History of a cGMP Medical Event Investigation

MICHAEL A. BROWN, PhD, 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.

• Preface xiPart One The Event 11 Francesca 3Part Two Drug Discovery: Five Years Earlier 92 Katlin Bioscience: Transgenic Mouse Study 113 Oxy-Fox Inhaler 213.1 Kinnen Laboratories 213.2 Kinnen Laboratories: Oxy-Fox Transfer 223.3 Due-Diligence Team and Katlin Data Acceptance 23Part Three Kinnen Oxy-Fox Inhaler Market Launch Program 254 Agency IND and NDA Requirements, Six Sigma Charter, and Device Master Record 274.1 Launch Team Meeting Number 1 274.2 Meeting with Medical Affairs: Toxicity Studies 465 Meeting Minutes Guidelines 495.1 Launch Team Meeting Number 2 496 Project Timing, Marketing Plan, and Offshore Molding 556.1 Launch Team Meeting Number 3 556.2 Project Financial Review 616.3 Progress Meeting: Who Takes Credit for What? 646.4 Morning Meeting: Just-in-Time Manufacturing 657 cGMP Process Validation Requirements 697.1 Launch Team Meeting Number 4 698 Failure Mode Effects Analysis 818.1 Launch Team Meeting Number 5 819 Design for Manufacturability, Design for Six Sigma, Concurrent Design 939.1 Product Development Meeting Number 1 939.2 Update Meeting with Ed Chase and Gordon Taylor 10210 Design Fishbone Diagram 10510.1 Launch Team Meeting Number 6 10511 Product Specifications 11111.1 Product Development Meeting Number 2 11112 Design Control 11512.1 Design Team Meeting Number 7 11512.2 Product Development Staff Meeting 11812.3 Engineering One-on-One 11912.4 Program Update 12013 Design of Experiments (DOE) 12313.1 Molding Team Meeting 12314 Start-Up Issues 12914.1 Oxy-Fox Inhaler Wrap-Up and Equipment Start-Up 12914.2 The Final Management Review 135Part Four Present Day: Funeral 13915 Grief 14116 The Autopsy Results 14517 The Agency 151Part Five Agency Medical Event Letter 15518 Kinnen Notification 15718.1 Another Agency Letter 15718.2 Medical Event Review Meeting 15819 Investigation Team Management 16119.1. Morning Meeting with Gail Strom, Marcia Hines, and Dan Garvey 16120 DMAIC Investigation Process 16321 Internal Quality Review 17121.1 Meeting with Gail Strom and Marcia Hines 17121.2 Executive Management Review 17422 The Agency Audit Letter 17923 Agency Arrival 18324 The Audit 18724.1 Agency Meeting to Review Qualification Documents and the Quality Acceptance Records of First Lot to Stock 18724.2 Agency Meeting to Review the Oxy-Fox Inhaler Lot Used in the NDA Clinical Studies 18924.3 Agency Meeting to Review the Design and Program Team Meeting Minutes 19024.4 Agency Meeting to Review the Due-Diligence Report Katlin Studies, and Oxy-Fox Design History File, 19225 End-of-Day Agency Wrap-Up Meeting 19726 Kinnen Management Review 201Part Six Reckoning 20727 Blame and Responsibility 20927.1 The Investigation Is a Public Record 20927.2 Kinnen Wrap-Up 21028 Closure 213Bibliography 215Index 217

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