Michael A. Brown 
A History of a cGMP Medical Event Investigation 

Case study details the right way and the wrong way to
successfully develop and market a new drug

Beginning with the untimely death of a young mother, A
History of a c GMP Medical Event Investigation unfolds a
fictitious case study that captures how unchecked human flaws
during the development and launch of a new drug can lead to
disastrous consequences. Moreover, it illustrates how and why Six
Sigma principles and methods should be applied to fully comply with
FDA regulations at every stage of drug development and
commercialization.

From initial transgenic mouse studies to the FDA fatality
investigation, this case study introduces all the key regulations
and practices that govern the development, manufacture, and
marketing of a new drug, including:

* FDA Investigational and New Drug Application Processes

* FDA Code of Federal Regulations’ current Good Manufacturing
Practice (c GMP)

* ISPE Good Automated Manufacturing Practice (GAMP)

Readers will also be introduced to a variety of managers and
researchers whose personal agendas conflict with best practices and
therefore compromise the safety and effectiveness of a new drug
product. Throughout the case study, the author offers tested and
proven practices and tips so that these human flaws are not
translated into drug product flaws. These practices and tips are
critical and typically can only be learned through years of
experience working in competitive drug development
environments.

A History of a c GMP Medical Event Investigation is ideal
for students in biotechnology, pharmacology, engineering, and
business management as well as professionals in biomedical and drug
development. All readers will discover what can go wrong in
developing and bringing a new drug to market. Most importantly,
they will also learn how to apply Six Sigma principles and methods
to ensure safe and effective product design, development, and
manufacturing.

Table of Content

Preface xi

Part One The Event 1

1 Francesca 3

Part Two Drug Discovery: Five Years Earlier 9

2 Katlin Bioscience: Transgenic Mouse Study 11

3 Oxy-Fox Inhaler 21

3.1 Kinnen Laboratories 21

3.2 Kinnen Laboratories: Oxy-Fox Transfer 22

3.3 Due-Diligence Team and Katlin Data Acceptance 23

Part Three Kinnen Oxy-Fox Inhaler Market Launch Program 25

4 Agency IND and NDA Requirements, Six Sigma Charter, and Device Master Record 27

4.1 Launch Team Meeting Number 1 27

4.2 Meeting with Medical Affairs: Toxicity Studies 46

5 Meeting Minutes Guidelines 49

5.1 Launch Team Meeting Number 2 49

6 Project Timing, Marketing Plan, and Offshore Molding 55

6.1 Launch Team Meeting Number 3 55

6.2 Project Financial Review 61

6.3 Progress Meeting: Who Takes Credit for What? 64

6.4 Morning Meeting: Just-in-Time Manufacturing 65

7 c GMP Process Validation Requirements 69

7.1 Launch Team Meeting Number 4 69

8 Failure Mode Effects Analysis 81

8.1 Launch Team Meeting Number 5 81

9 Design for Manufacturability, Design for Six Sigma, Concurrent Design 93

9.1 Product Development Meeting Number 1 93

9.2 Update Meeting with Ed Chase and Gordon Taylor 102

10 Design Fishbone Diagram 105

10.1 Launch Team Meeting Number 6 105

11 Product Specifications 111

11.1 Product Development Meeting Number 2 111

12 Design Control 115

12.1 Design Team Meeting Number 7 115

12.2 Product Development Staff Meeting 118

12.3 Engineering One-on-One 119

12.4 Program Update 120

13 Design of Experiments (DOE) 123

13.1 Molding Team Meeting 123

14 Start-Up Issues 129

14.1 Oxy-Fox Inhaler Wrap-Up and Equipment Start-Up 129

14.2 The Final Management Review 135

Part Four Present Day: Funeral 139

15 Grief 141

16 The Autopsy Results 145

17 The Agency 151

Part Five Agency Medical Event Letter 155

18 Kinnen Notification 157

18.1 Another Agency Letter 157

18.2 Medical Event Review Meeting 158

19 Investigation Team Management 161

19.1. Morning Meeting with Gail Strom, Marcia Hines, and Dan Garvey 161

20 DMAIC Investigation Process 163

21 Internal Quality Review 171

21.1 Meeting with Gail Strom and Marcia Hines 171

21.2 Executive Management Review 174

22 The Agency Audit Letter 179

23 Agency Arrival 183

24 The Audit 187

24.1 Agency Meeting to Review Qualification Documents and the Quality Acceptance Records of First Lot to Stock 187

24.2 Agency Meeting to Review the Oxy-Fox Inhaler Lot Used in the NDA Clinical Studies 189

24.3 Agency Meeting to Review the Design and Program Team Meeting Minutes 190

24.4 Agency Meeting to Review the Due-Diligence Report Katlin Studies, and Oxy-Fox Design History File, 192

25 End-of-Day Agency Wrap-Up Meeting 197

26 Kinnen Management Review 201

Part Six Reckoning 207

27 Blame and Responsibility 209

27.1 The Investigation Is a Public Record 209

27.2 Kinnen Wrap-Up 210

28 Closure 213

Bibliography 215

Index 217

About the author

MICHAEL A. BROWN, Ph D, PE, is a Visiting Professor at the
University of Illinois at Chicago. Dr. Brown has twenty-five years’
experience in the biomedical industry in a product and process
design capacity with responsibilities for worldwide engineering and
management. He has served as a lead engineer on numerous products,
process, and equipment projects including design, implementation,
and qualifications. He is a registered Professional Engineer and a
certified Six Sigma Black Belt with considerable experience in team
leadership. The material presented in this case, including the FDA
regulations and Six Sigma concepts, was tested in an engineering
senior design course taught by Dr. Brown over a three-year period.
Student feedback noted that the difficult design principles were
explained in an easy-to-read story that introduced them to the Six
Sigma methodologies in an engaging manner.