Free Download Active Pharmaceutical Ingredients Development, Manufacturing, and Regulation edited by Stanley H. Nusim S. H. Nusim Associates, Inc. Aventura, Florida, U.S.A. Boca Raton -Free Pharmacy Books download from pharmagupshup.in

Contents

Preface . . . . iii

Contributors . . . . xiii

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Stanley H. Nusim

I. Consolidation and Integration . . . . 2

II. Quality . . . . 2

III. Potency . . . . 5

IV. Computer Control and Automation . . . . 6

V. Summary . . . . 7

2. Process Development . . . . . . . . . . . . . . . . . . . . . 9

Carlos B. Rosas

I. Introduction . . . . 9

II. The Bulk Drug Process as Part of the

Drug Development Program . . . . 13

III. From the Bench to the Pilot

Plant and Beyond . . . . 39

IV. The Physicochemical Attributes of the

Bulk Drug . . . . 61

V. The Process Body of Knowledge . . . . 65

VI. Processing Responsibility in Bulk Drug

Process Development . . . . 73

VII. Outsourcing in Bulk Drug

Process Development . . . . 89

vii

VIII. In Closing . . . . 89

References . . . . 90

3. Bulk Drugs: Process Design, Technology Transfer,

and First Manufacture . . . . . . . . . . . . . . . . . . . 93

Carlos B. Rosas

I. Introduction . . . . 93

II. The Process Design Task in Bulk

Drugs . . . . 96

III. Technology Transfer of the Bulk Drug

Process and First Manufacture . . . . 106

IV. In Closing—The Processing Technologies of

Bulk Drugs . . . . 123

References . . . . 125

4. Design and Construction of Facilities . . . . . . . 127

Steven Mongiardo and Eugene Bobrow

I. Introduction . . . . 127

II. Business Requirements . . . . 129

III. Developing the Preliminary Scope . . . . 132

IV. Utilities and Building Systems . . . . 137

V. Preliminary Scope Deliverables . . . . 138

VI. Design Development . . . . 142

VII. Utilities . . . . 147

VIII. Safety . . . . 150

IX. Current Good Manufacturing Practices

Requirements . . . . 150

X. Qualification Plan . . . . 151

XI. Expansion Capabilities . . . . 152

XII. Hazard and Operability Analysis . . . . 152

XIII. Execution Strategy and Planning . . . . 154

XIV. Procurement Strategy . . . . 156

XV. Construction Management . . . . 161

XVI. Start–Up Acceptance . . . . 162

XVII. Project Turnover and Installation

Qualification . . . . 163

XVIII. Conclusions . . . . 165

References . . . . 166

viii Contents

5. Regulatory Affairs . . . . . . . . . . . . . . . . . . . . . . . 167

John Curran

I. Introduction . . . . 167

II. Requirements for Submission of

Regulatory CMC Documents . . . . 169

III. Contents of Regulatory

Submissions—API Sections . . . . 173

IV. Registration Samples . . . . 191

V. The Review and Approval Process . . . . 192

VI. Preapproval Inspections . . . . 195

VII. Postapproval Change Evaluations . . . . 196

VIII. The Future . . . . 199

IX. Helpful References . . . . 200

6. Validation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203

James Agalloco and Phil Desantis

I. History . . . . 203

II. Definition of Validation . . . . 205

III. Regulations . . . . 206

IV. Application of Validation . . . . 206

V. Life Cycle Model . . . . 206

VI. Validation of New Products . . . . 207

VII. Validation of Existing Products . . . . 208

VIII. Implementation . . . . 209

IX. Bulk Pharmaceutical Chemical

Validation . . . . 211

X. In-Process Controls . . . . 220

XI. Cleaning Validation . . . . 222

XII. Computerized Systems . . . . 225

XIII. Procedures and Personnel . . . . 225

XIV. Validation of Sterile Bulk Production . . . . 225

XV. Conclusion . . . . 231

References . . . . 231

7. Quality Assurance and Control . . . . . . . . . . . . 235

Michael C. VanderZwan

I. Introduction . . . . 235

II. Defining and Assuring the Quality of the Active

Pharmaceutical Ingredient . . . . 240

Contents ix

III. The Regulations for Quality . . . . 245

IV. The Quality Control and Quality

Assurance Department . . . . 273

Appendix A . . . . 280

8. Plant Operations . . . . . . . . . . . . . . . . . . . . . . . . 285

Stanley H. Nusim

I. Plant Organization . . . . 285

II. Batch vs. Continuous . . . . 286

III. Dedicated vs. Shared Manufacturing

Facilities . . . . 288

IV. Shift Operations . . . . 288

V. Sterile Operations . . . . 291

VI. Clean Room . . . . 294

VII. Cost Control . . . . 296

VIII. Fixed Overhead Absorption . . . . 299

IX. Safety . . . . 300

X. Environmental . . . . 303

9. Materials Management . . . . . . . . . . . . . . . . . . . 305

Victor Catalano

I. Introduction . . . . 305

II. Production Planning . . . . 306

III. Inventory Management . . . . 307

IV. Purchasing=Supply Management . . . . 308

V. Distribution=Transportation . . . . 315

VI. Information Technology . . . . 316

VII. Quality Management . . . . 317

References . . . . 318

10. Plant Maintenance . . . . . . . . . . . . . . . . . . . . . . 323

Raymond J. Oliverson

I. Introduction . . . . 323

II. Strategic Plan . . . . 324

III. Reliability-Balanced Scorecards . . . . 325

IV. Maintenance Basics . . . . 327

V. Condition Monitoring . . . . 329

VI. Operator-Driven Reliability . . . . 330

VII. Reliability Engineering . . . . 331

VIII. Risk Management . . . . 333

IX. Summary . . . . 334