Cleaning Validation: Practical Compliance Approaches for Pharmaceutical Manufacturing

216 Pages·2022·7.519 MB·English

by  Destin A. LeBlanc

Cleaning Validation
Pharmaceutical manufacturers and upper management are encouraged to meet the
challenges of the science-based and risk-based approaches to cleaning validation.
Using some of the principles and practices in this volume will help in designing a
more effective and efficient cleaning validation program.
Features
• Timely coverage of cleaning validation for the pharmaceutical industry,
a dynamic area in terms of health-based limits.
• The author encourages pharmaceutical manufacturers, and particularly
upper management, to meet the challenges of the science-based and risk-
based approaches to cleaning validation.
• Draws on the author’s vast experience in the field of cleaning validation
and hazardous materials.
• Discusses EMA vs. ISPE on Cleaning Limits and revised Risk-MaPP for
highly hazardous products in shared facilities.
• A diverse list of topics from protocol limits for yeasts and molds to
cleaning validation for homeopathic drug products.

Cleaning Validation
Practical Compliance
Approaches for Pharmaceutical
Manufacturing
Destin A. LeBlanc
Consultant
Cleaning Validation Technologies
First edition published 2023
by CRC Press
6000 Broken Sound Parkway NW, Suite 300, Boca Raton, FL 33487-2742
and by CRC Press
4 Park Square, Milton Park, Abingdon, Oxon, OX14 4RN
© 2023 Destin A LeBlanc
CRC Press is an imprint of Taylor & Francis Group, LLC
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ISBN: 978-1-032-43083-6 (hbk)
ISBN: 978-1-032-43173-4 (pbk)
ISBN: 978-1-003-36600-3 (ebk)
DOI: 10.1201/9781003366003
Typeset in Times
by SPi Technologies India Pvt Ltd (Straive)
Contents
Preface ..................................................................................................................ix
About the Author ..................................................................................................xi
Section I Terminology
Chapter 1 Use of the Term “Product” ..............................................................3
Chapter 2 Use of the Terms Grouping and Matrixing......................................7
Chapter 3 Deviations and Nonconformances .................................................11
Chapter 4 Clarifying Terms: Blanks vs. Controls ..........................................15
Chapter 5 Meaning of “Dedicated”? ..............................................................19
Chapter 6 Words (Again?) .............................................................................23
Section II Health-Based Limits
Chapter 7 What’s at Stake with HBELs .........................................................29
Chapter 8 A Look at the Revised Risk-MaPP ................................................35
Chapter 9 EMA’s Q&A Clarification: Part 1 .................................................39
Chapter 10 EMA’s Q&A Clarification: Part 2 .................................................43
Chapter 11 The EMA Q&A “Clarification” on Limits ....................................47
Chapter 12 The EMA Q&A on Routine Analytical Testing ............................51
Chapter 13 Other Issues in EMA’s Q&A .........................................................55
Chapter 14 Highly Hazardous Products in Shared Facilities ...........................57
Section III Limits: General
Chapter 15 EMA vs. ISPE on Cleaning Limits? ..............................................63
Chapter 16 Does a High “Margin of Safety” Protect Patients? .......................67
Chapter 17 What If the Next Product Is the Same Product? ............................71
v
vi Contents
Chapter 18 Limits for “Product A to Product A” .............................................75
Chapter 19 Surfaces Areas in Carryover Calculations .....................................79
Chapter 20 Carryover Calculation Errors to Avoid ..........................................81
Chapter 21 Protocol Limits for Yeasts/Molds? ................................................85
Chapter 22 Cleaning Validation for Homeopathic Drug Products ...................87
Chapter 23 A Possible Approach for Biotech Limits .......................................89
Chapter 24 Establishing Clearance for Degraded Protein Actives ...................93
Section IV Visually Clean
Chapter 25 Avoiding “Visually Dirty” Observations .......................................99
Chapter 26 What’s a Visual Limit? ................................................................103
Chapter 27 Visual Residue Limits: Part 1 ......................................................107
Chapter 28 Visual Residue Limits: Part 2 ......................................................111
Section V Analytical and Sampling Methods
Chapter 29 Two More Nails in the Coffin? ....................................................117
Chapter 30 Timing for Swab Sampling in a Protocol? ..................................121
Chapter 31 More Swab Sampling Issues .......................................................123
Chapter 32 Pass/Fail Analytical Test Methods ...............................................127
Section VI Product Grouping
Chapter 33 Issues in Product Grouping .........................................................133
Chapter 34 Toxicity as a Worst-Case Grouping Factor ..................................137
Chapter 35 Another “Worst Case” Product Grouping Idea ...........................139
Contents vii
Section VII Protocols and Procedures
Chapter 36 Issues in Rinsing: Part 1 ..............................................................145
Chapter 37 Issues in Rinsing: Part 2 ..............................................................149
Chapter 38 Routine Monitoring for Highly Hazardous Products ..................153
Chapter 39 “Concurrent Release” for Cleaning Validation ............................157
Chapter 40 Dirty and Clean Hold Time Protocols .........................................161
Section VIII API Manufacture
Chapter 41 A Critique of the APIC Guideline ...............................................165
Chapter 42 Another Issue for API Synthesis .................................................171
Chapter 43 Contaminants in API Manufacture ..............................................175
Section IX Miscellaneous Topics
Chapter 44 Significant Figures: Back to Basics .............................................179
Chapter 45 The Value of a Protocol Worksheet for Manual Cleaning ...........183
Chapter 46 Dealing with Used and New Equipment .....................................187
Chapter 47 Solving Cleaning Validation Problems by Analogy ....................191
Chapter 48 Causing Cleaning Validation Problems by Analogy ...................195
Appendix A ......................................................................................................199
Appendix B ......................................................................................................201
Index .................................................................................................................203

Preface
This Volume 5 complements my earlier four books on the same subject. What are
presented in this book are modifications and updates of my monthly Cleaning
Memos originally published on my website, www.cleaningvalidation.com, in
the period from January 2017 through December 2020. Each Cleaning Memo is
presented as a chapter, with the chapters then organized by common topics. For
example, topics related to setting limits are in one section, those related to sam-
pling in another section, and so forth. The updates made are sometimes relatively
simple, and sometimes more detailed. In all cases, I have tried to focus on changes
for improving clarity and applicability, as well as to modify the text with new
information. There is one appendix with a list of acronyms used in this volume,
as well as a second appendix dealing with my shorthand method of expressing
limits, just in case you get confused about what I mean by L0, L1, L2, L3, and L4.
A “hot topic” for these four years has continued to be limits, specifically
health-based limits. About half of these chapters deal with setting limits in one
way or another, so the use of health-based limits will require balanced reading
(and thinking) for an overall understanding.
I would also like to encourage pharmaceutical manufacturers, and particularly
upper management, to meet the challenges of the science-based and risk-based
approaches to cleaning validation (as opposed to a “cook book” approach). Using
some of the principles and practices in this volume may help in designing a more
effective and efficient cleaning validation program.
I should add a caveat here, much like the caveat before each of the FDA’s guid-
ance documents – nothing in this book should be considered mandatory or bind-
ing. I have tried to present alternatives where possible. However, achieving the
same objectives by utilizing scientifically justified procedures that are applicable
to a manufacturer’s specific situation is strongly encouraged. In a manufacturing
environment where process efficiencies as well as good compliance are manda-
tory, following “cookie cutter” recipes should be avoided.
Before you connect the dots,
make sure you collect the dots!
Destin A. LeBlanc
Knoxville, TN
ix