Department of Essential 21

Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22) 791 4730; 22

email: [email protected]. 23

The designations employed and the presentation of the material in this draft do not imply the expression of any opinion 24

whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or 25

of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate 26

border lines for which there may not yet be full agreement. 27

The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or 28

recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors 29

and omissions excepted, the names of proprietary products are distinguished by initial capital letters. 30

All reasonable precautions have been taken by the World Health Organization to verify the information contained in this 31

draft. However, the printed material is being distributed without warranty of any kind, either expressed or implied. The 32

responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health 33

Organization be liable for damages arising from its use. 34

This draft does not necessarily represent the decisions or the stated policy of the World Health Organization. 35

36

Should you have any comments on the attached text, please send these to:

Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies, Standards and Norms, World

Health Organization, 1211 Geneva 27, Switzerland; email: [email protected]; fax: (+41 22) 791 4730

([email protected]) and to Ms Marie Gaspard ([email protected]), by 1 May 2014.

Working documents are sent out electronically and they will also be placed on the Medicines website

for comment. If you do not already receive directly our draft guidelines please let us have your email

address (to [email protected]) and we will add it to our electronic mailing list.


page 2

SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF DOCUMENT QAS/14.582: 37



PROVISION BY HEALTH-CARE PROFESSIONALS OF CHILDREN-SPECIFIC 40

PREPARATIONS THAT ARE NOT AVAILABLE AS AUTHORIZED PRODUCTS 41

First draft prepared by Professor A. Nunn, UK,

commissioned by Dr S. Hill, Medicines Access and

Rational Use, Department of Essential Medicines and

Pharmaceutical Policies, World Health Organization

March 2011

Discussion at informal consultation on paediatrics and

generics guidelines development

4-6 May 2011

Revision prepared incorporating amendments by WHO

committee

August 2011

Revision sent out for comments August 2011

Consolidation of comments received September 2011

Discussion at forty-sixth meeting of the WHO Expert

Committee on Specifications for Pharmaceutical

Preparations

10-14 October 2011

Revision prepared and sent out for comments August 2012

Consolidation of comments received September 2012

Discussion at forty-seventh meeting of the WHO Expert

Committee on Specifications for Pharmaceutical

Preparations

October 2012

Review of comments received and recommendations of

WHO Expert Committee on Specifications for

Pharmaceutical Preparations, and in-depth discussion

between the Secretaries of the FIP Expert Group and

WHO Expert Committee on Specifications for

Pharmaceutical Preparations

February 2013

Preparation of new working document for circulation March 2013

Circulation of new working document for comments. March 2013

Discussion during Expert Committee on the Selection

and Use of Essential Medicines

8 April 2013

Compilation of feedback received June 2013

Any further action by WHO and FIP July-September 2013


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42

43

Presentation to the forty-eighth meeting of the WHO

Expert Committee on Specifications for Pharmaceutical

Preparations

14-18 October 2013

New document received by WHO from FIP March 2014

Circulation of new working document for comments. March 2014

Compilation of feedback received June 2014

Presentation to the forty-eighth meeting of the WHO

Expert Committee on Specifications for Pharmaceutical

Preparations

13-17 October 2014

Any further action as necessary …


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PROVISION BY HEALTH-CARE PROFESSIONALS OF CHILDREN-SPECIFIC 46

PREPARATIONS THAT ARE NOT AVAILABLE AS AUTHORIZED PRODUCTS 47

48

The present draft is based on working document QAS/13.525 discussed at the October 2013 49

meeting of the WHO Expert Committee on Specifications for Pharmaceutical Preparations. 50

The working document text has been reorganized and brought into balance with the contents 51

of the WHO document: Development of paediatric medicines: points to consider in 52

formulation. Parts of the original draft (QAS/11.399) have been reintroduced, e.g. Appendix 53

4 on potential problems in compounding. Comments received on the working document are 54

largely taken into account. At the October 2013 meeting experts expressed concern on good 55

manufacturing practices (GMP) aspects of compounded medicines for stock. A new section 56

on GMP aspects is therefore proposed. As the document is intended for a wide audience of 57

practitioners it is advisable to include a glossary. 58

59

1. Introduction and scope …………………………………………………………..… 60

1.1 Background …………………………………………………………………..… 61

1.2 Purpose ………………………………………………………………………… 62

1.3 Target audience and health-care settings ……………………………………… 63

2. Glossary…………………………………………………………………………..….. 64

3. Alternatives to compounding …………………………………………..………….. 65

3.1 Sourcing of a commercially available or manufactured product if available … 66

3.2 Dose rounding ………………………………………………………………… 67

3.3 Therapeutic alternatives ………………………………………………………. 68

3.4 Manipulation of dosage forms ………………………………………………… 69

3.4.1 Tablet splitting ………………………………………………………….. 70

3.4.2 Tablet/capsule dispersion for oral administration ………………………. 71

3.4.3 Crushing tablets/opening capsules and mixing powder with food 72

and drink ………………………………………………………………… 73

3.4.4 Giving the injectable form by the oral route …………………………… 74

3.4.5 Splitting suppositories ………………………………………………….. 75

3.4.6 Other possibilities ………………………………………………………. 76

4. Compounding ……………………………………………………….……………… 77


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4.1 Good manufacturing practices aspects ……….§………………………………..78

79

4.2 Potential problems ………………………………………………………….…. 80

4.3 Basic considerations …………………………………………………………... 81

5. Information, availability and access ……………………….………………….….. 82

5.1 Standards of practice and guidelines ……………………………………….…. 83

5.2 Formularies and compendia ……………………………………………….….. 84

5.3 Source and supply ……………………………………………………….……..85

5.4 Networks and information services ……………………………………….…... 86

6. References ……………………………………………………………………..……. 87

Annex 1. Examples of therapeutic alternatives ………………………………………...….. 88

Annex 2. Compounded preparations – consideration of potential problems …………...…. 89

90

91

1. INTRODUCTION AND SCOPE 92

93

1.1 Background 94

95

Paediatric patients should have access to authorized, age-appropriate preparations of 96

medicines that can be administered safely and effectively. Nothing in this document should 97

detract from this objective. However, it is recognized that such preparations are not always 98

available and a safe and effective alternative must be sought. 99

100

In the context of paediatric pharmacy practice, and for the purpose of this document, 101

compounding is the technique applied by pharmacists to produce medicines from active 102

pharmaceutical ingredients (APIs) or using authorized medicines when no commercially 103

available, authorized, age-appropriate or adequate dosage form exists. Unless stated explicitly 104

in this document, the compounded medicine is assumed to be dispensed immediately after 105

preparation and not kept in stock. Compounding does not apply to reconstitution of 106

authorized medicines prior to dispensing. 107

108

Compared to the use of authorized medicines there are significant risks associated with 109

compounding; quality, safety and efficacy can rarely all be assured, and there have been 110


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many errors reported in the preparation of such medicines. In some situations compounding 111

of a medicine for a child may be the only option, which may be supported by industry-112

verified compounding. There may be alternatives to compounding which also should be 113

considered, for example, use of a therapeutic alternative or manipulation of authorized dosage 114

forms. 115

116

This points-to-consider document is supported by a literature review of the evidence available: 117

Report for WHO on findings of a review of existing guidance/advisory documents on how 118

medicines should be administered to children, including general instructions on 119

extemporaneous preparations and manipulation of adult dosage forms (working document 120

QAS/11.400 – available on demand). 121

122

The document is to consider as a time-limited document that addresses current needs for 123

advice in the search for an alternative to an authorized, age-appropriate dosage form. 124

Wherever possible the guidance is informed by the relevant evidence. However, the evidence 125

base is weak or non-existent in most situations. Consequently, the guidance is predominantly 126

informed by best practice, based on sound scientific and therapeutic principles and expert 127

consensus. Whilst the guidance is a working practical document it is important to invite 128

comment and input from interested practitioners so that the guidance can be developed 129

further in response to feedback. 130

131

1.2 Purpose 132

133

The purpose of the document is to: 134

135

• provide evidence-based or best practice advice about alternatives to compounding of 136

medicines for paediatric patients; 137

• describe and educate practitioners in the potential problems of compounding and how 138

to avoid them; 139

• provide brief advice on compounding; 140

• provide a bibliography of relevant literature, supporting evidence and existing 141

guidance. 142

143


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The document will not reproduce areas where existing guidance and standards exist (e.g. 144

GMP standards for facilities and documentation). Where appropriate, reference is made to the 145

relevant resources and publications. 146

147

1.3 Target audience and health-care settings 148

149

The document is intended for a wide audience of health-care stakeholders including: 150

151

• all practitioners involved in health care of the paediatric population but mainly 152

pharmacists, physicians, paediatricians and nursing staff; 153

• national drug regulatory authorities and professional bodies, e.g. national paediatric 154

organizations, national pharmacy associations; 155

• general hospitals and health clinics; 156

• specialized paediatric hospitals and primary care clinics; 157

• pharmaceutical industry given its role in providing information. 158

159

Pharmaceutical manufacturers can often provide useful information on validated 160

compounded formulae and other information relating to the manipulations and specific 161

characteristics of formulations. 162

163

The document may be particularly useful in resource-poor situations where access to age-164

appropriate dosage forms is limited and where it may be difficult to obtain relevant 165

information and/or achieve the highest standards of quality assurance when dispensing 166

compounded preparations. 167

168

2. GLOSSARY 169

170

active pharmaceutical ingredient (API) 171

Any substance or mixture of substances intended to be used in the manufacture of a 172

pharmaceutical dosage form and that, when so used, becomes an active ingredient of that 173

pharmaceutical dosage form. Such substances are intended to furnish pharmacological 174


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activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of 175

disease, or to affect the structure and function of the body. 176

177

authorized dosage form 178

A pharmaceutical dosage form that has been authorized by the competent authority to be 179

marketed for the treatment of specific indications. 180

181

child-resistant container 182

A form of packaging difficult for young children to open but not unduly difficult for adults to 183

open properly. 184

185

compounding 186

The technique applied by pharmacists to produce non-authorized medicines from active 187

pharmaceutical ingredients or using authorized medicines. 188

189

dispensing pharmacy 190

The pharmacy receiving the prescription for a patient and providing the pharmaceutical 191

preparation to the patient. For compounded medicines, the dispensing pharmacy is not 192

necessarily the preparing pharmacy. 193

194

dose rounding 195

? 196

197

excipient 198

Any ingredient other than the active pharmaceutical ingredient, which has been evaluated for 199

safety and included in a pharmaceutical dosage form to (i) aid the processing of the dosage 200

form during its manufacture, (ii) protect, support or enhance stability, bioavailability or 201

patient acceptability, (iii) assist in product identification, or (iv) enhance any other attribute 202

of the overall safety and effectiveness of the dosage form during storage or use. 203

204

good manufacturing practices (GMP) 205

A philosophy of practice and processes to assure the quality and safety of manufactured 206

pharmaceutical products; specified in for example WHO guidelines. 207


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208

labelling information 209

Information to the user provided on the package label or in the patient information leaflet. 210

211

manipulation of a dosage form 212

Operation performed by the pharmacist or parent/caregiver to facilitate the administration of 213

a dosage form. It can be simple, e.g. breaking a tablet, or complex, for example, using tablets 214

as a source for an active pharmaceutical ingredient to prepare a suspension. 215

216

pharmaceutical dosage form 217

The physical form in which a medicine is presented; the name of a dosage forms combines its 218

physical form and the intended route of administration, e.g. a tablet (to be swallowed), oral 219

suspension (liquid suspension of solid particles intended for oral intake and swallowing). 220

221

route of administration 222

The way in which a medicine is given to a patient, e.g. oral administration (administration via 223

the oral route), rectal administration (administration to the rectum). 224

225

SmPC 226

Summary of product characteristics approved by the competent authority 227

228

3. ALTERNATIVES TO COMPOUNDING 229

230

Before deciding to compound consider possible alternatives that will give the greatest 231

assurance of clinical effectiveness and safety. 232

233

In some situations, for example, if the stability and method of preparation of an oral liquid are 234

well documented, e.g. if compounding has been industry-verified and all facilities and 235

ingredients are available, it may be less compelling to seek an alternative. On the other hand, 236

if there are no stability data and, for example, the API forms a caking suspension in the only 237

available excipients (e.g. a syrup), an alternative must be considered to ensure safe and 238

effective treatment. 239

240


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In any case, the decision on how to prepare and/or provide a non-authorized preparation 241

should be based on an assessment of risks and benefits of the dosing strategy. On a case-by-242

case basis, potential benefits from use should be weighed against all possible risks arising 243

from preparation and administration of such medicines. Even in cases where the compounded 244

preparation can be considered a validated formulation, the impact of compounding on 245

bioavailability may not be known. 246

247

Main alternatives to compounding are: 248

249

3.1 Sourcing of a commercially-available or manufactured product1 if available 250

251

The logistics of supply and access are obvious factors that might work against this but 252

practitioners should liaise with suppliers, importers and regulatory authorities to access these 253

products if possible. 254

255

Importation of products may be expensive and reputable suppliers should be used to avoid 256

spurious/falsely-labelled/falsified/counterfeit (SFFC) medicines. Quality assurance systems 257

should be in place, for example, to ensure that recall systems are available and information 258

provided in the local language. 259

260

Large-scale use of compounded oral liquids for children should not be justified on the 261

grounds that they are cheaper than commercial products. Other options, including local 262

manufacture using GMP standards, should be investigated. 263

264

3.2 Dose rounding 265

266

If the dose prescribed does not correspond to a dosage form which is commercially available, 267

consider whether the dose can be suitably amended whilst maintaining safety and efficacy. 268

The therapeutic index of the medicine and patient characteristics are to be considered before 269

making a decision. 270

271

1 This includes products prepared to GMP standards, for example at an accredited hospital manufacturing unit.


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Some drug doses are calculated accurately on the basis of body weight yet the therapeutic 272

index is such that one dose can be used for a broad weight or age band. Consult the WHO 273

Model Formulary for Children. Available from: 274

http://apps.who.int/medicinedocs/en/m/abstract/Js17151e/ 275

276

3.3 Therapeutic alternatives 277

278

If a medicine is prescribed in a formulation which is not available, e.g. in an age-appropriate 279

form, consider the possibility of using a medicine with a similar therapeutic action which is 280

available in a more suitable form. Examples are presented in Appendix 1. 281

282

3.4 Manipulation of dosage forms 283

284

In situations where the prescribed dose is less than what is commercially available, if there 285

are swallowing difficulties, or the stability of a compounded oral liquid cannot be assured, 286

consider the possibilities for manipulation of a dosage form as outlined below. 287

288

The practitioner should have in mind that manipulation, such as tablet splitting, tablet/capsule 289

dispersion or tablet crushing and mixing with food or drink, may increase the potential for 290

inaccurate dosing and it may affect the stability and bioavailability of the dosage form, in 291

particular when mixed with food or drink. Excipients that are safe for adults may not 292

necessarily be so for children. 293

294

When medicines are mixed with food or drink, an unpleasant taste of the mix may cause 295

aversion by the child. Mixing with breast milk could potentially be used in very young 296

children (< 6 months) but may cause aversion in breastfed children; the mother should 297

therefore observe milk intake and signs for breast-milk refusal. 298

299

3.4.1 Tablet splitting 300

Many tablets are designed to allow splitting, either by breaking if scored or by using a 301

purposely designed tablet cutter. If the child is able to take solid dose forms safely (age will 302

vary but usually from age 6–8 and above), a tablet fraction can be given, otherwise it can be 303

dispersed or mixed with food or juice as below. 304


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305

There is evidence that splitting of marketed tablet formulations may result in segments that 306

are far from meeting pharmacopoeia requirements for dose uniformity. Unless the tablet is 307

provided with a score line to facilitate breaking and swallowing the full dose, it is important 308

that regulatory authorities and manufacturers assure that such tablet formulations that may be 309

splitted also meet the relevant uniformity requirements for the tablet segments, and that 310

information about possible splitting occurs in the summary of product characteristics (SmPC). 311

312

In the lack of appropriate information and especially when the API is potent or has a narrow 313

therapeutic index, compounding may be preferable when an accurate dose cannot be assured. 314

Thus, consider on a case-by-case basis whether splitting of tablets might lead to toxicity or 315

reduced effect. 316

317

Not all tablets can be split. In general, those with a sustained release or enteric coating cannot 318

be split but it may be possible to split those with a sustained-release matrix. Formularies or 319

manufacturer’s information and the SmPC should be consulted. 320

321

Consideration should be given to splitting tablets with an appropriate commercial tablet 322

splitter in the pharmacy. If possible tablets with score lines and uniform distribution of the 323

active drug should be sourced and information sought on the stability of segments. If carers 324

are cutting segments, they should be given a commercial tablet splitter with adequate 325

instruction on the method of preparing and storing tablet segments. 326

327

3.4.2 Tablet/capsule dispersion for oral administration 328

It may be possible to disperse tablets or the contents of capsules in water or other liquid. If 329

the tablet disperses, the tablet or a fraction of the tablet can be dispersed in a small volume 330

appropriate for the concerned child, and the whole dose given when a suspension is formed, 331

mixed with a flavored vehicle if required. Assure that the whole dose is administered by 332

flushing the container. Consider the impact of dispersion and the risk for interactions with the 333

contents of the flavoured vehicle on bioavailability. 334

335

Conventional tablets do not disperse readily but some form a suspension within a short time. 336

Soluble tablets and dispersible tablets disintegrate and dissolve or disperse within a short time 337


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in water at room temperature. When the API is known to be soluble, dissolving or dispersing 338

the tablet in a known volume of water can allow a fractional dose to be appropriately 339

measured with a syringe as in the case of captopril. As extraction of soluble API from the 340

tablet excipients may be incomplete the suspension should be shaken or stirred prior to 341

measuring the dose and not filtered unless it has been established that the API is not removed. 342

In the case of a poorly soluble API the measurement of a fractional dose by taking an aliquot 343

from a suspension formed in this way is generally not recommended due to probable rapid 344

sedimentation of insoluble API and resultant dosage inaccuracy. 345

346

The remainder of a tablet or capsule dispersion shall not be stored and reused because of 347

stability reasons (microbiological, chemical, physicochemical). 348

349

Tablet dispersion may not always be practical for infants when the doses required are the 350

equivalent of small tablet fractions that are unable to be reliably prepared, e.g. a fifth of a 351

tablet or if the tablet is not scored. 352

353

When dispersion is intended for tube feeding, parameters such as particle size, viscosity, 354

dosing volume and compatibility of the oral preparation with the tube material should be 355

considered. Dispersions may be too viscous or contain large particles that can make the 356

administration by feeding tube not feasible. Adsorption of API to the tube material results in 357

inappropriate dosing; this concern is most relevant for lipophilic and potent APIs. 358

359

WHO is promoting the use of flexible solid oral dosage forms such as dispersible tablets (see 360

Development of paediatric medicines: points to consider in formulation, WHO Technical 361

Report Series, No. 970, Annex 5). The use of custom-made dispersible tablets for paediatric 362

dosing should be used wherever possible but there is a need to ensure that carers understand 363

how they are to be administered. 364

365

3.4.3 Crushing tablets/opening capsules and mixing powder with food or drink 366

The practice of crushing tablets or opening capsules and adding the powder to a palatable 367

drink or sprinkling onto solid food are common alternatives. However, there may be little 368

evidence to support the efficacy and safety since stability and bioavailability may be altered. 369

In case of potent APIs, consider the risks associated with handling of powdered material for 370


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parents/carers. Modified-release tablets and capsules cannot be crushed or opened without 371

affecting bioavailability and/or stability, and this should therefore not be done. 372

373

In general, the possibility to crush tablets should be based on bioavailability studies. 374

Information should be sought from manufacturers (e.g. the SmPC and website) and 375

formularies whenever possible. The process is acceptable only if bioavailability is not 376

affected by food or drink, and when the product is used immediately. 377

378

It is difficult to ensure that a complete dose has been taken and the practice of nurses and 379

carers handling powdered medicines may present health concerns. Tablet dispersion may be a 380

simpler, more reliable and potentially safer method. 381

382

Aliquots should usually not be taken from liquid-filled capsules since it is difficult to remove 383

and measure the total contents. 384

385

3.4.4 Giving the injectable form by the oral route 386

Oral administration is possible, although an expensive option, for some injections. If the 387

injectable form of the API is the same as the oral form (for example, labetalol hydrochloride, 388

ondansetron hydrochloride) it can be assumed that the API will be absorbed enterally from 389

the injectable formulation. However, as the API is in solution more rapid absorption and 390

higher peak levels may occur compared to the slower absorption from a solid oral dose form. 391

When evaluating whether an injection is suitable for oral use specialist advice, e.g. 392

consultation with a medicines information centre, should be sought because there are 393

important factors which must be considered, e.g. first-pass effect, oral bioavailability, gastric 394

acidity (e.g. effect on stability), pH effects (e.g. precipitation of soluble salts of weak acids) 395

and palatability. 396

397

Injections may contain excipients that are undesirable in some patients, e.g. propylene glycol 398

and ethanol. The pH of some injections may mean that they should not be given orally or be 399

diluted before administration to avoid irritation, e.g. furosemide injection (pH 9), 400

pantoprazole injection (pH 9–10.5), phenytoin sodium injection (pH 10–12). 401

402

403


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3.4.5 Splitting suppositories 404

There is little information on the accuracy with which suppositories can be split. Splitting is 405

usually associated with major problems with regard to accurate dosing. The majority of 406

commercially available suppositories are formulated as suspensions, which means that 407

sedimentation of the solid API particles may occur during solidification of the suppository; 408

therefore, if suppositories need to be split, this should be done lengthwise. 409

410

Suppositories have been melted and recast into smaller moulds. This option is associated with 411

a risk of recrystallization and for affecting the distribution of the API resulting in over- or 412

under-dosing. It is therefore generally discouraged. 413

414

Therapeutic index and the consequences of over- or under-dosing should be taken into 415

account when determining whether it is safe to split suppositories. If possible, this should be 416

done in the pharmacy and segments should be weighed to ensure the desired weight. 417

418

3.4.6 Other possibilities 419

In any case where a change of the route of administration as intended for an authorized 420

medicine is considered advice should be sought from formularies and the literature and even 421

specialist advice. In general, use of an altered route of administration results in a different 422

pharmacokinetic profile introducing a high risk of dosing errors and may compromise safety 423

and efficacy. 424

425

4. COMPOUNDING 426

427

4.1 Good manufacturing practices aspects 428

429

The dispensing pharmacy receives the prescription for a patient and provides the 430

compounded preparation to the patient. Preparation may take place in another pharmacy or 431

hospital manufacturing unit. 432

433

When a non-authorized medicine is prepared for stock the preparing pharmacy or hospital 434

unit should meet GMP requirements to personnel, premises and equipment, quality assurance 435

system, documentation and product dossier. Further, an authorization by the competent 436


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authority to carry out operations should be considered. Reference in this aspect is made to the 437

PIC/S Guide to Good Practices for the preparation of Medicinal Products in Healthcare 438

Establishments (www.picscheme.org) and to other guidelines, including WHO guidelines on 439

GMP and corresponding national guidelines. 440

441

In case of compounding as a single event and the preparation is dispensed immediately to the 442

patient, requirements may be less strict. Nevertheless, there are quality assurance 443

requirements to take into account: 444

445

• the preparing pharmacy should have appropriate premises and equipment; 446

• the pharmacist and staff must have sufficient training and background for 447

compounding; 448

• access to relevant literature (pharmacopoeias, handbooks, scientific journals, etc.) and 449

the Internet; 450

• general instructions for every type of preparation should be available; 451

• a record on each preparation should be retained showing the key processing and 452

packaging steps including the name of the person responsible for each step. 453

454

4.2 Potential problems 455

456

Formulation of a compounded medicine is associated with a number of potential problems 457

that may impact on the safety and effectiveness of the formulation. Awareness of the relative 458

complexity of the formulation and the things that can go wrong will help to avoid such 459

problems. Guidance on compounding can be found in, for example, Marc Jackson and 460

Andrew Lowey: Handbook of Extemporaneous Preparation, Pharmaceutical Press, 2010. 461

462

Consideration must be given to the properties of the API (e.g. aqueous solubility, pH effect 463

on solubility, particle size when poorly soluble) and stability of both API and the 464

compounded formulation, i.e. chemical, physical and microbiological instability. 465

466

Further consideration must be given to the selection of excipients and excipients present in 467

manipulated dose forms. It is important to consider any possible adverse effects of the 468

“inactive” components of the preparation. The use of preservatives, ethanol and sugars must 469


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be carefully considered. Some guidance and literature references on the formulation can be 470

found in Development of paediatric medicines: points to consider in formulation (WHO 471

Technical Report Series, No. 970, Annex 5). 472

473

Annex 2 presents examples of potential problems in compounding. 474

475

4.3 Basic considerations 476

477

• Quality of API and excipients 478

It is important to ensure that the API and excipients meet pharmacopoeia standards 479

with regard to both identity and purity. The choice of excipients should be restricted 480

to those that have been used in authorized medicines intended for the same route of 481

administration. 482

483

• Consider use of an authorized dosage form as a starting point 484

It may be safer and more effective to crush tablets or use the contents of hard capsules 485

with an appropriate suspending vehicle rather than preparing from API and excipients. 486

There are many formulations available with validated shelf-life but sourcing of 487

suspending agents may be difficult and/or expensive. 488

489

There might be instances where the pharmacist crushes a number of tablets or opens a 490

number of capsules, dilutes the powder with a suitable excipient and doses the powder 491

in ready-to-use single dose sachets. Before doing so, consider the stability of the 492

preparation including in-use stability against humidity and exposure to air. 493

494

• Consult literature and guidelines if available 495

If possible, always use a validated formulation (i.e. based on literature, stability 496

studies and guidelines). Consult product information and the latest national and 497

international guidelines and/or a specialist information centre if possible. 498

499

• Employ the principles of GMP 500

This involves the processes put in place to give the highest level of assurance possible 501

that the product will be safe and effective. It is accepted that few units will be able to 502


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conform to the requirements of GMP. However, as stated in Section 3.1, the 503

principles of quality assurance are possible and essential under any conditions. 504

505

• Medication error potential 506

There have been many examples of medication error when preparing compounded 507

medicines and some have resulted in death or serious harm to patients. The potential 508

for medication error must be recognized and steps taken to minimize the risk. This 509

will include as a minimum the use of a worksheet listing the formulation ingredients 510

and the identity of ingredients; quantities, calculations and measurements should be 511

double-checked by trained personnel and signatures provided. The pharmacist 512

responsible should check the final product and label against the signed worksheet, 513

ingredients and prescription. 514

515

• Caution in extrapolating from other formulations 516

Caution is required if extrapolating the formulation from a published study or 517

formulary. Formulations made from APIs may be more stable than formulations made 518

from solid dose forms and vice versa. Tablet and capsule excipients can increase or 519

decrease the stability of the API in an oral liquid preparation. The salt form of the 520

drug used in a published study could be different to the form locally available and this 521

may affect the drug’s solubility and stability. Consult pharmacopoeias and seek 522

specialist advice if possible. 523

524

Similarly, the results of a published study using a drug mixed with a commercial 525

suspending base (e.g. Ora-Plus®) cannot generally be extrapolated to a situation 526

where the same drug is mixed with a simple base of syrup or glycerol. 527

528

Formulations for compounded medicines based on APIs and crushed tablets are not 529

interchangeable. 530

531

• Dose uniformity may be a problem – explain importance of shaking prior to use 532

If the API is poorly soluble in water, it will generally be more chemically stable in an 533

aqueous suspension, but uniformity of dosing the suspension may be a problem. A 534

suspending agent will be required. Always check that the finished preparation 535


page 19

resuspends under in-use conditions and explain the importance of resuspension by 536

shaking to patients/carers. 537

538

If the API is soluble, it will generally be less stable in a liquid preparation. As the 539

API is soluble, the inclusion of a suspending agent is less important in a preparation 540

based on crushed tablets. 541

542

As excipients and other formulation components can affect solubility, all compounded 543

liquid formulations should be shaken prior to administration. The entire API may not 544

be in solution even if it is highly soluble. The only exception would be if the 545

preparation is made from pure API and it can be assured that the entire API is in 546

solution. 547

548

• Exceptionally, when no published formulation is available 549

The pharmacist must assess the risks for different options and use knowledge and 550

experience to formulate a product. 551

552

o Obtain physicochemical properties of the API if available 553

API solubility and the pH stability profile are useful when considering the 554

approach to formulation or dose administration. If possible, obtain basic 555

physicochemical information about the API, especially the aqueous solubility 556

of the API at the expected pH of the final preparation. This allows a 557

judgement on whether an API solution or suspension is formed. 558

559

o Test the physical characteristics prior to patient use 560

Tablet/capsule formulations vary worldwide, especially with respect to 561

excipients content. The differences can influence the effectiveness and 562

acceptability of the preparation. Basic performance tests should be done 563

before patient use, particularly on formulations prepared for the first time. 564

This includes ease of resuspension and pouring, degree of caking on storage, 565

observation of physical behaviour and characteristics. 566

567


page 20

o Consider risk of microbial growth 568

All compounded liquid formulations are highly susceptible to microbial 569

growth. An antimicrobial preservative must be included unless the final 570

product will be used completely within 2–3 days and stored under 571

refrigeration. Oral liquids that are not adequately preserved will support rapid 572

growth of bacteria and fungi especially at warm to hot temperatures and can 573

pose hazards to patients especially if immunosuppressed. 574

575

Preparation of compounded liquids should be carried out under conditions to 576

minimize the introduction of microbial contamination. 577

578

• Use appropriate final containers 579

Final containers and closures should be clean and free from dust and other residues. It 580

is recommended to use new containers. Containers that are reused should be 581

thoroughly washed, rinsed with sterile or freshly boiled water and dried. Light-582

protective (e.g. dark plastic or amber glass) containers should generally be used. 583

Consider the use of a light protective wrapping such as foil if a light-protective 584

container is not available. 585

586

Selection of the final container should consider potential drug adsorption to plastic 587

containers. 588

589

• Dosing device 590

In view of the dosing needs of liquid preparations the feasibility of appropriate dosing 591

should be confirmed as not all dosing devices may allow delivering the required 592

volume. As most compounded liquids should be shaken prior to administration, this 593

may introduce entrapped air in the liquid, which may cause problems with accurate 594

measurement of small volumes. 595

596

• Consider in-use storage 597

In-use storage conditions may vary considerably from those in a published study or 598

formulary recommendation. Always consider if it will be possible to store and use the 599

preparation under the optimal conditions described in the study, which usually are 600


page 21

refrigeration, protection from light and with minimal possibility of in-use 601

contamination. If these conditions are not possible locally it can be assumed that the 602

preparation will be less stable and more susceptible to microbial growth. Reduce the 603

shelf-life (e.g. from one month to one week) according to professional judgement. If 604

possible, consult expert advice. 605

606

• Expiry date 607

Chemical stability and potential for microbial growth under patient-use conditions are 608

seldom tested in published studies. 609

610

It is recommended that each compounded preparation be given an expiry date 611

assigned in a conservative way taking into account API-specific and general stability 612

documentation and literature when available. This will encourage regular fresh 613

preparations and help to assure effectiveness and safety. It also allows the practitioner 614

to regularly review the patient’s use of the preparation. 615

616

The following items should be considered when determining such expiry date: nature 617

of the API and its degradation mechanisms; dosage form and its components; 618

potential for microbial proliferation in the preparation; container in which the 619

preparation is packaged; expected storage conditions; and the intended duration of 620

therapy. 621

622

When an authorized medicine is used as the source of the API, stability information 623

could be obtained from the manufacturer. Otherwise, applicable information on 624

stability, compatibility and degradation of ingredients and use has to be sought in the 625

literature. 626

627

• Give clear instruction to caregivers/patients 628

This may include instructions on storage, resuspension, changes in taste, smell, 629

appearance, adverse effects and other pharmaceutical advices. 630

631

It is common practise that parents/carers add powdered dosage form to a liquid 632

(water, juice, etc.) or sprinkle it onto food to improve palatability and mask 633


page 22

unpleasant taste. This should be done only when bioavailability is not affected and 634

intake of the full dose can be ensured. Provide parents/carers with appropriate 635

information. 636

637

If an oral syringe or other measuring device is used it is important to check the 638

technique to ensure the correct dose is administered. Advise the use of clean 639

measuring devices and ways to avoid contaminating the preparation when preparing 640

the dose. 641

642

• Label information 643

In addition to dosage instructions, include at least the following information: 644

645

- if applicable, the name of the pharmaceutical preparation; 646

- the route of administration; 647

- the name(s) of the API(s) and excipients of known pharmacological action, 648

e.g. antimicrobial agents, antioxydants; 649

- if liquid, concentration(s) of the API(s), e.g. in mg/ml, and the amount or 650

volume of the preparation in the container; 651

- if solid, amount(s) of the API(s) in each dose and the number of doses in the 652

container; 653

- reference or batch number (or date of preparation); 654

- expiry date (“do not use after...”); 655

- any special storage conditions and handling precautions that may be 656

necessary, e.g. “to be shaken before use”; 657

- the pharmacy name and contact information; 658

- name of the patient. 659

660

• Document concerns and share information 661

Practitioners are encouraged to maintain dialogue with regulatory bodies and 662

international agencies and networks about problems and concerns associated with the 663

preparation and availability of age-appropriate medicines for children. The sharing of 664

solutions to problems is also important. 665

666


page 23

5. INFORMATION, AVAILABILITY AND ACCESS 667

668

A number of networks, websites and other resources are available which provide information 669

on standards of practice, formulas for compounded preparations, manufacturers, suppliers of 670

oral liquid formulations, and networks and responsive information services. These should be 671

consulted by practitioners and regulators to provide the safest and most effective treatment 672

options for children who require an age- appropriate formulation. 673

674

5.1 Standards of practice and guidelines 675

676

Some national, regional and international guidelines for extemporaneous formulations and 677

medicines administration to children have been published. Consulting these documents may 678

assist in forming local policies of practice and educational activities for practitioners. 679

680

5.2 Formularies and compendia 681

682

These may be helpful in providing formulation advice and general advice on dosage 683

manipulations. The information in these formularies may be difficult to transfer to a local 684

situation where the base ingredients (e.g. commercial suspending bases, antimicrobial 685

preservatives, pure drug powder) are not readily available. 686

687

The eMixt database (www.pharminfotech.co.nz) is being developed to provide 688

comprehensive information for all settings and environments. 689

690

Mark Jackson and Andrew Lowey: Handbook of Extemporaneous Preparations, 691

Pharmaceutical Press 2010, contains formulations and associated stability summaries for oral 692

liquid preparations. 693

694

5.3 Source and supply 695

696

A database of sources and prices of medicines for children has been compiled by Unicef. This 697

will be available electronically by mid-2011 698

(http://www.unicef.org/supply/index_47129.html) 699


page 24

700

The database can be searched to find worldwide suppliers of oral liquids and other age-701

appropriate formulations for paediatric use. 702

703

5.4 Networks and information services 704

705

- Local, national and international medicines information centres may respond to 706

questions about formulation such as the WHO Paediatric medicines Regulatory 707

Network (PmRN). Partnerships and twinning arrangements between hospitals in 708

poorly-resourced countries and developed countries can be explored and are often 709

beneficial. 710

711

Questions can also be posted via the eMIxt website www.pharminfotech.co.nz. 712

713

- Sharing of information and advice on paediatric formulations should be explored 714

whenever possible. 715

716

- International discussion lists can be useful for posting questions on formulations and 717

the archives can be searched for previous questions and answers. Examples include 718

eDrug and INDICES accessed via http://www.essentialdrugs.org/. 719

720

6. REFERENCES 721

722

1. Pharmaceutical development for multisource (generic) pharmaceutical products. In: WHO 723

Expert Committee on Specifications for Pharmaceutical Preparations. Forty-sixth report. 724

Geneva, World Health Organization. WHO Technical Report Series, No. 970, Annex 4, 725

2012 (http://www.who.int/medicines/areas/quality_safety/quality_assurance/en/). 726

727

2. Development of paediatric medicines: points to consider in pharmaceutical 728

development. In: WHO Expert Committee on Specifications for Pharmaceutical 729

Preparations. Forty-sixth report. Geneva, World Health Organization. WHO Technical 730

Report Series, No. 970, Annex 5, 2012 731

(http://www.who.int/medicines/areas/quality_safety/quality_assurance/en/). 732


page 25

733

3. WHO good manufacturing practices: main principles for pharmaceutical products 734

In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-735

eighth report. Geneva, World Health Organization. WHO Technical Report Series, No. 736

986, Annex 2, 2014 (in print). 737

738

4. Good manufacturing practices for pharmaceutical products. In: Quality assurance of 739

pharmaceuticals. WHO guidelines, related guidance and GXP training materials, 740

CD-ROM 2013. 741

742

5. The International Pharmacopoeia, Fourth Edition, including First, Second and Third 743

Supplements (http://who.int/medicines/publications/pharmacopoeia/en/index.html). 744

Available online and CD-ROM version (2013). 745

746

6. Report for WHO on findings of a review of existing guidance/advisory documents on 747

how medicines should be administered to children, including general instructions on 748

extemporaneous preparations and manipulation of adult dosage forms (working 749

document QAS/11.400). 750

751

7. The WHO Model Formulary for Children (2010) 752

(http://www.who.int/selection_medicines/list/WMFc_2010.pdf). 753

754

8. Report of the Informal Expert Meeting on Dosage Forms of Medicines for Children. 755

Geneva, World Health Organization. December 2008 756

[http://www.who.int/selection_medicines/committees/expert/17/application/paediatric/757

Dosage_form_re-port DEC2008.pdf. 758

759

9. Handbook of Extemporaneous Preparation: A guide to pharmaceutical compounding. 760

Part A. Standards: In Handbook of Extemporaneous Preparation, pages 1–65. Mark 761

Jackson and Andrew Lowey. Pharmaceutical Press, 2010. 762

763

10. Pharmaceutical Inspection Co-operation Scheme (http://www.picscheme.org/) 764

In particular the following documents which can be downloaded free of charge: PE 765


page 26

009-9 (Part I). PIC/S GMP guide (Part I: Basic requirements for medicinal products); 766

PE 010-3 Guide to good practices for the preparation of medicinal products in 767

healthcare establishments. 768

769

11. Kastango ES, Trissel LA, Bradshaw BD. An Ounce of Prevention: Controlling Hazards 770

in Extemporaneous Compounding Practices. International Journal of Pharmacy 771

Compounding. 2003; 7(5): 401-16. 772

773

774

775

776

777


page 27

ANNEX 1 778

779

Examples of therapeutic alternatives to extemporaneous formulations 780

781

Required Possible alternative Notes

Enalapril liquid Captopril liquid

Dispersed captopril tablets

Available commercially in

some countries.

Captopril tablets can be

easily dispersed prior to

giving the dose

Naproxen oral liquid Ibuprofen liquid if available NSAID may not be clinically

justified.

Paracetamol (acetaminophen)

may be a suitable and safer

alternative

Felodipine oral liquid Dispersed amlodipine tablets Salts of amlodipine are very

soluble and fractional doses

can be prepared.

Tinidazole oral liquid Metronidazole oral liquid Very few reasons why

tinidazole should be

preferred over metronidazole

782

In some cases the therapeutic alternative may not be available as an oral liquid but as a more 783

easily manipulated form (see felodipine example above). 784

785

786

787

788

789

790

791

792


page 28

ANNEX 2 793

794

Compounded preparations – consideration of potential problems 795

796

The most frequently used method is to grind the required number of tablets to a fine 797

powder in a mortar and form a slurry by adding a small volume of water. At this stage 798

there is the potential for the operator to be exposed to hazardous powdered drug and 799

microbial contamination of the product if clean equipment is not used. 800

801

Excipients such as antimicrobial preservatives, suspending agents and flavouring agents 802

are added to make the final product. A frequently used base is a mixture of glycerol or 803

syrup, a suspending agent such as methylcellulose and para-hydroxybenzoates (parabens) 804

as a preservative. Other agents sometimes added include alternative solvents such as 805

ethanol, particularly when the drug is poorly soluble in water, and buffer systems to 806

provide the optimum pH for drug stability or activity of the antimicrobial preservative. 807

Whilst ostensibly simple, such formulations can be complex, comprising a mixture of the 808

base and a suspension or solution (usually a combination of both) of tablet excipients and 809

active drug. If the drug is water soluble there is a temptation to filter out the insoluble 810

tablet excipients to leave a clear solution but filtration can remove significant amounts of 811

drug if extraction from tablets is incomplete. Insoluble tablet excipients are in suspension 812

and may compromise product appearance, whereas soluble excipients may alter drug 813

stability, for example, by changing the pH of the preparation. Added ingredients or 814

excipients may not be appropriate for babies and infants, e.g. ethanol, propylene glycol. 815

Whilst there may be advantages in using pure drug powder instead of tablets it may not be 816

easily obtainable. 817

818

The expiry date of a compounded oral liquid is assigned empirically or based on 819

published information on a particular formulation. A conservative approach must be 820

adopted when assigning an expiry date because of lack of information on API stability or 821

limitations in either the design or the conclusions of a published report. Also, it may be 822

impractical to entirely reproduce the conditions of a study which was performed in 823

another institution or country under the controlled conditions of an experiment rather than 824

clinical use. Most studies base their expiry date recommendation on chemical stability but 825


page 29

do not address possible physical or microbiological spoilage which may be significant 826

during actual use of the product. For these reasons extemporaneously prepared oral 827

liquids should only be used for a maximum of one month from the date of preparation to 828

minimize any unrecognized product deterioration. Longer expiry dates may be applied if 829

more extensive testing is performed. 830

831

Finally, when deciding on a formulation, it is important to consider any possible adverse 832

effects of the "inactive" components of the preparation. Sucrose (in syrup) can promote 833

the formation of dental caries, ethanol can cause hypoglycaemia and para-834

hydroxybenzoates can cause hypersensitivity reactions and exacerbate the symptoms of 835

asthma. It has also been suggested that benzoates and para-hydroxybenzoates can 836

aggravate neonatal hyperbilirubinaemia by displacing bilirubin which is bound to plasma, 837

proteins but this effect has not been demonstrated in vivo and the amounts present in oral 838

formulations are unlikely to pose any risk. Limits for the inclusion of ethanol in 839

paediatric formulations have been proposed by the American Academy of Pediatrics but 840

there is little supporting evidence for the recommendation. 841

842

Deterioration of an oral liquid may be due to chemical, physical or microbiological 843

instability which can lead to a subtherapeutic dose of drug, exposure to toxic degradation 844

products or ingestion of unacceptable numbers of microorganisms. It is important for 845

pharmacists, clinicians and nursing staff to be aware of potential problems caused by 846

instability to ensure that drug therapy is effective and safe. 847

848

Chemical instability 849

850

APIs in compounded liquids may be susceptible to chemical reactions leading to 851

degradation. The most common reactions are hydrolysis, oxidation and reduction. Usually 852

the reaction rate or type is influenced by pH, for example, azathioprine is rapidly 853

hydrolysed to 6-mercaptopurine at alkaline pH but is relatively stable in acidic or neutral 854

conditions. Other factors which may increase the rate of reaction include the presence of 855

trace metals which catalyse the oxidation of captopril, methyldopa or exposure to light, 856

which catalyses the oxidative degradation of 6-mercaptopurine. The rate of chemical 857

degradation usually increases with temperature, a factor which is the basis for accelerated 858


page 30

stability trials of pharmaceutical formulations. Preparations made from tablets contain 859

excipients such as binders and disintegrating agents in addition to the API. These 860

excipients may reduce chemical stability by changing the pH to a value at which more 861

rapid degradation occurs. This probably explains why amiloride solution prepared from 862

pure API is more stable than an oral liquid prepared from tablets. 863

864

The API in the preparation may be totally or partially in solution or predominantly in the 865

solid state as a suspension. APIs in solution are more susceptible to chemical degradation 866

than APIs in the solid state (i.e. suspensions), thus suspensions of acetazolamide and 867

chlorothiazide are more stable than solutions. However it cannot be assumed in all cases 868

that a compounded suspension is more stable than a solution. In a suspension, an 869

equilibrium exists between the API in the solid state and an API in solution, and even 870

though the amount of drug dissolved may be minimal the conditions could be optimal for 871

degradation. Furosemide is a notable example which undergoes hydrolysis in acidic 872

conditions where the solid state is predominant, but is much more stable at alkaline pH 873

where it is totally in solution. 874

875

Microbiological instability 876

877

Microbial growth in an oral liquid may cause foul odour and turbidity and adversely 878

effect palatability and appearance. High titres of microorganisms may be hazardous to 879

health especially in very young or immunocompromised patients. By-products of 880

microbial metabolism may cause a change in the pH of the preparation and reduce the 881

chemical stability or solubility of the drug. Microbial contamination during preparation 882

must be minimized by using clean equipment, sterile water (Water for Irrigation (BP)) 883

and avoiding contaminated raw materials and containers. If sodium benzoate or benzoic 884

acid are used as antimicrobial preservatives the final pH must be less than 5 so that the 885

active unionized form is predominant. Consequently the API must also be stable at this 886

pH. 887

888

Effective preservative systems require rigorous evaluation which is seldom performed on 889

compounded formulations. Many factors can reduce the effectiveness of the preservative 890

including use of contaminated materials, chemical degradation, binding of preservative to 891


page 31

suspending agents or tablet excipients, incorrect storage or unhygienic use of the final 892

product. 893

894

Physical instability 895

896

Compounded oral suspensions may be susceptible to sedimentation of insoluble API 897

causing caking. Difficulty in resuspending the API or rapid sedimentation following 898

shaking can lead to erratic dosage measurement as demonstrated with chlorothiazide 899

suspension and this inherent problem with compounded formulations is of considerable 900

concern. Some spironolactone suspensions have been reported to be excessively thick and 901

almost unpourable. Refrigeration, whilst usually desirable to maximize chemical stability 902

and reduce microbial growth, can also increase the viscosity of a suspension making 903

resuspension more difficult or cause the precipitation of API or preservatives. It is 904

important to consider the effect on pH of all components of the formulation and the 905

possible impact on stability. Syrup, for example, is relatively acidic and if used in 906

phenobarbitone sodium oral solution it will cause the precipitation of unionized 907

phenobarbitone. 908

909

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