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Sources of Contamination in Medicinal Products and Medical Devices

ISBN: 978-1-118-44905-9
592 pages
September 2012
Sources of Contamination in Medicinal Products and Medical Devices (1118449053) cover image

The first one-volume guide to sources of contamination in pharmaceuticals and medical devices

Most books dealing with contaminants in medicinal products often focus on analytical methods for detecting nonspecific impurities. Key to the work of the pharmaceutical chemist, this unique reference helps identify the sources of contamination in medicinal and pharmaceutical products and medical devices. Divided into three parts, Sources of Contamination in Medicinal Products and Medical Devices covers chemical, microbiological, and physical (particulate matter) contamination, including those originating from sterilization procedures.

As compelling as a medical documentary, the book sheds light on how impurities and contaminants can enter the human body transported via a specific product or treatment. Focusing on only those medicinal products and medical devices that may lead to exposure to contaminants harmful to human health, the book offers a comprehensive, systematic look at the entire universe of medical contamination:

  • Chemical contaminants including residual solvents, catalyst residuals, and genotoxic impurities in active pharmaceutical ingredients (APIs)
  • Diagnostic imaging agents (i.e., radiopharmaceuticals and contrast agents)
  • Microbiological and endotoxin contamination involving single and multiple dose products, medical devices, and biofilms
  • Contamination from sterilization procedures, residuals from radiation sterilization, ionizing radiation on packaging materials and medical devices
  • Medicinal gases and volatile anesthetics
  • Biopharmaceuticals including recombinant DNA technology products
  • Extractables and leachables from containers made of glass, plastics, and metal

Each section of the book contains information on what contaminants could be expected in a particular product, and how they were generated and reached that product. With up-to-date regulatory guidelines for determining contamination, as well as methods for assessing, quantifying, avoiding and removing contaminants, Sources of Contamination in Medicinal Products and Medical Devices is essential to fully understanding the specific threats that undermine the safety of medicines and medical devices.

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PREFACE xv

ACKNOWLEDGMENTS xix

1 Introduction 1

Reference 6

2 Directives for Contamination Control 7

PART I CHEMICAL CONTAMINATION 17

3 Raw Materials 19

3.1 Water 19

3.2 Inorganic Impurities 27

3.3 Organic Impurities 32

3.3.1 By-products 32

3.3.2 Genotoxic Impurities (GTIs) 35

3.3.3 Degradation Products 39

3.4 Additives 52

3.5 Residual Solvents 58

Concluding Remarks 63

References 65

4 Medicinal Gases and Volatile Anesthetics 70

4.1 Medicinal Gases 70

4.2 Volatile Anesthetics 80

Concluding Remarks 93

References 94

5 Diagnostic Imaging Agents 96

5.1 Radiopharmaceuticals 98

5.1.1 Technetium-Based Products 100

5.1.1.1 Production of Mo-99 100

5.1.1.2 Generation of Tc-99m 103

5.1.1.3 Labeling Procedures 107

5.1.2 Iodine-Based Products 113

5.1.3 Fluorine-Based Products 125

5.1.3.1 [18F]FDG Production and Labeling 127

5.1.3.2 Species Formed during [18O]H2O Irradiation 128

5.1.3.3 Residual Solvents and Components Used in the Labeling 137

5.1.3.4 Radiolysis Products Generated by Elevated Activity of the Labeled Compound 140

5.2 Contrast Agents 143

5.2.1 Gadolinium-Based Products 143

5.2.2 Iodine-Based Products 158

5.2.3 Barium Sulfate 172

Concluding Remarks 176

References 177

6 Containers 185

6.1 Glass Containers 185

6.2 Plastic Containers 199

6.2.1 Polymer Formation 199

6.2.2 PVC Containers 203

6.2.3 Other Plastic Containers 215

6.3 Metal Containers 220

Concluding Remarks 223

References 223

7 Closures 228

Concluding Remarks 256

References 256

8 Delivery Systems and Filters 259

8.1 Delivery Systems Made of PVC 260

8.2 Delivery Systems Made of Other Plastic Materials 275

8.3 Filters 282

Concluding Remarks 287

References 287

9 Medical Devices 290

9.1 General Use Devices 293

9.1.1 Medical Gloves 294

9.1.2 Syringes 294

9.2 Extracorporeal Circuits 300

9.3 Devices for Administration of Aerosolized Drugs 307

9.4 Reprocessed Medical Devices 308

9.5 Tissue Substitutes 309

9.5.1 Skin Substitutes and Surgical Dressings 310

9.5.2 Hard Tissue Substitutes 310

9.5.3 Soft Tissue Substitutes 311

Concluding Remarks 313

References 313

PART II PHYSICAL CONTAMINATION 317

10 Particulate Matter 319

Concluding Remarks 345

References 345

PART III MICROBIOLOGICAL CONTAMINATION 349

11 Microbiological and Endotoxin Contamination 351

11.1 Water 355

11.2 Raw Materials 361

11.3 Sterile Products 367

11.3.1 Single- and Multiple-Dose Products 368

11.3.2 Parenteral Nutrition (PN) 371

11.3.3 Propofol 378

11.3.4 Ophthalmic Products 384

11.4 Medicinal Gases 393

11.5 Medical Devices 394

11.5.1 Syringes 395

11.5.2 Endoscopes 398

11.5.3 Other Devices 401

11.6 Biofilms 406

11.7 Dialysis Circuits 407

11.8 Nosocomial Infections 413

Concluding Remarks 420

References 422

PART IV MISCELLANEOUS 433

12 Contamination from Sterilization Procedures 435

12.1 Residuals from Radiation Sterilization 437

12.1.1 Radiolysis of Water 438

12.1.2 Effect of Ionizing Radiation on Drug Products 439

12.1.3 Polymers in Drug Delivery 440

12.1.3.1 Polylactide (PLA) and Poly(lactide-co-glycolide) (PLGA) 443

12.1.3.2 Collagen 448

12.1.3.3 Cellulose and Other Polysaccharides 448

12.1.3.4 Alginate 450

12.1.4 Radiolysis of Selected Nondrug Components 450

12.1.4.1 Residual Solvents 450

12.1.4.2 Monosaccharides 451

12.1.4.3 Starch 451

12.1.5 Effect of Ionizing Radiation on Materials Used in Packaging and in Medical Devices 454

12.1.5.1 Ultra-High-Molecular-Weight Polyethylene (UHMWPE) 456

12.1.5.2 Polyurethane (PU) 458

12.1.5.3 Silicone 464

12.1.5.4 Polyamide (PA) 464

12.1.5.5 Poly(methyl methacrylate) (PMMA) 466

12.1.5.6 Polytetrafl uoroethylene (PTFE) 468

12.1.5.7 Polyvinyl Chloride (PVC) 468

12.1.5.8 Polyethylene (PE) 470

12.1.5.9 Polypropylene (PP) 473

12.1.5.10 Polyethylene Terephthalate (PET) 478

12.1.5.11 Polystyrene (PS) 478

12.1.5.12 Polysulfone (PSf) 478

12.1.5.13 Ethylene Vinyl Acetate (EVA) 480

12.1.5.14 Multilayer Materials 482

12.2 Heat Sterilization 483

12.3 Residuals from Chemical Disinfection and Sterilization Agents 486

12.3.1 Ethylene Oxide (EtO) 487

12.3.2 Peracetic Acid and Hydrogen Peroxide 494

12.3.3 Formaldehyde 497

Concluding Remarks 503

References 504

13 Biotechnological Products 512

13.1 DNA and HCP Residuals 516

13.2 Viruses and Mycoplasma 516

13.3 Endotoxin 518

13.4 Protein Degradation 522

13.5 Protein Aggregation 524

Concluding Remarks 530

References 530

Appendix Polymeric Materials: Components, Additives, Extractables, and Degradation Products 533

References 553

INDEX 555

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DENISE BOHRER, PhD, is Professor of Analytical Chemistry at the Federal University of Santa Maria, Brazil. Her research has focused on sources of contamination in pharmaceutical products, specifically, infusion solutions for patients with kidney disease and preterm infants. She has published sixty-eight papers and two book chapters on pharmaceutical manufacturing.

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