Pripravci Za Djecu

Working document QAS/14.
582
April 2014
Document for comment
1
2
3
FIP-WHO TECHNICAL GUIDELINES:
POINTS TO CONSIDER IN THE
PROVISION BY HEALTH-CARE PROFESSIONALS OF
CHILDREN-SPECIFIC PREPARATIONS THAT ARE NOT
AVAILABLE AS AUTHORIZED PRODUCTS
8
9
10
11
(APRIL 2014)
DRAFT FOR COMMENT
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: kopps@who.int; fax: (+41 22) 791 4730
(kopps@who.int) and to Ms Marie Gaspard (gaspardm@who.int), 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 bonnyw@who.int) and we will add it to our electronic mailing list.
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
World Health Organization 2014

All rights reserved.
This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The
draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole,
in any form or by any means outside these individuals and organizations (including the organizations' concerned staff and
member organizations) without the permission of the World Health Organization. The draft should not be displayed on any
website.
Please send any request for permission to:
Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies, Standards and Norms, Department of Essential
Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22) 791 4730;
email: kopps@who.int.
The designations employed and the presentation of the material in this draft do not imply the expression of any opinion
whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or
of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate
border lines for which there may not yet be full agreement.
The mention of specific companies or of certain manufacturers products does not imply that they are endorsed or
recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors
and omissions excepted, the names of proprietary products are distinguished by initial capital letters.
All reasonable precautions have been taken by the World Health Organization to verify the information contained in this
draft. However, the printed material is being distributed without warranty of any kind, either expressed or implied. The
responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health
Organization be liable for damages arising from its use.
This draft does not necessarily represent the decisions or the stated policy of the World Health Organization.
Working document QAS/14.582

page 2
37
38
39
40
41
SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF DOCUMENT QAS/14.582:

PROVISION BY HEALTH-CARE PROFESSIONALS OF CHILDREN-SPECIFIC
PREPARATIONS THAT ARE NOT AVAILABLE AS AUTHORIZED PRODUCTS
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

page 3
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

page 4
PROVISION BY HEALTH-CARE PROFESSIONALS OF CHILDREN-SPECIFIC
PREPARATIONS THAT ARE NOT AVAILABLE AS AUTHORIZED PRODUCTS
44
45
46
47
48
49
The present draft is based on working document QAS/13.525 discussed at the October 2013
50
meeting of the WHO Expert Committee on Specifications for Pharmaceutical Preparations.
51
The working document text has been reorganized and brought into balance with the contents
52
of the WHO document: Development of paediatric medicines: points to consider in
53
formulation. Parts of the original draft (QAS/11.399) have been reintroduced, e.g. Appendix
54
4 on potential problems in compounding. Comments received on the working document are
55
largely taken into account. At the October 2013 meeting experts expressed concern on good
56
manufacturing practices (GMP) aspects of compounded medicines for stock. A new section
57
on GMP aspects is therefore proposed. As the document is intended for a wide audience of
58
practitioners it is advisable to include a glossary.
59
60
1.
Introduction and scope ..
61
1.1
Background ..
62
1.2
Purpose
63
1.3
Target audience and health-care settings
64
2.
Glossary....
65
3.
Alternatives to compounding ....
66
3.1
Sourcing of a commercially available or manufactured product if available
67
3.2
Dose rounding
68
3.3
Therapeutic alternatives .
69
3.4
Manipulation of dosage forms
70
3.4.1 Tablet splitting ..
71
3.4.2 Tablet/capsule dispersion for oral administration .
72
3.4.3 Crushing tablets/opening capsules and mixing powder with food

and drink
73
74
3.4.4 Giving the injectable form by the oral route
75
3.4.5 Splitting suppositories ..
76
3.4.6 Other possibilities .
77
4.
Compounding .

page 5
4.1
Good manufacturing practices aspects ...
80
4.2
Potential problems ..
81
4.3
Basic considerations ...
78
79
82
5.
Information, availability and access ....
83
5.1
Standards of practice and guidelines ..
84
5.2
Formularies and compendia ...
85
5.3
Source and supply ...
86
5.4
Networks and information services ....
87
6.
References ...
88
Annex 1. Examples of therapeutic alternatives .....
89
Annex 2. Compounded preparations consideration of potential problems ....
90
91
92
1.
INTRODUCTION AND SCOPE
1.1
Background
93
94
95
96
Paediatric patients should have access to authorized, age-appropriate preparations of
97
medicines that can be administered safely and effectively. Nothing in this document should
98
detract from this objective. However, it is recognized that such preparations are not always
99
available and a safe and effective alternative must be sought.
100
101
In the context of paediatric pharmacy practice, and for the purpose of this document,
102
compounding is the technique applied by pharmacists to produce medicines from active
103
pharmaceutical ingredients (APIs) or using authorized medicines when no commercially
104
available, authorized, age-appropriate or adequate dosage form exists. Unless stated explicitly
105
in this document, the compounded medicine is assumed to be dispensed immediately after
106
preparation and not kept in stock. Compounding does not apply to reconstitution of
107
authorized medicines prior to dispensing.
108
109
Compared to the use of authorized medicines there are significant risks associated with
110
compounding; quality, safety and efficacy can rarely all be assured, and there have been

page 6
111
many errors reported in the preparation of such medicines. In some situations compounding
112
of a medicine for a child may be the only option, which may be supported by industry-
113
verified compounding. There may be alternatives to compounding which also should be
114
considered, for example, use of a therapeutic alternative or manipulation of authorized dosage
115
forms.
116
117
This points-to-consider document is supported by a literature review of the evidence available:
118
Report for WHO on findings of a review of existing guidance/advisory documents on how
119
medicines should be administered to children, including general instructions on
120
extemporaneous preparations and manipulation of adult dosage forms (working document
121
QAS/11.400 available on demand).
122
123
The document is to consider as a time-limited document that addresses current needs for
124
advice in the search for an alternative to an authorized, age-appropriate dosage form.
125
Wherever possible the guidance is informed by the relevant evidence. However, the evidence
126
base is weak or non-existent in most situations. Consequently, the guidance is predominantly
127
informed by best practice, based on sound scientific and therapeutic principles and expert
128
consensus. Whilst the guidance is a working practical document it is important to invite
129
comment and input from interested practitioners so that the guidance can be developed
130
further in response to feedback.
131
132
1.2
Purpose
133
134
The purpose of the document is to:
135
136
medicines for paediatric patients;
137
138
provide evidence-based or best practice advice about alternatives to compounding of
describe and educate practitioners in the potential problems of compounding and how
to avoid them;
139
140
provide brief advice on compounding;
141
provide a bibliography of relevant literature, supporting evidence and existing
142
143
guidance.

page 7
144
The document will not reproduce areas where existing guidance and standards exist (e.g.
145
GMP standards for facilities and documentation). Where appropriate, reference is made to the
146
relevant resources and publications.
147
148
1.3
Target audience and health-care settings
149
150
The document is intended for a wide audience of health-care stakeholders including:
151
152
pharmacists, physicians, paediatricians and nursing staff;
153
154
all practitioners involved in health care of the paediatric population but mainly
national drug regulatory authorities and professional bodies, e.g. national paediatric
organizations, national pharmacy associations;
155
156
general hospitals and health clinics;
157
specialized paediatric hospitals and primary care clinics;
158
pharmaceutical industry given its role in providing information.
159
160
Pharmaceutical manufacturers can often provide useful information on validated
161
compounded formulae and other information relating to the manipulations and specific
162
characteristics of formulations.
163
164
The document may be particularly useful in resource-poor situations where access to age-
165
appropriate dosage forms is limited and where it may be difficult to obtain relevant
166
information and/or achieve the highest standards of quality assurance when dispensing
167
compounded preparations.
168
169
2. GLOSSARY
170
171
active pharmaceutical ingredient (API)
172
Any substance or mixture of substances intended to be used in the manufacture of a
173
pharmaceutical dosage form and that, when so used, becomes an active ingredient of that
174
pharmaceutical dosage form. Such substances are intended to furnish pharmacological

page 8
175
activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of
176
disease, or to affect the structure and function of the body.
177
178
authorized dosage form
179
A pharmaceutical dosage form that has been authorized by the competent authority to be
180
marketed for the treatment of specific indications.
181
182
child-resistant container
183
A form of packaging difficult for young children to open but not unduly difficult for adults to
184
open properly.
185
186
compounding
187
The technique applied by pharmacists to produce non-authorized medicines from active
188
pharmaceutical ingredients or using authorized medicines.
189
190
dispensing pharmacy
191
The pharmacy receiving the prescription for a patient and providing the pharmaceutical
192
preparation to the patient. For compounded medicines, the dispensing pharmacy is not
193
necessarily the preparing pharmacy.
194
195
dose rounding
196
197
198
excipient
199
Any ingredient other than the active pharmaceutical ingredient, which has been evaluated for
200
safety and included in a pharmaceutical dosage form to (i) aid the processing of the dosage
201
form during its manufacture, (ii) protect, support or enhance stability, bioavailability or
202
patient acceptability, (iii) assist in product identification, or (iv) enhance any other attribute
203
of the overall safety and effectiveness of the dosage form during storage or use.
204
205
good manufacturing practices (GMP)
206
A philosophy of practice and processes to assure the quality and safety of manufactured
207
pharmaceutical products; specified in for example WHO guidelines.

page 9
208
209
labelling information
210
Information to the user provided on the package label or in the patient information leaflet.
211
212
manipulation of a dosage form
213
Operation performed by the pharmacist or parent/caregiver to facilitate the administration of
214
a dosage form. It can be simple, e.g. breaking a tablet, or complex, for example, using tablets
215
as a source for an active pharmaceutical ingredient to prepare a suspension.
216
217
pharmaceutical dosage form
218
The physical form in which a medicine is presented; the name of a dosage forms combines its
219
physical form and the intended route of administration, e.g. a tablet (to be swallowed), oral
220
suspension (liquid suspension of solid particles intended for oral intake and swallowing).
221
222
route of administration
223
The way in which a medicine is given to a patient, e.g. oral administration (administration via
224
the oral route), rectal administration (administration to the rectum).
225
226
SmPC
227
Summary of product characteristics approved by the competent authority
228
229
3.
ALTERNATIVES TO COMPOUNDING
230
231
Before deciding to compound consider possible alternatives that will give the greatest
232
assurance of clinical effectiveness and safety.
233
234
In some situations, for example, if the stability and method of preparation of an oral liquid are
235
well documented, e.g. if compounding has been industry-verified and all facilities and
236
ingredients are available, it may be less compelling to seek an alternative. On the other hand,
237
if there are no stability data and, for example, the API forms a caking suspension in the only
238
available excipients (e.g. a syrup), an alternative must be considered to ensure safe and
239
effective treatment.
240

page 10
241
In any case, the decision on how to prepare and/or provide a non-authorized preparation
242
should be based on an assessment of risks and benefits of the dosing strategy. On a case-by-
243
case basis, potential benefits from use should be weighed against all possible risks arising
244
from preparation and administration of such medicines. Even in cases where the compounded
245
preparation can be considered a validated formulation, the impact of compounding on
246
bioavailability may not be known.
247
248
Main alternatives to compounding are:
249
250
3.1
Sourcing of a commercially-available or manufactured product1 if available
251
252
The logistics of supply and access are obvious factors that might work against this but
253
practitioners should liaise with suppliers, importers and regulatory authorities to access these
254
products if possible.
255
256
Importation of products may be expensive and reputable suppliers should be used to avoid
257
spurious/falsely-labelled/falsified/counterfeit (SFFC) medicines. Quality assurance systems
258
should be in place, for example, to ensure that recall systems are available and information
259
provided in the local language.
260
261
Large-scale use of compounded oral liquids for children should not be justified on the
262
grounds that they are cheaper than commercial products. Other options, including local
263
manufacture using GMP standards, should be investigated.
264
265
3.2
Dose rounding
266
267
If the dose prescribed does not correspond to a dosage form which is commercially available,
268
consider whether the dose can be suitably amended whilst maintaining safety and efficacy.
269
The therapeutic index of the medicine and patient characteristics are to be considered before
270
making a decision.
271
This includes products prepared to GMP standards, for example at an accredited hospital manufacturing unit.

page 11
272
Some drug doses are calculated accurately on the basis of body weight yet the therapeutic
273
index is such that one dose can be used for a broad weight or age band. Consult the WHO
274
Model Formulary for Children. Available from:
275
http://apps.who.int/medicinedocs/en/m/abstract/Js17151e/
276
277
3.3
Therapeutic alternatives
278
279
If a medicine is prescribed in a formulation which is not available, e.g. in an age-appropriate
280
form, consider the possibility of using a medicine with a similar therapeutic action which is
281
available in a more suitable form. Examples are presented in Appendix 1.
282
283
3.4
Manipulation of dosage forms
284
285
In situations where the prescribed dose is less than what is commercially available, if there
286
are swallowing difficulties, or the stability of a compounded oral liquid cannot be assured,
287
consider the possibilities for manipulation of a dosage form as outlined below.
288
289
The practitioner should have in mind that manipulation, such as tablet splitting, tablet/capsule
290
dispersion or tablet crushing and mixing with food or drink, may increase the potential for
291
inaccurate dosing and it may affect the stability and bioavailability of the dosage form, in
292
particular when mixed with food or drink. Excipients that are safe for adults may not
293
necessarily be so for children.
294
295
When medicines are mixed with food or drink, an unpleasant taste of the mix may cause
296
aversion by the child. Mixing with breast milk could potentially be used in very young
297
children (< 6 months) but may cause aversion in breastfed children; the mother should
298
therefore observe milk intake and signs for breast-milk refusal.
299
300
3.4.1 Tablet splitting
301
Many tablets are designed to allow splitting, either by breaking if scored or by using a
302
purposely designed tablet cutter. If the child is able to take solid dose forms safely (age will
303
vary but usually from age 68 and above), a tablet fraction can be given, otherwise it can be
304
dispersed or mixed with food or juice as below.

page 12
305
306
There is evidence that splitting of marketed tablet formulations may result in segments that
307
are far from meeting pharmacopoeia requirements for dose uniformity. Unless the tablet is
308
provided with a score line to facilitate breaking and swallowing the full dose, it is important
309
that regulatory authorities and manufacturers assure that such tablet formulations that may be
310
splitted also meet the relevant uniformity requirements for the tablet segments, and that
311
information about possible splitting occurs in the summary of product characteristics (SmPC).
312
313
In the lack of appropriate information and especially when the API is potent or has a narrow
314
therapeutic index, compounding may be preferable when an accurate dose cannot be assured.
315
Thus, consider on a case-by-case basis whether splitting of tablets might lead to toxicity or
316
reduced effect.
317
318
Not all tablets can be split. In general, those with a sustained release or enteric coating cannot
319
be split but it may be possible to split those with a sustained-release matrix. Formularies or
320
manufacturers information and the SmPC should be consulted.
321
322
Consideration should be given to splitting tablets with an appropriate commercial tablet
323
splitter in the pharmacy. If possible tablets with score lines and uniform distribution of the
324
active drug should be sourced and information sought on the stability of segments. If carers
325
are cutting segments, they should be given a commercial tablet splitter with adequate
326
instruction on the method of preparing and storing tablet segments.
327
328
3.4.2 Tablet/capsule dispersion for oral administration
329
It may be possible to disperse tablets or the contents of capsules in water or other liquid. If
330
the tablet disperses, the tablet or a fraction of the tablet can be dispersed in a small volume
331
appropriate for the concerned child, and the whole dose given when a suspension is formed,
332
mixed with a flavored vehicle if required. Assure that the whole dose is administered by
333
flushing the container. Consider the impact of dispersion and the risk for interactions with the
334
contents of the flavoured vehicle on bioavailability.
335
336
Conventional tablets do not disperse readily but some form a suspension within a short time.
337
Soluble tablets and dispersible tablets disintegrate and dissolve or disperse within a short time

page 13
338
in water at room temperature. When the API is known to be soluble, dissolving or dispersing
339
the tablet in a known volume of water can allow a fractional dose to be appropriately
340
measured with a syringe as in the case of captopril. As extraction of soluble API from the
341
tablet excipients may be incomplete the suspension should be shaken or stirred prior to
342
measuring the dose and not filtered unless it has been established that the API is not removed.
343
In the case of a poorly soluble API the measurement of a fractional dose by taking an aliquot
344
from a suspension formed in this way is generally not recommended due to probable rapid
345
sedimentation of insoluble API and resultant dosage inaccuracy.
346
347
The remainder of a tablet or capsule dispersion shall not be stored and reused because of
348
stability reasons (microbiological, chemical, physicochemical).
349
350
Tablet dispersion may not always be practical for infants when the doses required are the
351
equivalent of small tablet fractions that are unable to be reliably prepared, e.g. a fifth of a
352
tablet or if the tablet is not scored.
353
354
When dispersion is intended for tube feeding, parameters such as particle size, viscosity,
355
dosing volume and compatibility of the oral preparation with the tube material should be
356
considered. Dispersions may be too viscous or contain large particles that can make the
357
administration by feeding tube not feasible. Adsorption of API to the tube material results in
358
inappropriate dosing; this concern is most relevant for lipophilic and potent APIs.
359
360
WHO is promoting the use of flexible solid oral dosage forms such as dispersible tablets (see
361
Development of paediatric medicines: points to consider in formulation, WHO Technical
362
Report Series, No. 970, Annex 5). The use of custom-made dispersible tablets for paediatric
363
dosing should be used wherever possible but there is a need to ensure that carers understand
364
how they are to be administered.
365
366
3.4.3 Crushing tablets/opening capsules and mixing powder with food or drink
367
The practice of crushing tablets or opening capsules and adding the powder to a palatable
368
drink or sprinkling onto solid food are common alternatives. However, there may be little
369
evidence to support the efficacy and safety since stability and bioavailability may be altered.
370
In case of potent APIs, consider the risks associated with handling of powdered material for

page 14
371
parents/carers. Modified-release tablets and capsules cannot be crushed or opened without
372
affecting bioavailability and/or stability, and this should therefore not be done.
373
374
In general, the possibility to crush tablets should be based on bioavailability studies.
375
Information should be sought from manufacturers (e.g. the SmPC and website) and
376
formularies whenever possible. The process is acceptable only if bioavailability is not
377
affected by food or drink, and when the product is used immediately.
378
379
It is difficult to ensure that a complete dose has been taken and the practice of nurses and
380
carers handling powdered medicines may present health concerns. Tablet dispersion may be a
381
simpler, more reliable and potentially safer method.
382
383
Aliquots should usually not be taken from liquid-filled capsules since it is difficult to remove
384
and measure the total contents.
385
386
3.4.4 Giving the injectable form by the oral route
387
Oral administration is possible, although an expensive option, for some injections. If the
388
injectable form of the API is the same as the oral form (for example, labetalol hydrochloride,
389
ondansetron hydrochloride) it can be assumed that the API will be absorbed enterally from
390
the injectable formulation. However, as the API is in solution more rapid absorption and
391
higher peak levels may occur compared to the slower absorption from a solid oral dose form.
392
When evaluating whether an injection is suitable for oral use specialist advice, e.g.
393
consultation with a medicines information centre, should be sought because there are
394
important factors which must be considered, e.g. first-pass effect, oral bioavailability, gastric
395
acidity (e.g. effect on stability), pH effects (e.g. precipitation of soluble salts of weak acids)
396
and palatability.
397
398
Injections may contain excipients that are undesirable in some patients, e.g. propylene glycol
399
and ethanol. The pH of some injections may mean that they should not be given orally or be
400
diluted before administration to avoid irritation, e.g. furosemide injection (pH 9),
401
pantoprazole injection (pH 910.5), phenytoin sodium injection (pH 1012).
402
403

page 15
404
3.4.5 Splitting suppositories
405
There is little information on the accuracy with which suppositories can be split. Splitting is
406
usually associated with major problems with regard to accurate dosing. The majority of
407
commercially available suppositories are formulated as suspensions, which means that
408
sedimentation of the solid API particles may occur during solidification of the suppository;
409
therefore, if suppositories need to be split, this should be done lengthwise.
410
411
Suppositories have been melted and recast into smaller moulds. This option is associated with
412
a risk of recrystallization and for affecting the distribution of the API resulting in over- or
413
under-dosing. It is therefore generally discouraged.
414
415
Therapeutic index and the consequences of over- or under-dosing should be taken into
416
account when determining whether it is safe to split suppositories. If possible, this should be
417
done in the pharmacy and segments should be weighed to ensure the desired weight.
418
419
3.4.6 Other possibilities
420
In any case where a change of the route of administration as intended for an authorized
421
medicine is considered advice should be sought from formularies and the literature and even
422
specialist advice. In general, use of an altered route of administration results in a different
423
pharmacokinetic profile introducing a high risk of dosing errors and may compromise safety
424
and efficacy.
425
426
4.
COMPOUNDING
4.1
Good manufacturing practices aspects
427
428
429
430
The dispensing pharmacy receives the prescription for a patient and provides the
431
compounded preparation to the patient. Preparation may take place in another pharmacy or
432
hospital manufacturing unit.
433
434
When a non-authorized medicine is prepared for stock the preparing pharmacy or hospital
435
unit should meet GMP requirements to personnel, premises and equipment, quality assurance
436
system, documentation and product dossier. Further, an authorization by the competent

page 16
437
authority to carry out operations should be considered. Reference in this aspect is made to the
438
PIC/S Guide to Good Practices for the preparation of Medicinal Products in Healthcare
439
Establishments (www.picscheme.org) and to other guidelines, including WHO guidelines on
440
GMP and corresponding national guidelines.
441
442
In case of compounding as a single event and the preparation is dispensed immediately to the
443
patient, requirements may be less strict. Nevertheless, there are quality assurance
444
requirements to take into account:
445
446
the preparing pharmacy should have appropriate premises and equipment;
447
the pharmacist and staff must have sufficient training and background for
compounding;
448
449
access to relevant literature (pharmacopoeias, handbooks, scientific journals, etc.) and

the Internet;
450
451
general instructions for every type of preparation should be available;
452
a record on each preparation should be retained showing the key processing and
packaging steps including the name of the person responsible for each step.
453
454
455
4.2
Potential problems
456
457
Formulation of a compounded medicine is associated with a number of potential problems
458
that may impact on the safety and effectiveness of the formulation. Awareness of the relative
459
complexity of the formulation and the things that can go wrong will help to avoid such
460
problems. Guidance on compounding can be found in, for example, Marc Jackson and
461
Andrew Lowey: Handbook of Extemporaneous Preparation, Pharmaceutical Press, 2010.
462
463
Consideration must be given to the properties of the API (e.g. aqueous solubility, pH effect
464
on solubility, particle size when poorly soluble) and stability of both API and the
465
compounded formulation, i.e. chemical, physical and microbiological instability.
466
467
Further consideration must be given to the selection of excipients and excipients present in
468
manipulated dose forms. It is important to consider any possible adverse effects of the
469
inactive components of the preparation. The use of preservatives, ethanol and sugars must

page 17
470
be carefully considered. Some guidance and literature references on the formulation can be
471
found in Development of paediatric medicines: points to consider in formulation (WHO
472
Technical Report Series, No. 970, Annex 5).
473
474
Annex 2 presents examples of potential problems in compounding.
475
476
4.3
Basic considerations
477
478
Quality of API and excipients
479
It is important to ensure that the API and excipients meet pharmacopoeia standards
480
with regard to both identity and purity. The choice of excipients should be restricted
481
to those that have been used in authorized medicines intended for the same route of
482
administration.
483
484
Consider use of an authorized dosage form as a starting point
485
It may be safer and more effective to crush tablets or use the contents of hard capsules
486
with an appropriate suspending vehicle rather than preparing from API and excipients.
487
There are many formulations available with validated shelf-life but sourcing of
488
suspending agents may be difficult and/or expensive.
489
490
There might be instances where the pharmacist crushes a number of tablets or opens a
491
number of capsules, dilutes the powder with a suitable excipient and doses the powder
492
in ready-to-use single dose sachets. Before doing so, consider the stability of the
493
preparation including in-use stability against humidity and exposure to air.
494
495
Consult literature and guidelines if available
496
If possible, always use a validated formulation (i.e. based on literature, stability
497
studies and guidelines). Consult product information and the latest national and
498
international guidelines and/or a specialist information centre if possible.
499
500
Employ the principles of GMP
501
This involves the processes put in place to give the highest level of assurance possible
502
that the product will be safe and effective. It is accepted that few units will be able to

page 18
503
conform to the requirements of GMP. However, as stated in Section 3.1, the
504
principles of quality assurance are possible and essential under any conditions.
505
506
Medication error potential
507
There have been many examples of medication error when preparing compounded
508
medicines and some have resulted in death or serious harm to patients. The potential
509
for medication error must be recognized and steps taken to minimize the risk. This
510
will include as a minimum the use of a worksheet listing the formulation ingredients
511
and the identity of ingredients; quantities, calculations and measurements should be
512
double-checked by trained personnel and signatures provided. The pharmacist
513
responsible should check the final product and label against the signed worksheet,
514
ingredients and prescription.
515
516
Caution in extrapolating from other formulations
517
Caution is required if extrapolating the formulation from a published study or
518
formulary. Formulations made from APIs may be more stable than formulations made
519
from solid dose forms and vice versa. Tablet and capsule excipients can increase or
520
decrease the stability of the API in an oral liquid preparation. The salt form of the
521
drug used in a published study could be different to the form locally available and this
522
may affect the drugs solubility and stability. Consult pharmacopoeias and seek
523
specialist advice if possible.
524
525
Similarly, the results of a published study using a drug mixed with a commercial
526
suspending base (e.g. Ora-Plus) cannot generally be extrapolated to a situation
527
where the same drug is mixed with a simple base of syrup or glycerol.
528
529
Formulations for compounded medicines based on APIs and crushed tablets are not
530
interchangeable.
531
532
Dose uniformity may be a problem explain importance of shaking prior to use
533
If the API is poorly soluble in water, it will generally be more chemically stable in an
534
aqueous suspension, but uniformity of dosing the suspension may be a problem. A
535
suspending agent will be required. Always check that the finished preparation

page 19
536
resuspends under in-use conditions and explain the importance of resuspension by
537
shaking to patients/carers.
538
539
If the API is soluble, it will generally be less stable in a liquid preparation. As the
540
API is soluble, the inclusion of a suspending agent is less important in a preparation
541
based on crushed tablets.
542
543
As excipients and other formulation components can affect solubility, all compounded
544
liquid formulations should be shaken prior to administration. The entire API may not
545
be in solution even if it is highly soluble. The only exception would be if the
546
preparation is made from pure API and it can be assured that the entire API is in
547
solution.
548
549
Exceptionally, when no published formulation is available
550
The pharmacist must assess the risks for different options and use knowledge and
551
experience to formulate a product.
552
553
o Obtain physicochemical properties of the API if available
554
API solubility and the pH stability profile are useful when considering the
555
approach to formulation or dose administration. If possible, obtain basic
556
physicochemical information about the API, especially the aqueous solubility
557
of the API at the expected pH of the final preparation. This allows a
558
judgement on whether an API solution or suspension is formed.
559
560
o Test the physical characteristics prior to patient use
561
Tablet/capsule formulations vary worldwide, especially with respect to
562
excipients content. The differences can influence the effectiveness and
563
acceptability of the preparation. Basic performance tests should be done
564
before patient use, particularly on formulations prepared for the first time.
565
This includes ease of resuspension and pouring, degree of caking on storage,
566
observation of physical behaviour and characteristics.
567

page 20
o Consider risk of microbial growth
568
569
All compounded liquid formulations are highly susceptible to microbial
570
growth. An antimicrobial preservative must be included unless the final
571
product will be used completely within 23 days and stored under
572
refrigeration. Oral liquids that are not adequately preserved will support rapid
573
growth of bacteria and fungi especially at warm to hot temperatures and can
574
pose hazards to patients especially if immunosuppressed.
575
576
Preparation of compounded liquids should be carried out under conditions to
577
minimize the introduction of microbial contamination.
578
579
Use appropriate final containers
580
Final containers and closures should be clean and free from dust and other residues. It
581
is recommended to use new containers. Containers that are reused should be
582
thoroughly washed, rinsed with sterile or freshly boiled water and dried. Light-
583
protective (e.g. dark plastic or amber glass) containers should generally be used.
584
Consider the use of a light protective wrapping such as foil if a light-protective
585
container is not available.
586
587
Selection of the final container should consider potential drug adsorption to plastic
588
containers.
589
590
Dosing device
591
In view of the dosing needs of liquid preparations the feasibility of appropriate dosing
592
should be confirmed as not all dosing devices may allow delivering the required
593
volume. As most compounded liquids should be shaken prior to administration, this
594
may introduce entrapped air in the liquid, which may cause problems with accurate
595
measurement of small volumes.
596
597
Consider in-use storage
598
In-use storage conditions may vary considerably from those in a published study or
599
formulary recommendation. Always consider if it will be possible to store and use the
600
preparation under the optimal conditions described in the study, which usually are

page 21
601
refrigeration, protection from light and with minimal possibility of in-use
602
contamination. If these conditions are not possible locally it can be assumed that the
603
preparation will be less stable and more susceptible to microbial growth. Reduce the
604
shelf-life (e.g. from one month to one week) according to professional judgement. If
605
possible, consult expert advice.
606
607
Expiry date
608
Chemical stability and potential for microbial growth under patient-use conditions are
609
seldom tested in published studies.
610
611
It is recommended that each compounded preparation be given an expiry date
612
assigned in a conservative way taking into account API-specific and general stability
613
documentation and literature when available. This will encourage regular fresh
614
preparations and help to assure effectiveness and safety. It also allows the practitioner
615
to regularly review the patients use of the preparation.
616
617
The following items should be considered when determining such expiry date: nature
618
of the API and its degradation mechanisms; dosage form and its components;
619
potential for microbial proliferation in the preparation; container in which the
620
preparation is packaged; expected storage conditions; and the intended duration of
621
therapy.
622
623
When an authorized medicine is used as the source of the API, stability information
624
could be obtained from the manufacturer. Otherwise, applicable information on
625
stability, compatibility and degradation of ingredients and use has to be sought in the
626
literature.
627
628
Give clear instruction to caregivers/patients
629
This may include instructions on storage, resuspension, changes in taste, smell,
630
appearance, adverse effects and other pharmaceutical advices.
631
632
It is common practise that parents/carers add powdered dosage form to a liquid
633
(water, juice, etc.) or sprinkle it onto food to improve palatability and mask

page 22
634
unpleasant taste. This should be done only when bioavailability is not affected and
635
intake of the full dose can be ensured. Provide parents/carers with appropriate
636
information.
637
638
If an oral syringe or other measuring device is used it is important to check the
639
technique to ensure the correct dose is administered. Advise the use of clean
640
measuring devices and ways to avoid contaminating the preparation when preparing
641
the dose.
642
643
Label information
In addition to dosage instructions, include at least the following information:
644
645
646
if applicable, the name of the pharmaceutical preparation;
647
the route of administration;
648
the name(s) of the API(s) and excipients of known pharmacological action,

e.g. antimicrobial agents, antioxydants;
649
650
if liquid, concentration(s) of the API(s), e.g. in mg/ml, and the amount or

volume of the preparation in the container;
651
652
if solid, amount(s) of the API(s) in each dose and the number of doses in the
container;
653
654
reference or batch number (or date of preparation);
655
expiry date (do not use after...);
656
any special storage conditions and handling precautions that may be

necessary, e.g. to be shaken before use;
657
658
the pharmacy name and contact information;
659
name of the patient.
660
661
Document concerns and share information
662
Practitioners are encouraged to maintain dialogue with regulatory bodies and
663
international agencies and networks about problems and concerns associated with the
664
preparation and availability of age-appropriate medicines for children. The sharing of
665
solutions to problems is also important.
666

page 23
667
5.
INFORMATION, AVAILABILITY AND ACCESS
668
669
A number of networks, websites and other resources are available which provide information
670
on standards of practice, formulas for compounded preparations, manufacturers, suppliers of
671
oral liquid formulations, and networks and responsive information services. These should be
672
consulted by practitioners and regulators to provide the safest and most effective treatment
673
options for children who require an age- appropriate formulation.
674
675
5.1
Standards of practice and guidelines
676
677
Some national, regional and international guidelines for extemporaneous formulations and
678
medicines administration to children have been published. Consulting these documents may
679
assist in forming local policies of practice and educational activities for practitioners.
680
681
5.2
Formularies and compendia
682
683
These may be helpful in providing formulation advice and general advice on dosage
684
manipulations. The information in these formularies may be difficult to transfer to a local
685
situation where the base ingredients (e.g. commercial suspending bases, antimicrobial
686
preservatives, pure drug powder) are not readily available.
687
688
The eMixt database (www.pharminfotech.co.nz) is being developed to provide
689
comprehensive information for all settings and environments.
690
691
Mark Jackson and Andrew Lowey: Handbook of Extemporaneous Preparations,
692
Pharmaceutical Press 2010, contains formulations and associated stability summaries for oral
693
liquid preparations.
694
695
5.3
Source and supply
696
697
A database of sources and prices of medicines for children has been compiled by Unicef. This
698
will be available electronically by mid-2011
699
(http://www.unicef.org/supply/index_47129.html)

page 24
700
701
The database can be searched to find worldwide suppliers of oral liquids and other age-
702
appropriate formulations for paediatric use.
703
704
5.4
Networks and information services
705
706
Local, national and international medicines information centres may respond to
707
questions about formulation such as the WHO Paediatric medicines Regulatory
708
Network (PmRN). Partnerships and twinning arrangements between hospitals in
709
poorly-resourced countries and developed countries can be explored and are often
710
beneficial.
711
Questions can also be posted via the eMIxt website www.pharminfotech.co.nz.
712
713
714
Sharing of information and advice on paediatric formulations should be explored

whenever possible.
715
716
717
International discussion lists can be useful for posting questions on formulations and
718
the archives can be searched for previous questions and answers. Examples include
719
eDrug and INDICES accessed via http://www.essentialdrugs.org/.
720
721
6.
REFERENCES
722
723
1.
Pharmaceutical development for multisource (generic) pharmaceutical products. In: WHO
724
Expert Committee on Specifications for Pharmaceutical Preparations. Forty-sixth report.
725
Geneva, World Health Organization. WHO Technical Report Series, No. 970, Annex 4,
726
2012 (http://www.who.int/medicines/areas/quality_safety/quality_assurance/en/).
727
728
2.
Development of paediatric medicines: points to consider in pharmaceutical
729
development. In: WHO Expert Committee on Specifications for Pharmaceutical
730
Preparations. Forty-sixth report. Geneva, World Health Organization. WHO Technical
731
Report Series, No. 970, Annex 5, 2012
732
(http://www.who.int/medicines/areas/quality_safety/quality_assurance/en/).

page 25
733
734
3.
WHO good manufacturing practices: main principles for pharmaceutical products
735
In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-
736
eighth report. Geneva, World Health Organization. WHO Technical Report Series, No.
737
986, Annex 2, 2014 (in print).
738
739
4.
Good manufacturing practices for pharmaceutical products. In: Quality assurance of
740
pharmaceuticals. WHO guidelines, related guidance and GXP training materials,
741
CD-ROM 2013.
742
743
5.
The International Pharmacopoeia, Fourth Edition, including First, Second and Third
744
Supplements (http://who.int/medicines/publications/pharmacopoeia/en/index.html).
745
Available online and CD-ROM version (2013).
746
747
6.
Report for WHO on findings of a review of existing guidance/advisory documents on
748
how medicines should be administered to children, including general instructions on
749
extemporaneous preparations and manipulation of adult dosage forms (working
750
document QAS/11.400).
751
752
7.
The WHO Model Formulary for Children (2010)

(http://www.who.int/selection_medicines/list/WMFc_2010.pdf).
753
754
755
8.
Report of the Informal Expert Meeting on Dosage Forms of Medicines for Children.
756
Geneva, World Health Organization. December 2008
757
[http://www.who.int/selection_medicines/committees/expert/17/application/paediatric/
758
Dosage_form_re-port DEC2008.pdf.
759
760
9.
Handbook of Extemporaneous Preparation: A guide to pharmaceutical compounding.
761
Part A. Standards: In Handbook of Extemporaneous Preparation, pages 165. Mark
762
Jackson and Andrew Lowey. Pharmaceutical Press, 2010.
763
764
765
10.
Pharmaceutical Inspection Co-operation Scheme (http://www.picscheme.org/)

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

page 26
766
009-9 (Part I). PIC/S GMP guide (Part I: Basic requirements for medicinal products);
767
PE 010-3 Guide to good practices for the preparation of medicinal products in
768
healthcare establishments.
769
770
11.
Kastango ES, Trissel LA, Bradshaw BD. An Ounce of Prevention: Controlling Hazards
771
in Extemporaneous Compounding Practices. International Journal of Pharmacy
772
Compounding. 2003; 7(5): 401-16.
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
Available commercially in
some countries.
Dispersed captopril tablets
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
783
In some cases the therapeutic alternative may not be available as an oral liquid but as a more
784
easily manipulated form (see felodipine example above).
785
786
787
788
789
790
791
792

page 28
ANNEX 2
793
794
795
Compounded preparations consideration of potential problems
796
797
The most frequently used method is to grind the required number of tablets to a fine
798
powder in a mortar and form a slurry by adding a small volume of water. At this stage
799
there is the potential for the operator to be exposed to hazardous powdered drug and
800
microbial contamination of the product if clean equipment is not used.
801
802
Excipients such as antimicrobial preservatives, suspending agents and flavouring agents
803
are added to make the final product. A frequently used base is a mixture of glycerol or
804
syrup, a suspending agent such as methylcellulose and para-hydroxybenzoates (parabens)
805
as a preservative. Other agents sometimes added include alternative solvents such as
806
ethanol, particularly when the drug is poorly soluble in water, and buffer systems to
807
provide the optimum pH for drug stability or activity of the antimicrobial preservative.
808
Whilst ostensibly simple, such formulations can be complex, comprising a mixture of the
809
base and a suspension or solution (usually a combination of both) of tablet excipients and
810
active drug. If the drug is water soluble there is a temptation to filter out the insoluble
811
tablet excipients to leave a clear solution but filtration can remove significant amounts of
812
drug if extraction from tablets is incomplete. Insoluble tablet excipients are in suspension
813
and may compromise product appearance, whereas soluble excipients may alter drug
814
stability, for example, by changing the pH of the preparation. Added ingredients or
815
excipients may not be appropriate for babies and infants, e.g. ethanol, propylene glycol.
816
Whilst there may be advantages in using pure drug powder instead of tablets it may not be
817
easily obtainable.
818
819
The expiry date of a compounded oral liquid is assigned empirically or based on
820
published information on a particular formulation. A conservative approach must be
821
adopted when assigning an expiry date because of lack of information on API stability or
822
limitations in either the design or the conclusions of a published report. Also, it may be
823
impractical to entirely reproduce the conditions of a study which was performed in
824
another institution or country under the controlled conditions of an experiment rather than
825
clinical use. Most studies base their expiry date recommendation on chemical stability but

page 29
826
do not address possible physical or microbiological spoilage which may be significant
827
during actual use of the product. For these reasons extemporaneously prepared oral
828
liquids should only be used for a maximum of one month from the date of preparation to
829
minimize any unrecognized product deterioration. Longer expiry dates may be applied if
830
more extensive testing is performed.
831
832
Finally, when deciding on a formulation, it is important to consider any possible adverse
833
effects of the "inactive" components of the preparation. Sucrose (in syrup) can promote
834
the formation of dental caries, ethanol can cause hypoglycaemia and para-
835
hydroxybenzoates can cause hypersensitivity reactions and exacerbate the symptoms of
836
asthma. It has also been suggested that benzoates and para-hydroxybenzoates can
837
aggravate neonatal hyperbilirubinaemia by displacing bilirubin which is bound to plasma,
838
proteins but this effect has not been demonstrated in vivo and the amounts present in oral
839
formulations are unlikely to pose any risk. Limits for the inclusion of ethanol in
840
paediatric formulations have been proposed by the American Academy of Pediatrics but
841
there is little supporting evidence for the recommendation.
842
843
Deterioration of an oral liquid may be due to chemical, physical or microbiological
844
instability which can lead to a subtherapeutic dose of drug, exposure to toxic degradation
845
products or ingestion of unacceptable numbers of microorganisms. It is important for
846
pharmacists, clinicians and nursing staff to be aware of potential problems caused by
847
instability to ensure that drug therapy is effective and safe.
848
849
Chemical instability
850
851
APIs in compounded liquids may be susceptible to chemical reactions leading to
852
degradation. The most common reactions are hydrolysis, oxidation and reduction. Usually
853
the reaction rate or type is influenced by pH, for example, azathioprine is rapidly
854
hydrolysed to 6-mercaptopurine at alkaline pH but is relatively stable in acidic or neutral
855
conditions. Other factors which may increase the rate of reaction include the presence of
856
trace metals which catalyse the oxidation of captopril, methyldopa or exposure to light,
857
which catalyses the oxidative degradation of 6-mercaptopurine. The rate of chemical
858
degradation usually increases with temperature, a factor which is the basis for accelerated

page 30
859
stability trials of pharmaceutical formulations. Preparations made from tablets contain
860
excipients such as binders and disintegrating agents in addition to the API. These
861
excipients may reduce chemical stability by changing the pH to a value at which more
862
rapid degradation occurs. This probably explains why amiloride solution prepared from
863
pure API is more stable than an oral liquid prepared from tablets.
864
865
The API in the preparation may be totally or partially in solution or predominantly in the
866
solid state as a suspension. APIs in solution are more susceptible to chemical degradation
867
than APIs in the solid state (i.e. suspensions), thus suspensions of acetazolamide and
868
chlorothiazide are more stable than solutions. However it cannot be assumed in all cases
869
that a compounded suspension is more stable than a solution. In a suspension, an
870
equilibrium exists between the API in the solid state and an API in solution, and even
871
though the amount of drug dissolved may be minimal the conditions could be optimal for
872
degradation. Furosemide is a notable example which undergoes hydrolysis in acidic
873
conditions where the solid state is predominant, but is much more stable at alkaline pH
874
where it is totally in solution.
875
876
Microbiological instability
877
878
Microbial growth in an oral liquid may cause foul odour and turbidity and adversely
879
effect palatability and appearance. High titres of microorganisms may be hazardous to
880
health especially in very young or immunocompromised patients. By-products of
881
microbial metabolism may cause a change in the pH of the preparation and reduce the
882
chemical stability or solubility of the drug. Microbial contamination during preparation
883
must be minimized by using clean equipment, sterile water (Water for Irrigation (BP))
884
and avoiding contaminated raw materials and containers. If sodium benzoate or benzoic
885
acid are used as antimicrobial preservatives the final pH must be less than 5 so that the
886
active unionized form is predominant. Consequently the API must also be stable at this
887
pH.
888
889
Effective preservative systems require rigorous evaluation which is seldom performed on
890
compounded formulations. Many factors can reduce the effectiveness of the preservative
891
including use of contaminated materials, chemical degradation, binding of preservative to

page 31
892
suspending agents or tablet excipients, incorrect storage or unhygienic use of the final
893
product.
894
895
Physical instability
896
897
Compounded oral suspensions may be susceptible to sedimentation of insoluble API
898
causing caking. Difficulty in resuspending the API or rapid sedimentation following
899
shaking can lead to erratic dosage measurement as demonstrated with chlorothiazide
900
suspension and this inherent problem with compounded formulations is of considerable
901
concern. Some spironolactone suspensions have been reported to be excessively thick and
902
almost unpourable. Refrigeration, whilst usually desirable to maximize chemical stability
903
and reduce microbial growth, can also increase the viscosity of a suspension making
904
resuspension more difficult or cause the precipitation of API or preservatives. It is
905
important to consider the effect on pH of all components of the formulation and the
906
possible impact on stability. Syrup, for example, is relatively acidic and if used in
907
phenobarbitone sodium oral solution it will cause the precipitation of unionized
908
phenobarbitone.
909
910
***

Pripravci Za Djecu

Caricato da

Informazioni sul documento

Titolo originale

Copyright

Formati disponibili

Condividi questo documento

Condividi o incorpora il documento

Opzioni di condivisione

Hai trovato utile questo documento?

Questo contenuto è inappropriato?

Copyright:

Formati disponibili

Pripravci Za Djecu

Caricato da

Copyright:

Formati disponibili

Working document QAS/14.

FIP-WHO TECHNICAL GUIDELINES:

POINTS TO CONSIDER IN THE

PROVISION BY HEALTH-CARE PROFESSIONALS OF

CHILDREN-SPECIFIC PREPARATIONS THAT ARE NOT

AVAILABLE AS AUTHORIZED PRODUCTS

World Health Organization 2014

Working document QAS/14.582

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

Discussion at informal consultation on paediatrics and

4-6 May 2011

Revision prepared incorporating amendments by WHO

Revision sent out for comments

Consolidation of comments received

Discussion at forty-sixth meeting of the WHO Expert

10-14 October 2011

Revision prepared and sent out for comments

Consolidation of comments received

Discussion at forty-seventh meeting of the WHO Expert

Review of comments received and recommendations of

Preparation of new working document for circulation

Circulation of new working document for comments.

Discussion during Expert Committee on the Selection

Compilation of feedback received

Any further action by WHO and FIP

Working document QAS/14.582

Presentation to the forty-eighth meeting of the WHO

14-18 October 2013

New document received by WHO from FIP

Circulation of new working document for comments.

Compilation of feedback received

Presentation to the forty-eighth meeting of the WHO

13-17 October 2014

Any further action as necessary

Working document QAS/14.582

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

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

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

practitioners it is advisable to include a glossary.

Introduction and scope ..

Target audience and health-care settings

Alternatives to compounding ....

Sourcing of a commercially available or manufactured product if available

Manipulation of dosage forms

3.4.1 Tablet splitting ..

3.4.2 Tablet/capsule dispersion for oral administration .

3.4.3 Crushing tablets/opening capsules and mixing powder with food

3.4.4 Giving the injectable form by the oral route

3.4.5 Splitting suppositories ..

3.4.6 Other possibilities .

Working document QAS/14.582

Good manufacturing practices aspects ...

Basic considerations ...

Information, availability and access ....

Standards of practice and guidelines ..

Formularies and compendia ...

Source and supply ...

Networks and information services ....

Annex 1. Examples of therapeutic alternatives .....

Annex 2. Compounded preparations consideration of potential problems ....

INTRODUCTION AND SCOPE

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

available and a safe and effective alternative must be sought.