The Manufacture of Sterile Pharmaceuticals and Liquid Medical Devices Using Blow-Fill-Seal Technology. K. Downey
section>
Former editions:
1st edition September 1993 by S. Probert, S. Forrester-Coles
1st main revision September 1998 (general update)
2nd main revision October 2002 (general update) by A. Löfgren
small revision January 2003(small revision/update of integrity testing sections) by A. Löfgren
3rd main revision April 2007 (update in general and regarding the revised FDA guidance)
by E. Dewhurst
4th main revision Nov. 2011/March 2012 (general update, Media Fills, SIP, implementation of
rotary machine type 4010) by K. Downey, M. Haerer, S. Marguiller, P. Åkerman
5th corrected version December 2016
The pictures on the front cover are sponsored by Brevetti Angela, Rommelag and Weiler Engineering.
Bibliographic data available from the German National Library
The German Library catalogs this publication in the German National Bibliography; detailed bibliographic information can be found on the internet website: http://dnb.ddb.de.
The Manufacture of Sterile Pharmaceuticals and Liquid Medical Devices Using Blow-Fill-Seal Technology: Points to Consider
ISBN 978-3-87193-443-8
© 2017 ECV · Editio Cantor Verlag für Medizin und Naturwissenschaften GmbH, Aulendorf (Germany).
All rights, in particular those of duplication, distribution, and translation are reserved by BFS International Operators Association c/o Melitek A/S, DK-4840 Nørre Alslev, and the publisher without any limit in time. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise without the prior written permission of the publisher. The absence of the symbol ® after any name does not imply that this name is not under trademark protection.
ECV · Editio Cantor Verlag on the internet www.ecv.de
Typesetting: Reemers Publishing Services GmbH, Krefeld
Printing: HOLZMANN DRUCK GMBH & CO. KG, Bad Wörishofen
Contents
3.2 Rotary Filling Machines 14
3.3 Additional Applications 16
4. ADVANTAGES & CHALLENGES OF BLOW-FILL-SEAL TECHNOLOGY 18
4.2 Challenges 19
5. DESIGN 21
5.1 Product Design 21
5.1.1 Aseptic processing versus terminal sterilisation 21
5.1.2 Terminal sterilisation 21
5.1.3 Polymer 22
5.1.4 Container design 23
5.1.5 Secondary packaging 24
5.2 Equipment Design 25
5.2.1 General 25
5.2.2 Control of critical zone environment 26
5.2.3 Air shower design (shuttle type machines) 27
5.2.4 Product pathway 28
5.2.5 Mould design 28
5.2.6 Deflashing 29
5.2.7 Equipment Monitoring 29
5.2.8 Container closure system leak detection 30
5.3 Facility Design 31
5.3.1 Aseptic Processing Area (APA) 31
5.3.2 Support areas 34
5.3.3 Polymer storage and distribution 34
5.3.4 Utilities 35
6. QUALIFICATION AND VALIDATION 36
6.1 PRODUCT VALIDATION 36
6.1.1 Container/Closure integrity testing 36
6.1.2 Process capability 36
6.2 Equipment Validation 37
6.2.1 Extruder 37
6.2.2 Air Flow 38
6.2.3 Clean in Place (CIP) of the product pathway 38
6.2.4 Sterilisation in Place (SIP) of the product pathway 38
6.2.5 Process simulation (media fill) for aseptic filling lines 40
6.2.6 Moulding and filling system 44
6.2.7 Downstream process 44
6.2.8 Controls 44
6.2.9 Filtration 45
6.3 Facility Validation 45
7. OPERATION 46
7.1 Process Operation 46
7.1.1 In-process controls 46
7.1.2 Start-up procedures 47
7.1.3 Interventions 47
7.1.4 Environmental monitoring 48
7.2 Equipment Operation 51
7.2.1 Sanitisation of “critical” surfaces 51
7.2.2 Equipment cleaning 51
7.2.3 Cooling systems 51
7.2.4 Extruder control 51
7.2.5 Maintenance 52
7.3 Facility Operation 52
7.3.1 Gowning 52
7.3.2 Polymer handling 53
7.3.3 Use of regrind polymer material 53
7.3.4 Training 53
8. RISK ASSESSMENT 55
8.1 Product contamination 55
8.2 Other product quality attributes