handbook of extemporaneous preparation a guide to pharmaceutical compounding

Handbook of Extemporaneous
Preparation



Handbook of
Extemporaneous
Preparation
A guide to pharmaceutical
compounding

Edited by
Mark Jackson

BSc, MPhil, MRPharmS

Deputy Director, QCNW/Head of QA/QC, Liverpool Pharmacy Practice Unit,
Liverpool, UK

Andrew Lowey

DPharm, MRPharmS
Clinical Pharmacy Manager, Leeds Teaching Hospitals, Leeds, UK
On behalf of
The NHS Pharmaceutical Quality Assurance Committee


Published by Pharmaceutical Press
1 Lambeth High Street, London SE1 7JN, UK
1559 St. Paul Avenue, Gurnee, IL 60031, USA

Ó The NHS Pharmaceutical Quality Assurance Committee 2010
is a trade mark of Pharmaceutical Press
Pharmaceutical Press is the publishing division of the Royal Pharmaceutical Society
of Great Britain
First published 2010
Typeset by Thomson Digital, Noida, India
Printed in Great Britain by TJ International, Padstow, Cornwall
ISBN 978 0 85369 901 9
All rights reserved. No part of this publication may be reproduced, stored in a retrieval
system, or transmitted in any form or by any means, without the prior written
permission of the copyright holder.
The publisher makes no representation, express or implied, with regard to the
accuracy of the information contained in this book and cannot accept any legal
responsibility or liability for any errors or omissions that may be made.
The right of Mark Jackson and Andrew Lowey on behalf of the NHS
Pharmaceutical Quality Assurance Committee to be identified as the authors
of this work has been asserted by them in accordance with the Copyright, Designs
and Patents Act, 1988.
A catalogue record for this book is available from the British Library.


Contents

Preface
About the editors
Membership of the editorial board
Acknowledgements

Part A Standards
1

2
3
4
5
6
7
8
9
10
11
12

Introduction
Risk management
Quality management
Personnel and training
Premises and equipment
Documentation
Preparation
Formulation and stability
Quality control
Complaints, product recalls and adverse events
Procurement and quality assessment of extemporaneously
prepared medicines
Audit and monitoring

Part B Extemporaneous preparation formulary
13
14

viii
xi
xiii
xiv

1
3
11
23
27
31
35
41
47
55
59
61
65

67

Introduction
Formulary of extemporaneous preparations

69
87

Acetazolamide oral liquid
Allopurinol oral liquid
Amiodarone hydrochloride oral liquid

L-Arginine hydrochloride oral liquid
Azathioprine oral liquid
Bendroflumethiazide oral liquid
Captopril oral liquid
Clobazam oral liquid

89
96
103
110
113
120
125
134


vi | Contents

Clonazepam oral liquid
Clonidine hydrochloride oral liquid
Clozapine oral liquid
Co-careldopa oral liquid (levodopa and carbidopa)
Co-enzyme Q10 oral liquid
Dexamethasone oral liquid and dexamethasone sodium
phosphate oral liquid
Diazoxide oral liquid
Dinoprostone (prostaglandin E2) oral liquid
Ergocalciferol oral liquid
Ethambutol hydrochloride oral liquid
Gabapentin oral liquid

Gliclazide oral liquid
Hydrocortisone oral liquid
Indometacin (indomethacin) oral liquid
Isosorbide mononitrate oral liquid
Joulie's solution (oral phosphate supplement)
Knox mouthwash
Levothyroxine sodium oral liquid
Lorazepam oral liquid
Magnesium glycerophosphate oral liquid
Menadiol sodium phosphate oral liquid
Metformin hydrochloride oral liquid
Midazolam hydrochloride oral liquid
Morphine sulfate oral liquid
Omeprazole oral liquid
Phenobarbital and phenobarbital sodium oral liquid
Phenoxybenzamine hydrochloride oral liquid
Potassium acid phosphate oral liquid
Primidone oral liquid
Pyrazinamide oral liquid
Pyridoxine hydrochloride (vitamin B6) oral liquid
Quinine sulfate oral liquid
Sildenafil citrate oral liquid
Sodium bicarbonate oral liquid
Sodium chloride oral solution
Sodium phenylbutyrate oral liquid
St Mark's solution
Tacrolimus oral mouthwash
Tacrolimus oral suspension
Thiamine hydrochloride oral liquid
Tranexamic acid oral mouthwash

Vancomycin hydrochloride oral liquid
Warfarin sodium oral liquid

138
144
150
158
166
171
178
183
189
194
200
205
209
217
227
231
237
243
255
264
268
272
276
288
300
315
329

336
339
344
351
357
363
368
373
377
380
383
387
396
404
408
417


Contents | vii

Appendix 1: Change control request form

425

Appendix 2: Deviation reporting form

427

Appendix 3: Example raw material specification

429

Appendix 4: Example worksheet

431

Appendix 5: Technical agreement for commissioning
of extemporaneous product preparation service

433

Appendix 6: Audit tool for extemporaneous preparation

437

Appendix 7: Suspending agents

445

Glossary

447

Index

449


Preface

My first experience of extemporaneous dispensing was sitting in the corner of
the dispensary after school watching my father being handed pieces of paper
from customers written in an unfamiliar foreign language with strange hieroglyphics and indecipherable handwriting. He would then peer at the paper
from under his glasses, consult a tattered little black book and proceed to
select a variety of powders and liquids. Out would come the scales, the pestle
and mortar, and he would proceed to make up a mystical potion which would
be bottled up, labelled and gratefully received by the customer. The process
had an air of mystery to it and I was intrigued. It was these early first-hand
experiences of compounding that were my inspiration for a career in
pharmacy.
Extemporaneous preparation or pharmaceutical compounding has historically been a core component of the pharmaceutical profession since its inauguration. However in the modern era, the large-scale manufacture of medicines
in industry has led to the majority of medicines becoming commercially
available. Now, when a patient has a special need for a custom-made product,
the majority of pharmacy departments, quite rightly, outsource the service to
a specialist company or hospital. Hence the need for pharmacists to retain
compounding skills has diminished as it is no longer part of their daily work
and consequently this has led to decline in expertise within the profession in
this area.
However, there are still circumstances where custom-made products are
required for patients and we need to ensure that we as a profession retain the
skills to ensure this is done safely, whether to prepare it locally in the pharmacy or to establish the credentials of a third party to make it on our behalf.
Unfortunately there have been some well-publicised incidents where due
diligence has not been taken, resulting in patient harm.
Licensed medicines represent the ‘gold standard’ for quality, safety and
efficacy. There are, however, circumstances in which there is no licensed
medicine which fully meets the clinical needs of a particular patient or
patients. In these circumstances it is sometimes necessary for the pharmacist
to extemporaneously prepare a limited quantity of a custom-made product for

Preface | ix

a specific patient. Oral liquid medicines are commonly prepared extemporaneously because of a relative lack of licensed formulations for groups such
as the young and the elderly who are unable to swallow tablets or capsules, or
for whom the required dose is less than a single tablet or capsule.
It is widely recognised that the extemporaneous preparation of medicines
carries significant risks. Pharmacists and pharmacy departments have a key
role in ensuring that patients receive medicines of the appropriate quality
whatever the source, whether dispensed, manufactured locally or procured
from a third party. This book aims to provide an updated standard for
extemporaneous preparation, taking into account previous NHS standards
and regulatory guidance.
To give some historical background to the book, a working party of the
NHS Pharmaceutical Quality Assurance Committee first produced the Guide
to the Preparation of Extemporaneous Products in 2001. This guide provides
detailed guidance to pharmacists relating to the extemporaneous preparation
of medicines in accordance with a prescription, under the exemption conferred on pharmacists under Section 10 of the UK Medicines Act 1968.
In December 2005, the UK National Advisory Board for the
Modernisation of NHS Hospital Medicines Manufacturing and Preparation
Services commissioned a study into improving the quality and formulation of
unlicensed, non-sterile oral medicines made by the NHS.
In April 2008, the Pharmaceutical Inspection Convention, Pharmaceutical
Inspection Co-operation Scheme (PIC/S) published a Guide to Good Practices
for the Preparation of Medicinal Products in Healthcare Establishments. This
document sets out guidance for the preparation of medicines for human use
normally performed by healthcare establishments for supply directly to
patients. The UK Medicines and Healthcare products Regulatory Agency
(MHRA) have stated that this guidance is not applicable to NHS hospitals
working under a manufacturer’s ‘Specials’ licence. However, it is applicable
to products prepared under Section 10 exemption to the Medicines Act 1968,

including extemporaneous dispensing.
The NHS Pharmaceutical Quality Assurance Committee reviewed this
document and the authors of this book were tasked with updating the 2001
‘Guide to the preparation of extemporaneous products’ in line with the PIC/S
guidance.
This book aims to provide the reader with comprehensive and relevant
guidance about extemporaneous preparation that incorporates the principles
of the PIC/S guidance document. It also incorporates the key findings and
outputs from the UK National Advisory Board study, including a formulary of
individual stability summaries for the top 50 most commonly extemporaneously prepared medicines in NHS hospitals. It will be adopted as the standard
for extemporaneous dispensing for NHS patients. Although the standards set


x | Preface

out in this book are primarily written for implementation in NHS hospitals,
the principles should be equally applied across the profession.
The focus for the formulary section of the book is oral liquid medicines,
due to the remit of the National Advisory Board study; however, the standards
equally apply to other extemporaneously prepared dosage forms (e.g. creams,
ointments, lotions).
The book is an important reference for any pharmacist, pharmacy technician or student involved with extemporaneous preparation. It also includes
sections relating to clinical risk assessment and advice for procuring ‘Specials’
from manufacturers, and is an important reference for both clinical and
procurement pharmacists.
The Editors would like to thank members of the Editorial Board for all
their hard work and conscientiousness in preparing these standards, and the
members of the UK NHS QA Committee and UK National Paediatric
Pharmacists’ Group (NPPG) for their help and advice. Our hope is that this
book will keep these essential skills alive and that the art of compounding can

be practised safely throughout the profession, offering inspiration to future
generations.
Mark Jackson
Leeds, February, 2010

Further reading
Fenton May V’I (2003). Guide to the Preparation of Non Sterile Extemporaneous Products in
NHS Hospitals. Regional Pharmaceutical Quality Control Committee.
Pharmaceutical Inspection Convention, Pharmaceutical Inspection Co operation Scheme (2008).
Guide to Good Practices for the Preparation of Medicinal Products in Healthcare Estab
lishments. Pharmaceutical Inspection Convention Pharmaceutical Inspection Co operation
Scheme. April 2008. www.picscheme.org (accessed April, 2006).


About the editors

Mark Jackson
Mark graduated from Brighton School of Pharmacy in 1990; he subsequently
gained an MPhil from Bradford University and has completed the
Pharmaceutical Technology and Quality Assurance (PTQA) postgraduate
diploma at Leeds University.
Mark started his career as a clinical/QA pharmacist at Bradford Royal
Infirmary before moving to New Zealand to take up the post of production
manager at Dunedin Hospital. He returned to the UK in 2001 to take up the
post of QA/QC manager at Leeds Teaching Hospitals NHS Trust and
performs the role of regional QA specialist for Yorkshire and Humber. In
March 2010 Mark moved to Liverpool Pharmacy Practice Unit to take up the
post of Head of QA and Deputy Director for Quality Control North West.
Mark is a member of the National NHS Pharmaceutical Quality
Assurance Committee and is chairman of the Working Party for Extemporaneous Preparation. He also acted as the project manager for the UK

research project entitled ‘Improving the Quality and Formulation of
Unlicensed, Non-Sterile, Oral Medicines Prepared in the NHS’, sponsored
by the UK National Advisory Board.

Andrew Lowey
Andrew graduated from Bradford University in 1999 and went on to study
for a clinical diploma at the University of Wales, Cardiff. Following this,
he entered the DPharm doctoral degree programme at Bradford University
in 2001, during which he practised as a hospital pharmacist in a variety of
clinical and technical roles around Yorkshire.
While at Harrogate District Hospital, he won the Pharmaceutical Care
Award for Innovation in Hospital Pharmacy (2002) for helping to develop a
pharmacist-led cardiac risk clinic for patients with type 2 diabetes mellitus.
In 2004, he moved to the Quality Assurance Department in Leeds to carry
out a doctoral thesis focusing on the quality of unlicensed, oral liquid


xii | About the editors

medicines in the NHS. The funding for the underpinning project was provided
by the UK National Advisory Board for the Modernisation of NHS Hospital
Medicines Manufacturing and Preparation Services, and much of the final
work is included in this book. While carrying out the project, Andrew also
served on the British Pharmacopoeia Working Group for Unlicensed
Medicines.
After graduating from the DPharm programme in 2007, he moved back to
clinical pharmacy in 2008 to take up the post of clinical pharmacy manager
for Leeds Teaching Hospitals NHS Trust. He has published several articles on
clinical and technical aspects of pharmacy, and is passionate about promoting
high-quality pharmacy research.

Membership of the editorial
board

Mark Jackson
Deputy Director, QCNW/Head of QA/QC, Liverpool Pharmacy Practice
Unit, Liverpool, UK
Andrew Lowey
Clinical Pharmacy Manager, Leeds Teaching Hospitals NHS Trust, St James’
University Hospital, Leeds, UK
Simon Bath
Production Manager, Tayside Pharmaceuticals, Ninewells Hospital, Dundee,
UK
Alison Beaney
Regional Quality Assurance Specialist–North East, Royal Victoria Infirmary,
Newcastle upon Tyne, UK
Ian Beaumont
Director, Quality Control North West, Regional Quality Assurance
Pharmacist, North West England, Stepping Hill Hospital, Stockport, UK
Dan Kirby
Medicines for Children Research Network (MCRN) Formulation Research
Fellow, Medicines Research Unit, Aston University, Birmingham, UK
Tim Root
Specialist Pharmacist, Clinical Governance and Technical Services, East and
South East England Specialist Pharmacy Services, Chelsea and Westminster
Hospital, UK
Mark Santillo
Regional Quality Assurance Officer, South Devon Healthcare NHS
Foundation Trust, Torbay Hospital, UK

Acknowledgements

The editors would like to thank:
NHS Pharmaceutical QA Committee members
The Neonatal and Paediatric Pharmacists’ Group (NPPG) Committee
members
All the pharmacists at Leeds Teaching Hospitals NHS Trust
Chris Acomb, Clinical Pharmacy Manager, Leeds Teaching Hospitals
NHS Trust
Dr Christine Alexander, Quality Assurance Manager, Tayside
Pharmaceuticals
John Bane, Senior Pharmacist, Sheffield Children’s Hospital
Richard Bateman, QA Regional Specialist Pharmacist, Guy’s Hospital
Brian McBride, Royal Pharmaceutical Laboratory Service, Belfast City
Hospital
Phil Bendell, Principal Pharmacist, Unit Manager, Torbay PMU, South
Devon Healthcare
Caroline Brady, Senior Pharmacy Technician, County Durham and
Darlington Acute Hospitals NHS Trust
Roger Brookes, Technical Services Manager, Royal Hallamshire Hospital
(at the time of the project)
Professor Henry Chrystyn, Professor of Pharmacy Practice, Bradford
University (at the time of the project)
Professor David Cousins, Head of Safe Medication Practice, National
Patient Safety Agency
Peter Cowin, Deputy Quality Assurance Manager, Pharmacy, Charing
Cross Hospital, Hammersmith Hospitals NHS Trust
Dr Diana Crowe, Principal Pharmacist, Regional Pharmaceutical

Laboratory Service, Belfast City Hospital
Philip Dale, Paediatric Pharmacist, Royal Cornwall Hospital
Jackie Eastwood, Specialist Pharmacist (Gastroenterology), St. Mark’s
Hospital, London


Acknowledgements | xv

V’Iain Fenton-May, Quality Controller, St Mary’s Pharmaceutical Unit,
Cardiff and Vale NHS Trust (at the time of the project)
Andy Fox, Principal Pharmacist, Southampton University Hospitals NHS
Trust
Wayne Goddard, Laboratory Manager, Quality Control West Midlands,
University Hospitals Birmingham NHS Foundation Trust
Dr Frank Haines-Nutt, Quality Controller, South Devon Healthcare,
Long Rd, Paignton, Devon
David Harris, Principal Paediatric Pharmacist, Leicester Royal Infirmary
Dr Chris Hiller, Quality Control Department, Newcastle Upon Tyne
Hospitals NHS Trust
Dr Denis Ireland, Deputy Director, Quality Control North West,
Pharmacy Practice Unit, Liverpool
Sue Jarvis, Senior Pharmacist (PICU), Bristol Royal Hospital for Children
Professor Liz Kay, Clinical Director of Medicines Management and
Pharmacy, Leeds Teaching Hospitals NHS Trust
Simon Keady, Principal Pharmacist, University College London Hospitals
NHS Foundation Trust
Tasneem Khalid, Principal Pharmacist Clinical Services/Chair, Paediatric
Oncology Pharmacist’s Group, Central Manchester and Manchester
Children’s University Hospitals NHS Trust
Martin Knowles, Regional QA Specialist Pharmacist, London and the

South-East
Lisa Lawrie, Pharmacy Technician, Bradford Teaching Hospitals NHS
Foundation Trust
Robert Lowe, Director of Quality Assurance Specialist Services, East of
England and Northamptonshire
Rowena McArtney, Senior Information Pharmacist, Welsh Medicines
Information Centre
Liz Mellor, Lead Pharmacist for Clinical Governance, Leeds Teaching
Hospitals NHS Trust
Peter Mulholland, Pharmacy Department, Southern General Hospital,
Glasgow
Dr Trevor Munton, Regional QA Pharmacist, Blackberry Hill Hospital,
Bristol
Tony Murphy, University College London Hospital
Jodi New, Quality Assurance Pharmacist, Calderdale and Huddersfield
NHS Foundation Trust
Catherine Norris, Consultant Pharmacist, Harrogate and District NHS
Foundation Trust
Penny North-Lewis, Paediatric Liver Pharmacist, Leeds Teaching
Hospitals NHS Trust


xvi | Acknowledgements

Claire Norton, Lead Pharmacist for Clinical Trials and Psychiatry, West
Midlands Medicines for Children Research Network Pharmacist Adviser,
Birmingham Children’s Hospital
Tony Nunn, Clinical Director of Pharmacy, Royal Liverpool Children’s
NHS Hospital
Hema Patel, University Hospital Lewisham

Reena Patel, Children’s University Hospital, Dublin, Eire
Susan Phillips, Production Technician, Whittington Hospital NHS Trust
Pharmacy Department
Bob Shaw, NHS Pharmacy Practice Unit, University of East Anglia
Tim Sizer, Assistant Course Director, PTQA, Leeds University (at the time
of the project)
Jon Silcock, Lecturer in Pharmacy, School of Healthcare, University of
Leeds
Julian Smith, Quality Controller, St Mary’s Pharmaceutical Unit, Cardiff
and Vale NHS Trust
Professor Peter Taylor, Director of Pharmacy, Airedale NHS Trust (at the
time of the project)
John Timmins, Clinical Director of Pharmacy and Medicines
Management, Sheffield Children’s NHS Foundation Trust
Bob Tomlinson, Principal Pharmacist, Calderdale and Huddersfield NHS
Foundation Trust
Dr Catherine Tuleu, School of Pharmacy, University of London
Dr Andrew Twitchell, Compounding Manager, Nova Laboratories
Limited (at the time of the project)
Ross Walker, Pharmacist, United Bristol Healthcare Trust
Don Wallace, Regional QA Pharmacist, Belfast City Hospital
Angela Watkinson, Senior Technician for Extemporaneous Preparation,
Leeds Teaching Hospitals (at the time of the project)
Susan Williamson, Senior Pharmacist, DIAL Information Service, Royal
Liverpool Children’s NHS Hospital
Louise Wraith, Non-Sterile Production Manager, Royal Free Hospital
Dr David Wright, Senior Lecturer in Pharmacy Practice, School of
Chemical Sciences and Pharmacy, University of East Anglia
David Woods, School of Pharmacy, University of Otago, Dunedin, New
Zealand

PART

A

Standards



1
Introduction
1.1

Background

Pharmacists are responsible for ensuring that drug use is safe and effective.
Wherever practicable, licensed medicines are used and represent the ‘gold
standard’ for quality, safety and efficacy. There are, however, circumstances
in which there is no licensed medicine that fully meets the clinical needs of a
particular patient or patients. In these circumstances it is sometimes necessary
for the pharmacist to extemporaneously prepare a limited quantity of a
custom-made medicine for a specific patient. Oral liquid medicines are commonly extemporaneously prepared because of a relative lack of licensed formulations for groups such as the young or elderly who are unable to swallow
tablets or capsules, or for whom the required dose is less than a single tablet/
capsule.
Extemporaneous preparation remains one of the highest risk preparative
activities carried out in the pharmacy, as the risks of unlicensed medicines are
combined with inherent risks associated with the pharmaceutical compounding process (Marshall and Daly, 1996). In addition, extemporaneously prepared medicines are commonly given to some of the most vulnerable patients
in hospitals and communities (e.g. neonates, children, elderly patients, stroke
victims, patients with feeding tubes in situ). These vulnerable patients are

often not capable of alerting carers or staff to any adverse drug events they
may be experiencing.
There have been a number of reports of errors associated with the use of
extemporaneously prepared medicines, resulting in serious harm to patients.
The most notable incident in recent UK history was the ‘peppermint water
case’, where the use of the wrong strength of chloroform water led to the death
of a child (Anon, 1998). This case highlighted the issues of toxic ingredients
and calculation errors, particularly where the strength of one or more ingredients is stated in a historical or non-standard fashion. Similar incidents have
occurred in the USA, including the death of a child from a superpotent
imipramine liquid, and another of a 5-year-old child who received a
thousand-fold overdose of clonidine (Kaye, 2003; Kirsch, 2005).


4 | Handbook of Extemporaneous Preparation

Administration errors have also been reported, including five-fold, tenfold, hundred-fold or thousand-fold mistakes in calculating or measuring
doses. Some of these errors have been attributed to inadequate labelling
(e.g. confusion between strengths expressed per mL or per 5 mL).
The relative lack of research and development work supporting these
products is associated with the potential for formulation failure or poor dose
uniformity, resulting in the risk of overdose or underdose. The lack of highquality data to support historical formulae has been acknowledged by authors
across the world (Stewart and Tucker, 1982; Crawford and Dombrowski,
1991; Woods, 1997).
Even where a given formulation has been shown to achieve suitable physical, chemical and microbiological stability, the bioavailability and palatability of the preparation may be unproven. Very few extemporaneous
preparations are supported by any data to demonstrate a suitable absorption
profile and/or bioequivalence with a licensed preparation. Other issues
include concerns about inadequate access to equipment and materials needed
to provide a safe extemporaneous dispensing service and the highest possible
quality products (Fisher et al., 1991; Davis, 1997).
All these risks have been potentiated by declining expertise in pharmaceutics and formulation within the pharmacy profession (Crawford and

Dombrowski, 1991; Pappas et al., 2002; Chowdhury et al., 2003). Compounding of oral medicines is often delegated to junior or trainee staff, and
there is commonly no quality assurance system in place to support practice
(Pappas et al., 2002). Until the publication of the Guide to the Preparation of
Non-Sterile Extemporaneous Products in National Health Service (NHS)
Hospitals in 2003 (Fenton-May et al., 2003), there were no agreed, detailed
standards for this area of extemporaneous preparation in the UK.
There is therefore an identified need to investigate and improve the quality
of formulation of the oral medicines currently prepared, with a view to
offering further guidance to pharmacists in order to minimise risks to patient
safety.
This book has been written on behalf of the NHS Pharmaceutical Quality
Assurance Committee, following the completion of a UK research project
entitled ‘Improving the quality and formulation of unlicensed, non-sterile,
oral medicines prepared in the NHS’. The project was supported by
Modernisation Board funding and directed by the NHS Pharmaceutical
Quality Assurance Committee – Working Group for Extemporaneous Preparation. It aimed to consider patient needs with regard to non-sterile preparation and manufacture, and formed one part of a wider programme of
research and development. The book includes an update of the Guide to the
Preparation of Non-Sterile Extemporaneous Products in National Health
Service (NHS) Hospitals, together with the 50 technical monographs generated from the research project.


Introduction | 5

1.2

The NHS Modernisation Agenda

The NHS Modernisation Agency (now superseded by the NHS Institute for
Innovation and Improvement) was established in the UK in 2001 to support
the NHS and its partner organisations in the task of modernising services and

improving outcomes and experiences for patients. Key standards and frameworks were developed by the Department of Health, against which continuous improvements can be measured (Department of Health, 2004).
In 2000, concerns about risk management and the sustainability of NHS
hospital manufacturing units led ministers to commission a UK-wide risk
assessment of NHS medicines manufacture. A multidisciplinary Advisory
Group was established. Their main recommendation was that ‘the NHS
Manufacturing Service should be restructured as a national service and the
move to this national service should be facilitated by an over-arching
Implementation Board’ (Department of Health, 2003). The Modernisation
Board generated an implementation plan for the service.
Integration into the patient safety agenda and creation of strong working
links with the Medicines and Healthcare products Regulatory Agency
(MHRA), the National Patient Safety Agenda (NPSA) and other key UK
stakeholders was deemed essential, as was embedding NHS medicines
manufacturing services in clinical practice to ensure that patients get the best
from their medicines. The four central pillars of modernisation are:
*
*
*
*

national coordination
clinical governance
working with partners in industry
capital investment.

A key part of modernisation strategy is to review which products the NHS
should continue to use, by which processes they should be made, and where
and by whom they would most appropriately be made. For products for which
continued use has been justified by clinical need, the review should also
consider whether manufacture should continue in the NHS or whether outsourcing to non-NHS manufacturers might be more appropriate and release

NHS capacity for other purposes and products. Collaboration with independent providers is essential if this is to be achieved.
The ultimate goal is to ensure that the NHS has a rational approach
to provision and cost-effective use of unlicensed medicines by ensuring that:
*
*

*

patients have ready access to all the medicines they need
unlicensed medicines are used only when there is no licensed medicine
which meets the clinical needs of a particular patient or group of
patients
the NHS makes and uses only a limited range of clinically essential
unlicensed medicines


6 | Handbook of Extemporaneous Preparation

*
*

all medicines are of the highest possible quality
NHS medicine manufacturing capacity is used cost effectively and is
prioritised for clinically essential products which only the NHS can make.

In order to facilitate this process, mutually agreed guidelines for working
with commercial partners are necessary in order to make sure that all available manufacturing capacity is used to best effect.

1.3

Clinical governance and quality assurance

Clinical governance is defined by the Department of Health (England) as ‘the
system through which NHS organisations are accountable for continuously
improving the quality of their services and safeguarding high standards of
care, by creating an environment in which clinical excellence will flourish’.
Clinical governance must be applied to all aspects of medicines management.
The principles of clinical governance and quality assurance should underpin all modernisation strategies and the modernisation strategy highlighted
that pharmacy quality assurance services play a key role in the provision of
manufacturing and aseptic services preparation through:
*
*

*
*
*
*
*

assessment of quality and risk potential of purchased medicines
coordination of minor product defect reports and communication of drug
alerts
audit and advising on standards
stability testing to support allocated shelf-lives
research, often in relation to new product development
technical information and advice
quality assessment and testing of devices and dressings.

The relationship between the environment in which medicines are prepared, the level of quality assurance applied to the processes involved and the
level of residual risk to patients treated with those medicines is shown

in Figure 1.1.
Preparation in clinical areas and extemporaneous preparation in the pharmacy represent the lowest levels of quality assurance and the highest risk,
whereas manufacture of licensed medicines provides the most robust assurance of quality, safety and efficacy. Manufacture of unlicensed medicines
under a manufacturer’s ‘Specials’ licence (MS) represents a level of intermediate overall quality and risk. The key difference between licensed medicines
and ‘Specials’ is that all licensed medicines are supported by robustly assessed
evidence for the pharmaceutical quality of the formulation and for safety and
efficacy in clinical use, whereas the evidence for most ‘Specials’ is much
weaker and has not been subjected to regulatory assessment.


Introduction | 7

Preparation
on wards

Preparation
in pharmacy
specials unit

Preparation in
pharmacy

Licensed
product
(industry
or hospital)

Scale
Risk
Figure 1.1

1.4

The progression of risk. (From Alison Beaney, personal communication, January 2006.)

Rationalisation and standardisation

A key objective for clinical governance of unlicensed medicines is to ensure
that use of products prepared in clinical areas or by extemporaneous preparation in the pharmacy is limited in favour of products manufactured
under a manufacturer’s ‘Specials’ licence (MS) or, ideally, a full manufacturer’s licence (ML). In order to achieve this, it is essential that key
decisions about product choice and presentation are made in conjunction
with expert clinicians and are subject to peer review. This process may need
to involve professional bodies such as the relevant Royal Colleges and
other key stakeholders. In the UK, senior doctors, pharmacists and other
allied healthcare professionals sit on Drug and Therapeutics Committees.
These committees also play (or should play) a key role in evaluating the
evidence base to support the use of unlicensed medicines as well as licensed
medicines.
In the UK, unlicensed non-sterile, oral, liquid (and other) medicines
may be made by ‘Specials’ manufacturers under an MS, or can be extemporaneously prepared under the supervision of a pharmacist. Extemporaneous dispensing is carried out under the exemptions allowed by
Section 10 of the 1968 Medicines Act. The modernisation agenda aims
to improve the extemporaneous dispensing practice and identify opportunities to replace preparation in clinical areas or extemporaneously in the
pharmacy by preparation under an MS or, where possible, an ML. It is
essential to involve colleagues in ‘Specials’ units and in the pharmaceutical
industry to move preparations along the quality and risk progression in
this way.
Rationalisation of the product inventory and standardisation of the
remaining product range offers safety and quality benefits:
*

Practitioners and patients become more familiar with the products
available: greater familiarity reduces risks of prescribing, dispensing and
administration errors.


8 | Handbook of Extemporaneous Preparation

*

*

Opportunities are created for product development to improve
formulations, enhance stability and shelf-life, improve patient
acceptability and improve availability.
Opportunities for batch manufacture and economies of scale may lead to
cheaper products as well as higher quality.

Historical UK legal restrictions on advertising named unlicensed medicines have severely restricted the amount of information readily available
to inform decision-making by practitioners trying to identify and source
‘Specials’. We hope that the data, formulae and supporting information contained in this handbook, together with the continued use of the NHS ‘Pro-File’
database, will help procurement and clinical colleagues. We also hope it will
help those working in ‘Specials’ units (both NHS and non-NHS) and the
pharmaceutical industry to identify products, particularly oral liquid medicines, for which the potential market is large enough to make production as
licensed products commercially viable.

1.5

Summary

After preparation in clinical areas, extemporaneous preparation represents

the preparative activity posing the highest risk to patient safety and subject to
the lowest level of quality assurance. An update of the existing standards
together with the standardisation and rationalisation of current products
and formulae will help to improve product quality, decrease the overall risk
to patient safety, and will support the progressive transfer of preparation of
many products to batch manufacture in a controlled environment.

1.6

References

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Davis NM (1997). Do you really need glacial acetic acid on your shelf? Hosp Pharm 32: 611.
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