ISPE Baseline® Guide:
Active Pharmaceutical Ingredients
Page 7
Table of Contents
1
Introduction ....................................................................................................................... 11
1.1
1.2
1.3
1.4
1.5
2
Regulatory Philosophy 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
Architectural ..................................................................................................................... 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
Product and Process Considerations ............................................................................ 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 Assessment Approach ......................................................................................... 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
Facility 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
ISPE Baseline® Guide:
Active Pharmaceutical Ingredients
Page 8
7
Process Support and Utility Systems ............................................................................ 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
Instrumentation and Controls ....................................................................................... 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
Electrical ......................................................................................................................... 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 of API Pharmaceutical Manufacturing ................................................... 125
12.1
12.2
12.3
Introduction ........................................................................................................................................... 125
Containment Philosophy ....................................................................................................................... 126
Elements of Containment ...................................................................................................................... 128
ISPE Baseline® Guide:
Active Pharmaceutical Ingredients
13
Scale-Up Facilities 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-Active Pharmaceutical Ingredients ....................................................................... 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
Multi-Purpose Facilities ................................................................................................. 147
14.1
14.2
14.3
14.4
15
Page 9
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
Appendix 1 – HVAC User Requirements ...................................................................... 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
Appendix 4 – Glossary and Acronyms ......................................................................... 171
20.1
20.2
21
Glossary ................................................................................................................................................ 171
Acronyms and Abbreviations ................................................................................................................ 179
Appendix 5 – References ............................................................................................... 183