Combination products : regulatory challenges and successful product development

The field of combination product development (products born of the integration of medical devices, biologics, and drugs) is so new that, while literature abounds on each part individually, there are very few publications, including FDA documents, available concerning the unique challenges posed by this nascent but fast-growing area.
Providing the first in-depth look at this breakthrough field, Combination Products includes practical guidelines and a detailed step-by-step process for the development of these novel technologies. It addresses the technical, scientific, regulatory, and quality issues that arise when combining drugs, biologics, and medical devices into a single product. It takes a practical, readily applicable approach to discussing the challenges, victories, and pitfalls associated with merging technologies and systems and how to implement these products into the market successfully and in a timely manner.
Specifically, this text explores the process from start to finish, establishing a workable design and development plan complete with relevant definitions. It reviews FDA and other regulatory expectations and covers resource requirements, manufacturing pitfalls, post-launch compliance requirements, and agency audits and challenges.
Drawing on the experience and expertise of two leaders in their respective fields, Combination Products boasts the credentials of Dr. Smita Gopalaswamy, a 20 year veteran of technical consulting responsibilities in medical device, biologics, and pharmaceutical industries as well as combination products, along with the support of Dr. Venky Gopalaswamy, an expert in business improvement methodologies such as six sigma, lean, and change management, to provide a comprehensive assessment of the field and an efficient and effective approach to the creation and implementation of combination products.

About the authors	p. xv
1 Introduction	p. 1
Market	p. 4
International potential	p. 5
2 Overview of combination products	p. 7
Combination product classification	p. 7
Novel drug delivery systems	p. 7
Traditional drug delivery systems	p. 7
Drug-enhanced devices	p. 8
Regenerative medicinal products	p. 8
Examples of combination products	p. 8
Biologic-device combination product	p. 10
Bioartificial organs (tissue engineered)	p. 10
Recently approved combination products	p. 10
Breath test combination products	p. 12
Drug-device combination catheter lock/flush solutions	p. 13
Biologic-device: Vitagel Surgical Hemostat	p. 14
Differently regulated constituent parts (drug, device, biological product)	p. 14
Copackaged (21 CFR 3.2 (e)(2))	p. 15
GMP guidance	p. 15
European union (EU) definitions	p. 20
Bibliography	p. 21
3 Ensuring successful combination product development	p. 23
Benefits of developing combination products	p. 23
The road map to achieve control of design	p. 27
Establishing a development plan	p. 28
Product development in healthcare product industries	p. 30
Innovation domain	p. 30
Opportunity identification (innovation and customer domain)	p. 33
Customer domain	p. 34
The project charter	p. 35
Customer wants and needs: Design inputs (customer domain)	p. 37
Concept selection	p. 40
Proof-of-concept testing	p. 41
Risk analysis and management	p. 42
Functional domain	p. 43
Management of design requirements (from initial design inputs to final design outputs)	p. 44
A systems engineering approach to management of requirements	p. 46
Initiating the requirements cascade (from the customer domain to the functional domain)	p. 47
Requirements cascade	p. 48
What is the difference between a requirement and a parameter?	p. 48
What is functional?	p. 49
From the functional domain to the design and process domains	p. 50
Stability studies	p. 52
Design domain	p. 53
Process analytical technology (PAT)	p. 54
Governance	p. 55
Process domain	p. 56
Technology transfer/scale-up	p. 56
Production scale-up	p. 56
Process development	p. 57
Process validation	p. 57
Supplier selection and qualification	p. 57
Transfer to operations	p. 58
Postmarket domain	p. 58
Bibliography	p. 62
4 Overview of FDA and other regulatory agency expectations	p. 63
Regulatory requirements for FDA/EU of combination products	p. 65
Regulation of combination products by FDA agency	p. 69
Number of marketing applications for a combination product	p. 69
When one marketing application may be appropriate	p. 70
When two marketing applications may be necessary	p. 70
Flowcharts	p. 71
FDA agency: CDRH (devices)	p. 71
Examples of the regulatory pathway for several different combination products	p. 71
FDA interactions: early interaction and communication with the FDA	p. 76
Combination product regulation in the EU	p. 76
Mode of action	p. 77
How are the regulations applied to combination products?	p. 78
The regulatory pathway for a drug-eluting stent in the EU	p. 81
Component 1 The bare-metal stent	p. 81
Component 2 The drug (active ingredient)	p. 81
Component 3 Drug delivery (carrier)	p. 82
Clinical studies	p. 82
Investigation brochure	p. 82
Notified body selection	p. 83
Design dossier	p. 83
Global regulatory requirements	p. 84
Canada	p. 84
Pharmaceuticals: Prescription and nonprescription drugs	p. 86
Medical devices	p. 86
Medical Devices Bureau	p. 87
Combination products	p. 87
Classification of drug-medical device combination products by therapeutic products committee: decisions	p. 88
Classification examples of products	p. 88
Japan	p. 89
Medical devices	p. 89
MHLW	p. 93
Pharmaceutical and Medical Safety Bureau	p. 93
Division of drugs	p. 95
Division of biological chemistry and biologicals	p. 95
Division of medical devices	p. 95
China	p. 95
Agencies and regulations	p. 96
The State Food and Drug Administration (SFDA)	p. 96
The SFDA department of medical devices	p. 97
SFDA departments	p. 97
India	p. 99
The regulation of medical devices	p. 100
Information required to be included with the application for a registration certificate in India	p. 100
Bibliography	p. 103
5 Resource requirements	p. 105
Resources	p. 105
Addition of a drug or biologic to a device	p. 107
Addition of a device to a biologic-device combination product	p. 108
Facilities	p. 110
In-house testing	p. 110
Developing analytical laboratory capabilities	p. 111
Clean rooms	p. 111
Manufacturing operations	p. 111
Quality	p. 111
A GMP-compliant quality system for a combination product	p. 113
Cost and financial factors	p. 114
Fundamental differences in regulations between pharmaceuticals and medical devices	p. 114
The stability program	p. 115
Regulatory approval process	p. 116
Bibliography	p. 116
6 Manufacturing of combination products	p. 119
Manufacturing considerations	p. 120
Manufacturing plan	p. 122
Manufacturing risk assessment	p. 123
Process characterization	p. 124
Facilities, equipment, and media	p. 126
Contract manufacturing and testing	p. 129
Sterilization of combination products	p. 130
Lower sterilization dose	p. 131
Dosimetry and modeling	p. 132
Packaging and labeling	p. 132
Storage, logistics, and shipping	p. 133
Process and method validation	p. 134
Bibliography	p. 135
7 Challenges and pitfalls to avoid with combination products	p. 137
Challenges and pitfalls	p. 137
Management responsibilities	p. 139
Collaborative partnerships	p. 140
Developmental challenges	p. 140
Development team	p. 140
Technical challenges	p. 142
Preclinical/clinical studies	p. 144
Preclinical challenges	p. 145
Preclinical in vivo studies	p. 145
Preclinical testing	p. 147
Common preclinical testing deficiencies	p. 149
Common preclinical animal study deficiencies	p. 150
Clinical investigation	p. 150
Clinical evaluation	p. 151
Clinical trials	p. 152
Phase 1 Clinical trials	p. 152
Phase 2 Clinical trials	p. 153
Phase 3 Clinical trials	p. 153
Regulatory challenges	p. 154
How are combination products regulated?	p. 154
The HepatAssist system as a biologic-device combination product	p. 156
Preapproval issues	p. 156
Premarket review	p. 157
User fees for combination products	p. 160
What are user fees?	p. 160
How are application user fees determined for combination products?	p. 161
What user fee waivers are available under MDUFMA?	p. 162
Combination product strategies	p. 162
International regulations	p. 165
Quality and compliance challenges	p. 166
QSR versus GMP	p. 166
Drug-eluting cardiovascular stent	p. 169
Drug versus device components	p. 169
Application of cGMP regulations to combination products	p. 170
Facility, infrastructure, and manufacturing challenges	p. 175
Postlaunch challenges	p. 177
Bibliography	p. 178
8 Postlaunch compliance requirements	p. 181
FDA's role in regulation of products	p. 182
Medical devices	p. 183
Postmarket monitoring	p. 183
Postmarket adverse event reporting	p. 185
Postmarket safety reporting for combination products	p. 186
Adverse events	p. 187
Possible options for adverse event reporting	p. 188
Combination products approved under one marketing application	p. 188
Combination products approved under separate marketing applications	p. 189
Other combination products, where the constituent parts are approved under separate marketing applications, by different sponsors	p. 189
How are adverse events reported for combination products?	p. 190
Postmarket challenges for combination products	p. 190
Modification of combination products postmarket	p. 191
Postmarket monitoring	p. 192
Complaints	p. 192
Risk management	p. 195
Bibliography	p. 197
9 Agency audits and challenges	p. 199
Postmarket monitoring	p. 199
FDA's post-approval audit program	p. 201
Traditional FDA inspections by agency	p. 201
CBER: Biological products	p. 201
CDER: Drug products	p. 202
The Division of Compliance Risk Management and Surveillance	p. 203
Inspections for drug manufacturers	p. 204
Options for surveillance inspections	p. 206
Compliance inspections	p. 206
CDRH: medical devices	p. 207
The quality system (QS) regulation	p. 207
The MDR regulation	p. 208
The medical device tracking regulation	p. 208
The corrections and removal regulation	p. 209
The registration and listing regulation	p. 209
Inspections of medical device manufacturers	p. 209
FDA inspections and combination product manufacturers	p. 210
FDA inspections	p. 211
Agency audits for combination products	p. 211
Various types of FDA inspections	p. 213
Pre-approval inspections	p. 213
Post-approval or surveillance inspections	p. 214
Specific issue-directed inspections	p. 217
A compliance program for combination product manufacturers	p. 217
Agency audit readiness	p. 218
Bibliography	p. 219
10 Conclusions	p. 221
The medical device industry	p. 221
The biotechnology industry	p. 221
The pharmaceutical industry	p. 221
Examples of combination products	p. 222
Drug-device combination	p. 222
Diagnostic-device-drug	p. 224
Factors involved in combination product development	p. 225
Success for a combination product company	p. 226
Pitfalls and challenges of developing combination products	p. 226
Component development	p. 227
Integration of components	p. 227
Material selection for combination products	p. 227
Choice of pathway for a combination product	p. 228
Regulatory challenges	p. 228
Manufacturing of combination products	p. 229
Packaging challenges	p. 230
Sterilization	p. 231
Bibliography	p. 234
Index	p. 235

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