ISPE Active pharmaceuticals production

Volume 1

Active Pharmaceutical Ingredients Second Edition / June 2007 Revision to Bulk Pharmaceutical Chemicals

Disclaimer:

This Gu This Guid ide e is is mea mean nt to assi assist st phar arm mac aceu euttic ical al man anu ufac actturer ers s in in the des desig ign n an and d co con nst strruct ctio ion n of new an and d ren enov ovat ated ed facilities that are required to comply with the requirements of the US Food and Drug Administration (FDA). The International Society for Pharmaceutical Engineering (ISPE) cannot ensure, and does not warrant, that a facility built in accordance with this Guide will be acceptable to the FDA. Limitation of Liability In no event shall ISPE or any of its affiliates, or the officers, directors, employees, employees, members, or agents of each of them, be liable for any damages of any kind, including without limitation any special, incidental, incidental, indirect, or consequential damages, whether or not advised of the possibility of such damages, and on any theory of liability whatsoever,, arising out of or in connection with the use of this information. whatsoever

©Copyright ISPE 2007. All rights reserved. All right rights s reserved. res erved. No part of this this documen documentt may may be reproduced or copied in any form or by any means – graphic, electronic, or or mechanical, including photocopying, taping, or information information storage and retrieval system sys tems s – without written permission of ISPE. All trademarks used are acknowledged.

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ISPE Baseline® Guide: Active Pharmaceutical Ingredients


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Foreword For many years, the pharmaceutical industry has experienced a ratcheting effect in the cost of new facilities. These increases in cost have been driven in part by uncertainty about the requirements for regulatory compliance. The absence of a consistent and widely accepted interpretation of regulatory requirements has led to “creeping incrementalism.” The practice of discretionary investment in plant features that are neither required nor indicated has led to increased cost, longer facility construction and qualification times, and in many cases, delays in bringing new products to market. In May 1994, engineering representatives from the pharmaceutical industry engaged in a discussion with the International Society for Pharmaceutical Engineering (ISPE) and the US Food and Drug Administration (FDA). That first discussion led to a plan to create a family of nine facility engineering Guides, now known as the Baseline ® Pharmaceutical Engineering Guides. In November 1994, the ISPE sanctioned the beginning of this important project and the first, “Bulk Pharmaceutical Chemicals,” was published in J une 1996. The second, “Oral Solid Dosage,” was published in 1998. The third, “Sterile Manufacturing Facilities,” was published in early 1999. The fourth and fifth Baseline® Guides, “Water and Steam Systems” and “Commissioning and Qualification,” were published in 2001. The sixth such Guide, covering Biopharmaceutical Manufacturing Facilities, was published in 2004. The seventh Baseline® Guide, covering Packaging, Labeling, and Warehouse Facilities, is expected to be published in the second quarter of 2007. This is the second edition of ISPE’s Baseline® Pharmaceutical Engineering Guide for New and Renovated Facilities Volume 1 “Active P harmaceutical Ingredients.” It was the first of the Baseline® Guide series to be produced and is now the first to be revised. This revision is prompted by a number of developments within the industry requiring the guidance to be realigned and refreshed. One of the realignments is the change in the title of the Guide from Bulk Pharmaceutical Chemicals (BPCs) to Active Pharmaceutical Ingredients (APIs) to reflect more current and global practice. A more thorough discussion of the terms AP I and BP C is included in Section 1.2 of this Guide. Each Baseline® Engineering Guide was created by, and is owned solely by, ISPE. The FDA provided comments on this and previous Guides, and many of their suggestions have been incorporated. As with the prior Guides, the “Active Pharmaceutical Ingredients” Baseline ® Guide has been sponsored by engineering executives from owner companies, the FDA, and ISPE senior management. Overall planning, direction, and technical guidance in the preparation this Guide was provided by a Steering Committee of seven people, some of whom were involved in earlier Guide projects. The Guide itself was produced by Task Teams of well more than 40 individuals who expended a great deal of their own time in its preparation and development. An effort was made to not replicate materials and issues already addressed in other Guides, most notably the Commissioning and Qualification Guide. The reader is referred to related ISPE Technical Documents for a complete discussion of the “support” issues affecting the design and operation of Active Pharmaceutical Ingredients Manufacturing Facilities.


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Acknowledgements This Guide was developed by an integrated US-European team under the co-leadership of Simon Shelley of GlaxoSmithKline and Patrick Wong of Bristol-Myers Squibb Co. The Technical Cons ultant for the United States team was Stanley Newberger of CE&IC Inc., and the Technical Consultant for the European team was John Nichols of Foster Wheeler. The Project Manager for the integrated team was Andr ew Ro ber ts of MIME Solutions Ltd. The early stage Project Manager was Gregor McNab of GlaxoSmithKline. The Steering Team was comprised of: Betsy Fritschel Trish Melton Stanley Newberger J ohn Nichols Andrew Roberts Simon Shelley Patrick Wong

J ohnson & J ohnson MIME Solutions Ltd. CE&IC Inc. Foster Wheeler MIME Solutions Ltd. GlaxoSmithKline Bristol-Myers Squibb Co.

We would like to thank An thon y Char ity of the FDA for his input to this Guide. The Chapter Credits are as follows: Chapter 1: Introduction Simon Shelley GlaxoSmithKline Patrick Wong Bristol-Myers Squibb Co.

(Lead Author) (Contributing Author)

Chapter 2: Regulatory Philo sophy and Guid e Concepts Stanley Newberger CE&IC Inc. (Lead Author) Betsy Fritschel J ohnson & J ohnson (Contributing Author) Chapter 3: A Risk Assessment App roach Trish Melton MIME Solutions Ltd.

(Lead Author)

Chapter 4: Product and Process Considerations Chapter 18: Appendix 2 – The Nature and Manufacture of Act ive Pharmaceutical Ingredients Chapter 19: Appendix 3 – Examples of Current Trends for Closing or Containing Open Operations Melody Armstrong CE &IC Inc. (Lead Author) Chapter 5: Facility L ayout Andrew Stoker AMEC Dennis Fortune Foster Wheeler Carole Kuzian CE &IC Inc.

(Lead Author) (Contributing Author) (Contributing Author)


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Chapter 6: Architectural Andrew Stoker AMEC Dennis Fortune Foster Wheeler Carole Kuzian CE &IC Inc.

(Lead Author) (Contributing Author) (Contributing Author)

Chapter 7: Process Suppo rt and Utilit y Systems Phil Mason J acobs Engineering Ltd.

(Lead Author)

Chapter 8: HVAC Chapter 17: Appendix 1 – HVAC User Requirements Norman Koller CE&IC Inc. (Lead Author) Donald Moore Eli Lilly and Company (Contributing Author) Chapter 9: Electrical Thomas Brennan J ohn Linder

Schering-Plough Corp. CE&IC Inc.

Chapter 10: Instrumentation and Controls J ohn Linder CE&IC Inc. Karl Koch CE&IC Inc. Chapter 11: Facility and Equi pment Cleaning Anthony Ward Pfizer Ltd. Ross DeNisco J ohnson & J ohnson




Chapter 12: Containment o f API Pharmaceutical Manufacturin g J ames Wood Eli Lilly and Company (Lead Author) J ohn Nichols Foster Wheeler (Contributing Author) Chapter 13: Scale-Up Facilities and Pilot Plants Stanley Newberger CE&IC Inc. Betsy Fritschel J ohnson & J ohnson Anthony Ward P fizer Ltd. Karl Koch CE&IC Inc. Benny Auyeung S chering Andrew Stoker AMEC Eric Sipe Chapter 14: Multi- Purpose Plants Trish Melton MIME Solutions Ltd. Chapter 15: Non-Acti ve Pharmaceutical Ingredients P ierre Le Meur SP EC Conseils

(Lead Author) (Contributing Author) (Contributing Author) (Contributing Author) (Contributing Author) (Contributing Author) (Contributing Author)

(Lead Author)

(Lead Author)

Chapter 16: Other Considerations Trish Melton MIME Solutions Ltd.

(Lead Author)

Chapter 20: Appendi x 4 – Glossary and Acr onyms J ohn Nichols Foster Wheeler

(Lead Author)


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The Chapter writers would like to express their grateful thanks to the following people for their contribution as technical contributors and reviewers Louis Angelucci J effrey Biskup Matthew Corns J an EC Gustafsson Art Meisch Roland Mugeli Robert Myers Roger Shillitoe Ian Waldron Edmund Whalley Stephanie Wilkins

Bristol-Myers Squibb Co. (Lead Author) CRB Consulting Engineers Inc. Hosakawa Micron Ltd. Novo Nordisk A/S CE&IC Inc. (Contributing Author) Simon Carves Ltd. Pfizer Inc. CEL International Ltd. AstraZeneca GlaxoSmithKline (Contributing Author) PharmaConsult US Inc.


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Table of Contents 1

Intr odu ction .......................................................................................................................11 1.1 1.2 1.3 1.4 1.5

2

Regulator y Philos ophy and Guide Concepts ................................................................ 17 2.1 2.2 2.3 2.4

3

Introduction .............................................................................................................................................49 Understanding the Process .................................................................................................................... 49 API Starting Materials .............................................................................................................................50 Intermediate Products ............................................................................................................................. 51 Process Equipment Considerations .......................................................................................................51 Process Water ........................................................................................................................................ 54 Recovered Solvents ................................................................................................................................ 54

Arc hitectural ..................................................................................................................... 57 5.1 5.2 5.3 5.4

6

Introduction .............................................................................................................................................33 Types of Facility ......................................................................................................................................36 Process Review ......................................................................................................................................36 Contamination Review............................................................................................................................39 Impact Assessment................................................................................................................................. 46 Deviations ...............................................................................................................................................46

Produc t and Proc ess Considerati ons ............................................................................ 49 4.1 4.2 4.3 4.4 4.5 4.6 4.7

5

Introduction .............................................................................................................................................17 Regulatory Philosophy............................................................................................................................ 17 Guide Concepts and Framework ............................................................................................................19 Additional Concepts ................................................................................................................................ 32

A Risk Ass essment Appr oach ......................................................................................... 33 3.1 3.2 3.3 3.4 3.5 3.6

4

Background to the Revision.................................................................................................................... 11 Scope of this Guide ................................................................................................................................ 11 Key Features of the Revised Guide ........................................................................................................ 13 Bulk Sterile APIs......................................................................................................................................15 Key Enhancements from the Previous Edition ....................................................................................... 15

Introduction .............................................................................................................................................57 Philosophies ...........................................................................................................................................57 Functional Areas .....................................................................................................................................59 Surface Finishes and Materials of Construction ..................................................................................... 65

Facili ty Layout .................................................................................................................. 69 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 6.9 6.10

Introduction/Layout Principles................................................................................................................. 69 Layout Development ............................................................................................................................... 69 Layout Considerations ............................................................................................................................73 Principles of Material and Equipment Flows ........................................................................................... 75 Principles of People Flows ......................................................................................................................76 Changing/Gowning .................................................................................................................................76 Additional Layout Issues .........................................................................................................................77 Layout Design to Enhance Value............................................................................................................ 77 Facility Construction Issues ....................................................................................................................77 Additional Considerations ....................................................................................................................... 78


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7

Process Suppor t and Util ity Syst ems ............................................................................ 81 7.1 7.2 7.3 7.4 7.5

8

HVAC .................................................................................................................................. 89 8.1 8.2 8.3 8.4 8.5 8.6 8.7

9

Introduction ........................................................................................................................................... 109 Principles .............................................................................................................................................. 110 Field Instrumentation ............................................................................................................................ 111 Calibration and Preventive Maintenance .............................................................................................. 112 Instrumentation Installation Methods .................................................................................................... 112 Instrumentation Wiring Methods ........................................................................................................... 112 General Considerations of Control Systems ........................................................................................ 113 Configurable/Programmable Control System Software ........................................................................ 113 Control System Hardware ..................................................................................................................... 114 Operator Interface................................................................................................................................. 114 Control System Qualification Considerations ....................................................................................... 115 21 CFR Part 11 Considerations ............................................................................................................ 115

Facility and Equipment Cleaning ...................................................................................117 11.1 11.2 11.3 11.4 11.5 11.6

12

Introduction ........................................................................................................................................... 105 Power Distribution.................................................................................................................................106 Electrical Classification.........................................................................................................................106 Lighting .................................................................................................................................................106 Grounding/Earthing...............................................................................................................................107 Telephones, Paging, Data Wiring Radio Systems, and Miscellaneous Equipment ............................. 107 Fire Detection and Alarms Systems...................................................................................................... 107 Wiring Methods .....................................................................................................................................108

Inst rumentation and Cont rols ....................................................................................... 109 10.1 10.2 10.3 10.4 10.5 10.6 10.7 10.8 10.9 10.10 10.11 10.12

11

Introduction .............................................................................................................................................89 HVAC System Parameters ...................................................................................................................... 89 HVAC Controls and Monitors .................................................................................................................. 98 Typical HVAC Systems ...........................................................................................................................99 Cost Considerations ............................................................................................................................. 102 Cleaning and Maintenance of HVAC .................................................................................................... 102 Commissioning Considerations ............................................................................................................103

Electr ical ......................................................................................................................... 105 9.1 9.2 9.3 9.4 9.5 9.6 9.7 9.8

10

Introduction .............................................................................................................................................81 System Impact Descriptions ................................................................................................................... 82 System Layout and Routing....................................................................................................................83 Design Considerations ............................................................................................................................84 Examples ................................................................................................................................................ 87

Introduction ........................................................................................................................................... 117 Design for the Ability to Clean............................................................................................................... 117 Cleaning Techniques – Design Features .............................................................................................. 120 Cleaning Agents – Design Impact......................................................................................................... 121 Design of the Cleaning Process ........................................................................................................... 122 Design for Testing of Cleanliness ......................................................................................................... 123

Containment o f API Pharmaceutic al Manufactu rin g ................................................... 125 12.1 12.2 12.3

Introduction ........................................................................................................................................... 125 Containment Philosophy ....................................................................................................................... 126 Elements of Containment...................................................................................................................... 128


13

Scale-Up Facil ities and Pilot Plants .............................................................................. 135 13.1 13.2 13.3 13.4 13.5 13.6 13.7 13.8 13.9 13.10 13.11

14

Introduction ........................................................................................................................................... 157 Manufacture of Non-Active Pharmaceutical Ingredients ...................................................................... 158 Risk Assessment ..................................................................................................................................159

Other Considerations ..................................................................................................... 161 16.1 16.2 16.3 16.4 16.5 16.6 16.7 16.8

17

Introduction ........................................................................................................................................... 147 Definitions ............................................................................................................................................. 147 Multi-Purpose Facility Design ............................................................................................................... 150 GMP Risk Assessment .........................................................................................................................152

Non-Ac ti ve Pharmaceuti cal Ingr edients ....................................................................... 157 15.1 15.2 15.3

16

Introduction ........................................................................................................................................... 135 How Do Scale-Up Facilities Differ from Manufacturing......................................................................... 135 Flexibility and Its Impact........................................................................................................................ 136 Application of cGMPs with Respect to Equipment and Facilities ......................................................... 136 Layout ................................................................................................................................................... 137 Instrumentation and Controls................................................................................................................ 138 Facility Environment ............................................................................................................................. 140 Containment and Potent Compound Handling ..................................................................................... 140 Safety Issues ........................................................................................................................................ 143 External Environmental Issues ............................................................................................................. 144 Documentation...................................................................................................................................... 144

Mult i-Purpos e Facilities ................................................................................................. 147 14.1 14.2 14.3 14.4

15

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Introduction ........................................................................................................................................... 161 Health and Safety Considerations ........................................................................................................ 161 Environmental Protection...................................................................................................................... 162 Operational Considerations .................................................................................................................. 163 Materials of Construction ...................................................................................................................... 163 Documentation...................................................................................................................................... 163 Construction and Commissioning ......................................................................................................... 163 Ethical Considerations ..........................................................................................................................164

App endix 1 – HVAC User Requir ements ...................................................................... 165 17.1 17.2

Introduction ........................................................................................................................................... 165 Examples of Typical Analysis During the Development of the User Requirements Document............ 165

18 18

Appendix 2 – The Nature and Manufacture of Active Pharmaceutical Appendix 2 – Ingredients ............................................................................................... 167

19 19

Appendix 3 – Examples of Current Trends for Closing or Containing Appendix 3 – Open Operations ..................................................................................... 169

20

Appendi x 4 – Glo ssary and Acro nyms ......................................................................... 171 20.1 20.2

21

Glossary ................................................................................................................................................171 Acronyms and Abbreviations ................................................................................................................ 179

App endix 5 – Referenc es ............................................................................................... 183

1

Introduction


1

Introduction

1.1

Bac kg ro und to the Rev is io n

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The design, construction, commissioning, qualification, and validation of pharmaceutical facilities are significant challenges for manufacturers, engineering professionals, and equipment suppliers. In most cases, these facilities are required to follow cGMP s, while remaining in compliance with other governing codes, laws, and regulations. The cost of bringing these facilities on-line continues to rise, in many cases, due to inconsistent interpretation of regulatory expectations. ISPE and engineering representatives from the pharmaceutical industry have entered into a partnership with the US Food and Drug Administration (FDA) to enhance understanding of Baseline cGMP expectations for facilities. This Guide is intended to offer a consistent interpretation, while still allowing a flexible and innovative approach to facility design, construction, commissioning, qualification, and validation. This is the second edition of ISPE’s Baseline® Pharmaceutical Engineering Guide for New and Renovated Facilities Volume 1 – Bulk Pharmaceutical Chemicals, (now entitled Active Pharmaceutical Ingredients), which was originally published in J une 1996. It was the first of the Baseline® Guide series to be produced and is now the first to be revised. This revision is prompted by a number of developments within the industry requiring the guidance to be realigned and refreshed. This revised Guide builds on the original principles, but also incorporates and builds on new guidance such as: •

ICH Q7 (Section 21, reference 1)

•

ICH Q9 (Section 21, reference 2)

•

GAMP 4 (Section 21, reference 3)

•

ISPE Baseline® Pharmaceutical Engineering Guide Series (Section 19, reference 4)

•

21 CFR Part 11 (Section 21, reference 5)

•

“Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice”, issued September 2004

•

FDA Draft Guidance for Industry PAT – A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance, August 2003

It is recognized that industry standards evolve and this document reflects the understanding of these standards as of the publication date.

1.2

Scope of this Guide This Guide may be used by industry for the design, construction, commissioning, qualification, and validation of Active Pharmaceutical Ingredients (APIs) facilities. It is neither a standard nor a detailed design Guide. It is not intended to replace governing laws or regulations that apply to facilities of this type. It also is not intended to apply to existing facilities, which may fall short of the baseline described. The use of this Guide for new or existing facilities is at the discretion of the facility owner or operator; however, the principles can be followed for refurbishments and renovations. The question of how much refurbishment or renovation constitutes a new facility will be unique to each project and should be assessed by the owner or operator, and the Guide used accordingly.

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The original 1996 version of this Guide was written in the United States and was intended primarily for facilities supplying BPCs to the US. However, with adoption of ICH Q7 and this revision of the Baseline® Guide to Bulk Pharmaceutical Chemicals, the scope is expanded to include international API manufacturing. The scope of the Guide now covers Active Pharmaceutical Ingredients (APIs) facilities, and includes Bulk Pharmaceutical Chemicals, intermediates, and non-APIs (excipients) facilities. It is important to note that the terms ‘BPC’ and ‘AP I’ are not equivalent terms and should not be used interchangeably. These terms are used specifically in this Guide. All APIs are BPCs, but not all BPCs are APIs. The term BPC also includes non-APIs (excipients). To allow alignment to ICH Q7 in the context of this Guide, APIs are considered equivalent to ‘Drug Substances’. Figure 1.1 illustrates the relationship between Bulk Pharmaceutical Chemicals and Active Pharmaceutical Ingredients. Figure 1.1: Relationship between BPC and API

The scope of this Guide focuses on the manufacture of APIs and intermediates. In addition, there are chapters on scale-up facilities, pilot plants, and non-APIs (excipients). The Guide is applicable to dedicated facilities, as well as multi-purpose facilities, and multi-product facilities. This Guide may not be appropriate for laboratory settings where compounds are synthesized for early development studies. Bulk biological, secondary manufacturing, and secondary sterile and aseptic processing are the subjects of other Baseline® Pharmaceutical Engineering Guides. This Guide makes reference to, and should be used in conjunction with, other ISPE Baseline® Guides. The purpose of this Guide is to focus on engineering issues and how to provide cost effective facilities. Where nonengineering issues are covered (e.g., microbiological topics, operational issues unrelated to the facility), this information is included only to show engineers the importance of such topics, and the impact that they have on facility design.

ISPE Active pharmaceuticals production

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