ISPE Baseline® Guide:
Risk-Based Manufacture of Pharmaceutical Products
Page 5
Table of Contents
1
Introduction.......................................................................................................................... 7
1.1
1.2
1.3
1.4
1.5
1.6
1.7
2
Concepts and Regulatory Philosophy............................................................................. 13
2.1 Overview of the Risk Management Approach............................................................................................. 14
2.2 Acceptable Risk.......................................................................................................................................... 15
2.3 The GMP and Industrial Hygiene Balance.................................................................................................. 16
Approach to Identify Highly Hazardous Drugs.............................................................................................. 8
Risk Management/Assessment Model to Address the Controls to Comply with 21 CFR 211.42(c)............. 8
How the Approach Fits Into Cleaning Validation........................................................................................... 9
Background................................................................................................................................................... 9
Scope of this Guide.................................................................................................................................... 10
Current Situation......................................................................................................................................... 10
How to Use this Guide................................................................................................................................ 11
3
3.1
3.2
3.3
3.4
3.5
3.6
4
Risk Assessment............................................................................................................... 31
5
6
7
8
Quality System Requirements.......................................................................................... 19
GxP Quality Policies................................................................................................................................... 19
GxP Quality Standards............................................................................................................................... 20
Gap Analysis............................................................................................................................................... 20
Auditing of Quality Systems........................................................................................................................ 20
Application to Cross-Contamination........................................................................................................... 20
The Logic Diagram..................................................................................................................................... 21
Risk Identification.............................................................................................................. 33
5.1
5.2
5.3
5.4
5.5
Definition of Hazard.................................................................................................................................... 33
Hazard Continuum and Prioritization for Risk Assessment........................................................................ 34
Establishing Health-Based Exposure Limits............................................................................................... 35
Setting Health-Based Safety Thresholds/Acceptance Limits...................................................................... 42
Setting Occupational Exposure Limits (OELs)............................................................................................ 46
Risk Analysis...................................................................................................................... 47
6.1
6.2
6.3
6.4
6.5
6.6
Holistic Approach to Risk Analysis.............................................................................................................. 48
Tools............................................................................................................................................................ 48
Routes for Cross-Contamination................................................................................................................ 50
Probability of Occurrence........................................................................................................................... 55
Product Exposure Risk in Non-Product Contact Areas............................................................................... 60
Detection..................................................................................................................................................... 61
Risk Evaluation.................................................................................................................. 63
7.1 Cleaning Process Performance Capability................................................................................................. 64
7.2 Cleaning Evaluation for New Products....................................................................................................... 64
7.3 Residue on Non-Product Contact Surfaces................................................................................................ 64
Risk Control....................................................................................................................... 67
8.1 Holistically Balanced Approach................................................................................................................... 68
ISPE BG: Risk-MaPP – TOC
©2010 ISPE. All rights reserved.
www.ISPE.org
Page 6
ISPE Baseline® Guide:
Risk-Based Manufacture of Pharmaceutical Products
9
10 Risk Acceptance................................................................................................................ 87
11 Risk Management Tools.................................................................................................... 89
12 Risk Review........................................................................................................................ 95
13 Risk Communication......................................................................................................... 97
14 Appendix 1 – Risk-MaPP Application Examples........................................................... 101
Risk Reduction................................................................................................................... 71
9.1
9.2
9.3
9.4
9.5
9.6
9.7
9.8
Hierarchy of Risk Reduction....................................................................................................................... 72
Risk Reduction: Routes of Exposure.......................................................................................................... 73
The Role of Pharmaceutical Research and Development in Risk Reduction............................................. 76
Process and Related Technologies............................................................................................................. 77
The Role of Facility Engineering in Risk Reduction.................................................................................... 79
HVAC.......................................................................................................................................................... 84
Containment Related Technologies............................................................................................................ 85
Personal Protective Equipment (PPE) and Gowning.................................................................................. 86
11.1 Risk Ranking or Risk Matrix........................................................................................................................ 90
11.2 Failure Mode and Effects Analysis (FMEA)................................................................................................ 91
13.1 Summary Document Template.................................................................................................................... 98
14.1
14.2
14.3
14.4
14.5
14.6
Introduction............................................................................................................................................... 101
Scenario 1 (Obviously Acceptable)........................................................................................................... 102
Scenario 2 (Obviously Unacceptable)...................................................................................................... 105
Scenario 3 (Apparently Acceptable (but was not)).................................................................................... 107
Scenario 4 (Apparently Unacceptable (but was))..................................................................................... 117
Logic Diagram........................................................................................................................................... 128
15 Appendix 2 – Bibliography............................................................................................. 129
15.1 References................................................................................................................................................ 129
15.2 Reading List.............................................................................................................................................. 133
16 Appendix 3 – Glossary.................................................................................................... 137
16.1 Abbreviations and Acronyms.................................................................................................................... 137
16.2 Definitions................................................................................................................................................. 141
ISPE BG: Risk-MaPP – TOC
©2010 ISPE. All rights reserved.
www.ISPE.org