Pharmaceutical Production Facilities: Design and Applications (Pharmaceutical Sciences Series)

343 Pages·2003·3.88 MB·English

by  Graham C. Cole

Pharmaceutical Production Facilities
Design and Applications

Pharmaceutical
Production Facilities
Design and
Applications
2nd Edition
GRAHAM COLE
Pharmaceutical Process Specialist
Higham, Suffolk
UK Taylor & Francis Ltd, 1 Gunpowder Square, London EC4A 3DE
USA Taylor & Francis Inc., 1900 Frost Road, Suite 101, Bristol, PA 19007
This edition published in the Taylor & Francis e-Library, 2003.
Copyright © Graham Cole 1998
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, electronic, electrostatic, magnetic
tape, mechanical, photocopying, recording or otherwise, without the prior permission of
the copyright owner.
British Library Cataloguing in Publication Data
A catalogue record for this book is available from the British Library
ISBN 0-203-48311-1 Master e-book ISBN
ISBN 0-203-79135-5 (Adobe eReader Format)
ISBN 0-7484-0438-4 (cased)
Library of Congress Cataloging Publication Data are available
Cover design by Jim Wilkie
Front cover photograph courtesy of Niro-Fielder
Contents
Contributors vi
Preface vii
1 Introduction 1
2 Project Design and Management 7
3 Site Selection 25
4 Process Flow 29
5 Pharmaceutical Process Utility Systems 47
6 Considerations in the Design of a Pharmaceutical Facility 63
7 Cleanrooms 91
8 Tablet Production Systems 125
9 Tablet Coating Systems 145
10 Capsule Filling Systems 175
11 The Design of a Sterile and Aseptic Manufacturing Facility 197
12 Special Production Systems 223
13 Flexible Manufacturing Systems and Automation 245
14 Packaging Systems 293
15 Validation 297
Index 329
v
Contributors
Nigel Stephen Cole has an MSc from Bradford University in Chemical Engineering
and has spent 10 years in the process automation industry. Six years were spent
with a leading supplier of process control systems and four years as an information
technology project manager with Glaxo Wellcome. At Glaxo Wellcome he has
been implementing manufacturing execution systems and shop floor solutions.
Michael Walden, who provided the excellent material for Chapter 7 and a new
section in Chapter 6, is registered as an architect in the United Kingdom, and has
worked on projects in the pharmaceutical industry virtually exclusively for the past
20 years.
His experience includes a period working as project manager with the
International Facilities Group of American healthcare company, Baxter Travenol
and time with several major design build contractors. Following a period as Technical
Director of a cleanroom construction company Michael Walden has for the last six
years worked with Clean Design involved with projects in the United Kingdom,
Europe and South East Asia.
Michael holds a diploma in Architecture from Leeds and is a corporate member
of the Royal Institute of British Architects and a Member of the Society of
Environmental Engineers.
vi
Preface
Thus grew the tale of Wonderland,
Thus slowly, one by one,
Its quaint events were hammered out
And now the tale is done,
And home we steer, a merry crew,
Beneath the setting sun.
Lewis Carroll: Alice’s Adventures in Wonderland
The regulatory requirements for production facilities within the pharmaceutical
industry are being continually and incessantly tightened. On the one hand this
leads to a higher quality product on a consistent basis, but on the other it has made
production itself an increasingly costly part of the overall process of drug discovery,
development, manufacture and distribution.
In 1990, in the first edition of this book, Graham Cole made an excellent attempt
to set out the requirements of the major elements of the facilities required for
secondary pharmaceutical manufacture (i.e. the manufacture of the dosage form
rather than the bulk drug chemical). This was the first book of its type to attempt
this and it made a valuable contribution. However, due to the current ever changing
practice it was inevitable that a second edition would become necessary. Graham
Cole has therefore produced this new, up-to-date version of the text.
The first edition has been substantially enlarged and revised. In this second
edition, Graham retains the basic structure of the previous edition but has
considerably updated and modified the text, particularly in the areas of process
flow, architectural considerations, clean room design (including a discussion of
the latest regulations), tablet coating systems, special production systems and,
inevitably, validation. This revised edition serves its purpose well—it is an excellent
introduction to concepts and practical problems associated with pharmaceutical
secondary manufacturing.
The book illustrates the many concepts and constraints and ‘state of the art’
control that must be considered in the design of small-, medium- and large-scale
production plants. The layout of a facility and the flow of materials and personnel
through the facility are considered with reference to ensuring compliance with
current good manufacturing practice.
The benefits that can be obtained from using totally automated enclosed systems
vii
Preface
for small production runs are demonstrated using sterile operations and the
manufacture of solid dosage forms as examples. Mike Walden shows how clean
rooms have developed and how the latest regulations affect their design. The latest
techniques for reducing contamination levels from the operator and the product are
discussed. A solid dosage facility is used as a model to show how integration can be
achieved with a corresponding minimization of costs and improvement in productivity,
and even in product elegance. The ideal facilities are outlined, illustrating the design
considerations that need to be applied in modern dosage manufacturing facilities in
order to enable the systems to be validated to current standards.
The chapters on validation have been updated to include current thinking on
process and computer control, such as the Guide to Automated Manufacturing
Practice document (GAMP). New concepts such as Computer Integrated
Manufacturing (CIM) and Just in Time (JIT) manufacturing are discussed.
Secondary production is no longer an add-on to the overall process of medicines
design and manufacture. In the early years the pharmaceutical industry did not
invest heavily in dosage form production facilities because the cost of the drug
itself was so high that manufacturing costs were a minor component of the total
cost of medicines and any inefficiencies in that area were of no great importance.
Now production has to be much more efficient as medicines costs are driven
downwards by governments and by the ever increasing pressure from generic
products. The industry has had to become more sophisticated and its production
procedures increasingly efficient. The extensive manual procedures of yesteryear
have virtually disappeared and process automation has improved out of all
recognition. Most of the recent pharmaceutical company mergers have been driven
by the design for increased efficiency of all aspects of drug discovery—including
rationalizing production facilities on a worldwide basis.
It is also inevitable that the rate of changes that we have seen over the last few
years will never plateau. We will be forced forever into greater and greater
sophistication—driven either by financial or regulatory requirements. So we thank
Graham for his efforts in collating this valuable and timely information into one
text. This single book will not tell you all that you need to know about pharmaceutical
production facilities, but it is the ideal starting point to enable you to understand
the concepts which lie behind the problems before you have to delve into a detailed
consideration of the regulations themselves.
Michael Aulton
Professor of Pharmaceutical Technology and
Head of Pharmaceutics
De Montford University
Leicester, UK
viii
1
Introduction
‘When I use a word’, Humpty Dumpty said, in rather a scornful tone, ‘it means just
what I choose it to mean—neither more nor less’.
The pharmaceutical industry has undergone fundamental changes and restructuring
since the Second World War. The substantial and rapid progress that has been
made is based on research and development of new compounds with outstanding
rewards for those companies that have developed ‘winners’. Products like
ALDOMET, TAGAMET, and ZANTAC have rewarded those companies with sales
running into thousands of millions of dollars. The costs in research and development
alone (safety testing programmes, clinical trials, manufacture and marketing costs)
to market one of these products is probably in the region of between 150–200
million US dollars. One result of these costs has been the mergers and restructuring
that have taken place between companies: Glaxo and The Wellcome Trust;
SmithKline Beckman and Beecham; Squibb and Bristol-Myers; Rhone Poulenc-
Rorer; Roussel and Hoechst; Astra and Fisons; and Boots Pharmaceutical Division
and BASF, to name but a few. These will continue as the top companies strive to
maintain their market share and the Japanese attempt to increase their presence
outside of Japan in the world market. These mergers have been designed to minimize
spiralling costs in research and development, rationalize the research base by
concentrating on specific therapeutic classes, and maximizing productivity in drugs
manufacture.
The rewards in the pharmaceutical industry have been the result of developing
unique chemotherapeutic products, and traditionally these products were
manufactured by using a collection of different types of facility, a variety of
construction materials, and equipment generally borrowed from other industries.
For example the planetary mixer originated in the bakery. Probably the tablet
machine with systems to regulate its operation is the best example of innovation in
the industry. Computer integrated manufacture has taken a lot longer to develop
for plants designed to produce sophisticated modern dosage forms.
However, with the impact of regulatory authorities such as the Medicines Control
Agency and the US Food and Drug Administration, and the rationalization of
manufacturing to supply various markets, this position is changing. There is no
manual or textbook which details all the design requirements for a modern
pharmaceutical plant; there is, however, a collection of documents such as The
Orange Guide, The Code of Federal Regulations, and various guidelines whose
impact necessitates that task forces formed within manufacturing companies require
1