1. PHARMACEUTICALPACKAGINGHANDBOOK

2. PHARMACEUTICALPACKAGINGHANDBOOKE DWA R D J. B AU E RPittsburgh, Pennsylvania, USA 3. Informa Healthcare USA, Inc.52 Vanderbilt AvenueNew York, NY 10017# 2009 by Informa Healthcare USA, Inc.Informa Healthcare is an Informa businessNo claim to original U.S. Government worksPrinted in the United States of America on acid-free paper10 9 8 7 6 5 4 3 2 1International Standard Book Number-10: 1-5871-6151-6 (Hardcover)International Standard Book Number-13: 978-1-5871-6151-3 (Hardcover)This book contains information obtained from authentic and highly regarded sources. Reprinted material isquoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable effortshave been made to publish reliable data and information, but the author and the publisher cannot assumeresponsibility for the validity of all materials or for the consequence of their use.No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic,mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, andrecording, or in any information storage or retrieval system, without written permission from the publishers.For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 RosewoodDrive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses andregistration for a variety of users. For organizations that have been granted a photocopy license by the CCC,a separate system of payment has been arranged.Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are usedonly for identification and explanation without intent to infringe.Library of Congress Cataloging-in-Publication DataBauer, Edward J., 1947-Pharmaceutical packaging handbook / Edward J. Bauerp. ; cm.Includes bibliographical references and index.ISBN-13: 978-1-5871-6151-3 (hardcover : alk. paper)ISBN-10: 1-5871-6151-6 (hardcover : alk. paper) 1. DrugsPackagingHandbooks, manuals, etc. I. Title.[DNLM: 1. Drug Packaging. QV 825 B344p 2008]RS159.5.B38 20096150.10688dc222008051340For Corporate Sales and Reprint Permissions call 212-520-2700 or write to: Sales Department,52 Vanderbilt Avenue, 16th floor, New York, NY 10017.Visit the Informa Web site atwww.informa.comand the Informa Healthcare Web site atwww.informahealthcare.com 4. PrefacePharmaceutical packaging is a subject that rarely comes to mind when thinkingof drugs, medical devices, or other divisions of the health care industry.Packaging done well provides protection, sterility, and safety. Health careprofessionals and patients hardly give it a thought. Packaging done poorlyusually means a package that is hard to open. These perceptions and the almostinvisible presence of packaging science in most peoples understanding ofpharmaceuticals was the idea behind this book.Pharmaceutical products, or more appropriately biopharmaceutical prod-ucts,and health care in developed countries are wonders of the modern world.Pharmaceutical products and health care in developing countries and remoteparts of the world seems like magic. Diseases that were once fatal and chronicconditions that destroyed lives have slowly been conquered by modern medicine.Views of the body, unimaginable for most of the last century with X rays,are now possible with new imaging techniques that let us see the body inexquisite detail. We have come to expect a steady stream of new technology thatcures or vaccinates us from ailments and potentially deadly viruses. We take forgranted that new and better diagnostic techniques will improve our ability tounderstand and fix our bodies. We have grown accustomed to transplants,angioplasty, stents to open clogged arteries, joint replacements, and otherdevices that fix and repair our parts of our body.The packaging and protection of these modern wonders of pharmaceuticaland medical technology are almost as important as the drugs themselves.Without packaging, drugs and medical devices would never leave a factory ora laboratory. Packaging provides containment, protection, and safe delivery ofproducts everywhere health care is needed and makes possible the availabilityand use of drugs, vaccines and medical devices in hostile environments. Itiii 5. iv Prefaceensures safe delivery of drugs and devices to accident scenes as easily as it doesto hospitals. Labels and information contained in packaging communicates andexplains to doctors, pharmacists, nurses, health care workers, and patients abouthow to use a product. It warns you of dangers and communicates how and whento take a drug, what is safe, what precautions to take, and what to avoid whenundergoing treatment. This is an amazing set of packaging tasks that few, if any,notice.Packaging is an emerging science and engineering discipline that touchespeople everywhere. A combination of natural sciences, engineering, materialsscience, and other social disciplines contribute to the design, development, anddelivery of products, not pharmaceuticals alone. It is a high-technology field thatwe count on everyday to deliver billions of safe, sterile, and easy-to-openpackages that touch every part of our lives.This book was written as an introduction to pharmaceutical packaging. Ithas been kept simple and accessible to the average reader with some technicaltraining in chemistry, physics, and engineering. It attempts to introduce you tothe many things beyond packaging that are part of the drug, dosage, andregulatory environment. It highlights many of the problems a packaging engineermust face when developing a package for a new product. It uses shortexplanations of drug composition and interaction with the body to help explainhow these issues answer many questions about packaging a drug or medicaldevice. It introduces many issues that are part of the normal compromises andquestions surrounding different drugs. It tries to highlight regulatory difficultiesby explaining some of the concerns and safeguards various regulations introduceinto the package, the product, and the process by which it is made. It provides ashort introduction to package-manufacturing processes and the many materialsused in pharmaceutical packaging.Hopefully, the book will help you understand the role packaging technol-ogyplays in pharmaceutical and medical device design and development. It triesto introduce you to several basic concepts of packaging.The book highlights concepts in chemistry, polymer science, packagingand other disciplines to help you understand the product, its composition, whatthe package must do to protect the product. It provides examples on how theproduct can change depending on its chemistry and the environment the packagemust withstand prior to delivery to the patient. It tries to provide you with apractical sense of how the package, the product, and the way it is manufacturedall play an important role in producing a safe sterile product.The book attempts to highlight the whats, whys, and hows that go intopharmaceutical packaging, and attempts to do this while explaining the inter-actionsbetween the drug or device and the package. It is an introduction to themany diverse skills and needs of pharmaceutical packaging. It highlightsthe diverse and complimentary skills employed by packaging professionalswho are great scientific generalists, that is, people who can combine science,engineering, materials, manufacturing, consumer issues, and societal issues like 6. Preface venvironmentalism into packaging. All of these factors are part of the inputneeded to deliver a drug or medical device in a safe and responsible way.Packaging has become a new stand-alone scientific and engineeringdiscipline within corporations.Regulation of drugs and medical devices by governments around the worldis a big part of packaging. Many reading this book will be surprised to discoverthe FDA and other regulatory agencies around the world are as critical of thepackaging and its performance as they are in examining the efficacy of the drugproduct.One liberty taken while writing this book is the use of the words drugand pharmaceutical as synonyms. Technically drug refers to the active pharma-ceuticalingredient in a product, and pharmaceutical refers to the finishedproduct. This means that the pharmaceutical is the product being packaged,not the drug.Hopefully, this book will provide some basic insight into an exciting andchallenging science that goes unnoticed by so many.Edward J. Bauer 7. ContentsPreface . . . . . . . iii1. Introduction to the Pharmaceutical Industry: An Overview . . . 1Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1General Aspects of Drug Packaging . . . . . . . . . . . . . . . . . . . . 1Brief History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3General Business Overview of the Pharmaceutical Industry . . . . . . . 6General Industry Challenges and Trends . . . . . . . . . . . . . . . . . 9The Evolution and Structure of the Pharmaceutical Business . . . . . 9Therapeutic Areas of Concentration . . . . . . . . . . . . . . . . . . . 11General Worldwide Pharmaceutical Trends . . . . . . . . . . . . . . . . . 12Cost and Pricing Trends . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Generic Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13OTC Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14Definition of a Drug . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14The Differences Between Pharmaceutical and Food Packaging . . . 15Drug Regulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18The Function of Packaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19Trends in Pharmaceutical Packaging . . . . . . . . . . . . . . . . . . . 20Current Trends in Packaging . . . . . . . . . . . . . . . . . . . . . . . . 20Influences Impacting Packaging . . . . . . . . . . . . . . . . . . . . . . 21Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292. Pharmaceutical Dosage Forms and Their PackagingRequirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32Chemical Change . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32Thermal Protection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36vii 8. viii ContentsChemical Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37Moisture ProtectionProtecting the API fromHydrolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38OxidationReactions with Oxygen . . . . . . . . . . . . . . . . . . . 40Light Protection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41Mathematical Methods and Accelerated Methods for AssessingShelf Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42Purity and Sterility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42Drug Purity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43Quality Assurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44Drug Sterility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45Drug Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48Oral Administration of Drug ProductsGastrointestinalMethods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48Direct Injection of Drug Products . . . . . . . . . . . . . . . . . . . . 50Topical Administration of Drugs, Transdermal Methods . . . . 51Topical Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51Administration of Drugs through Mucus Membranes,Inhalation, and Nasal Administration . . . . . . . . . . . . . . . . 52Rectal Administration of Drugs . . . . . . . . . . . . . . . . . . . . . . 54Dosage Forms of Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54Solids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55Liquids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75Gases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 913. Vaccines and Biologically Produced Pharmaceuticals . . . . . . 93Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93Biologic Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94Biologic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99Types of Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1094. Medical Foods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111History of Medical Foods . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112Regulatory Requirements of Medical Foods . . . . . . . . . . . . . . . 113Medical Foods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114Composition and Formulation of MedicalNutritional Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115Nutritionally Complete Products . . . . . . . . . . . . . . . . . . . . 117Nutritionally Incomplete Products . . . . . . . . . . . . . . . . . . . 118 9. Contents ixFormulas for Metabolic or Genetic Disorders . . . . . . . . . . . 118Oral Rehydration Solutions . . . . . . . . . . . . . . . . . . . . . . . . 118Enteral Packaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118Medical Food Administration to the Patient . . . . . . . . . . . . . . . 119Tube Feeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120Parenteral Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121Parenteral Formulations for Intravenous Feeding . . . . . . . . . . . 121Infant Formulas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124Prenatal Nutritional Products . . . . . . . . . . . . . . . . . . . . . . . . . . 127Juvenile Nutritional Products . . . . . . . . . . . . . . . . . . . . . . . . . . 127Medical Foods: Legislative Overview and Regulations . . . . . . . . 127Infant Formula Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . 129Manufacture of Infant Formula and MedicalNutritional Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130Retort Processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131Aseptic Processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133Cold Aseptic SterilizationAseptic Filtration . . . . . . . . . . . . . . 135Aseptic Manufacturing Equipment . . . . . . . . . . . . . . . . . . . . . . 137Aseptic Package Sterilization . . . . . . . . . . . . . . . . . . . . . . . . . . 138Mechanical Processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139Thermal Processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140Irradiation Processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140Chemical Processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140Combination Processes . . . . . . . . . . . . . . . . . . . . . . . . . . . 141Aseptic Packaging Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141Fill and Seal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141Erect, Fill, and Seal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141Form, Fill, and Seal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142Thermoform, Fill, and Seal . . . . . . . . . . . . . . . . . . . . . . . . 142Blow Mold, Fill, and Seal . . . . . . . . . . . . . . . . . . . . . . . . . 142Bulk Storage and Packaging . . . . . . . . . . . . . . . . . . . . . . . 143Basic Principles of Thermal Processing . . . . . . . . . . . . . . . . . . . 144Thermobacteriology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144Heat Exchange/Heat Transfer . . . . . . . . . . . . . . . . . . . . . . 147Deaeration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148Aseptic Surge Tanks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149Processing Authority . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149The U.S. FDA/CFSAN Grade A Pasteurized MilkOrdinance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151USDA Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152Sterilization Technologies Under Development . . . . . . . . . . . . . 153Future Trends . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1545. The Regulatory Environment . . . . . . . . . . . . . . . . . . . . . . . . 157Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157Stages in the Identification and Qualification of a Drug . . . . 159 10. x ContentsDrug Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160Preclinical Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161Investigational New Drug Review . . . . . . . . . . . . . . . . . . . . . . 162Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163Phase I Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163Phase II Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . 163Phase III Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . 164FDA Approval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165Post-Marketing Surveillance and Phase IV Studies . . . . . . . . . . . 165The Regulatory Arena . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166The United States Food and Drug Administration . . . . . . . . . . . 167A General Overview of the Drug Approval Process . . . . . . . . . . 170The Drug Packaging Approval Process . . . . . . . . . . . . . . . . . . . 171Current Good Manufacturing Practices . . . . . . . . . . . . . . . . . . . 173Validation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174Electronic Data Submission, Electronic SpecificationsSystems, Elimination of Paper Records 21 CFR Part 11Electronic Records . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176Change Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179Structured Product Labeling: Enterprise Content Management,Digital Asset Management . . . . . . . . . . . . . . . . . . . . . . . . . . 180The United States Pharmacopeia-National Formulary . . . . . . . . 183The United States Pharmacopeia Dictionary . . . . . . . . . . . . . . . 185Consumer Product Safety Commission . . . . . . . . . . . . . . . . . . . 185Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1876. Pharmaceutical Packaging Materials . . . . . . . . . . . . . . . . . . 189Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189Glass Pharmaceutical Packaging . . . . . . . . . . . . . . . . . . . . . . . . 192Glass Composition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192Types of Glass Used for Pharmaceutical Packaging . . . . . . . . . . 195USP Type I Glass . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196USP Type II Glass . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197USP Type III Glass . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197USP Designation NP Glass . . . . . . . . . . . . . . . . . . . . . . . . . . . 198Glass as a Pharmaceutical Packaging Material . . . . . . . . . . . . . . 198Metal Pharmaceutical Packaging . . . . . . . . . . . . . . . . . . . . . . . 200Tinplate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201Can Coatings for Tinplate and Aluminum Cans . . . . . . . . . 202Aluminum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202Metals as Pharmaceutical Packaging Materials . . . . . . . . . . . . . 203Aerosol Cans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205Plastic Pharmaceutical Packaging . . . . . . . . . . . . . . . . . . . . . . . 206Plastics Overview and Definition . . . . . . . . . . . . . . . . . . . . 206Introduction to Plastics . . . . . . . . . . . . . . . . . . . . . . . . . . . 208A Plastic Primer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208Polymer Descriptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212 11. Contents xiClasses of Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216Determinants of a Polymers Properties . . . . . . . . . . . . . . . . 218Chemical Attributes of Polymers . . . . . . . . . . . . . . . . . . . . . . . 219Chemical Bonding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219Molecular Shape and Intramolecular Forces . . . . . . . . . . . . 222Viscoelastic Behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225Physical Properties of Polymers . . . . . . . . . . . . . . . . . . . . . 227Temperature Dependence on Reaction Rates . . . . . . . . . . . . . . . 228Plastics as Drug Packaging Materials . . . . . . . . . . . . . . . . . . . . 229Density Differences/Consumer Preference forPlastic/Easy Handling . . . . . . . . . . . . . . . . . . . . . . . . . . 230Design Freedom . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231Plastic Disadvantages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231Chemical Inertness/Stress Cracking/Additives/ElectricalProperties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231Common Plastic Pharmaceutical Packaging Materials . . . . . . . . 232Polyethylene Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232High-Density Polyethylene . . . . . . . . . . . . . . . . . . . . . . . . . 234Low-Density Polyethylene . . . . . . . . . . . . . . . . . . . . . . . . . 235Linear Low-Density Polyethylene . . . . . . . . . . . . . . . . . . . . 235Polyethylene Restrictions in Drug Packaging . . . . . . . . . . . . . . . 237Other Ethylene Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238Ethylene Vinyl Acetate . . . . . . . . . . . . . . . . . . . . . . . . . . . 238Ethylene Acrylic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240Ionomers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241Ethylene Vinyl Alcohol . . . . . . . . . . . . . . . . . . . . . . . . . . . 242Polyvinyl Alcohol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244Polypropylene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245Catalyst Background for Ethylene and Propylene Polymers . . . . 248Polyvinyl Chloride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249Polyvinylidene Chloride Copolymers . . . . . . . . . . . . . . . . . . 252Fluoropolymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254Polystyrene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255Other Styrene-Modified Copolymers . . . . . . . . . . . . . . . . . . . . . 257Polyamides (Nylon) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258Polyester . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259Polyethylene Terephthalate . . . . . . . . . . . . . . . . . . . . . . . . 260Amorphous PET . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263Crystallized PET . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263PET Films . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264Glycol-Modified Polyester . . . . . . . . . . . . . . . . . . . . . . . . . 264Polyethylene Naphthalate . . . . . . . . . . . . . . . . . . . . . . . . . 264Polycarbonate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265Polyurethane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266Acrylonitrile Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267Rubbers and Elastomers . . . . . . . . . . . . . . . . . . . . . . . . . . 268Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271 12. xii Contents7. Medical Device Packaging . . . . . . . . . . . . . . . . . . . . . . . . . . 273Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273Regulation of Medical Devices . . . . . . . . . . . . . . . . . . . . . . . . . 275Medical Device Definitions and Testing Standards . . . . . . . . . . . 276510 (k) Pre-market Notification . . . . . . . . . . . . . . . . . . . . . 278Pre-market Approval of a Medical Device . . . . . . . . . . . . . . 279Good Manufacturing Compliance (CGMP) . . . . . . . . . . . . . 280Establishment Registration . . . . . . . . . . . . . . . . . . . . . . . . . 281Medical Device Reporting . . . . . . . . . . . . . . . . . . . . . . . . . 282Harmonization of Standards for Terminally Sterilized MedicalDevice PackagingUnited States and Europe . . . . . . . . . . . . 282An Overview of a Package Validation . . . . . . . . . . . . . . . . . . . . 285Major Elements of a Package Validation . . . . . . . . . . . . . . . . . . 288Validation Testing, Process Sampling, and Validation Reporting . . . . 289Sample Size Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290Test Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290Distribution Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291Accelerated Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292ISO Standards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2938. Container Fabrication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295Glass Containers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297Blow Molding of Glass Containers . . . . . . . . . . . . . . . . . . . 297Annealing and TreatingGlass Finishing . . . . . . . . . . . . . . 300Tubular Glass FabricationUSP Type I Glass . . . . . . . . . . 303Metal ContainersCans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305DrawRedraw Cans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308Draw and Iron Cans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309Welded CansThree-Piece Cans . . . . . . . . . . . . . . . . . . . . 311Metal Tubes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314Plastic Containers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314Bottles and Vials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315Thermoforming of Pharmaceutical Containers . . . . . . . . . . . . . . 320Blister Packaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320Large Thermoformed PackagesStrip, Tray, and ClamshellPackages for Medical Devices . . . . . . . . . . . . . . . . . . . . . 327Pouches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330Form, Fill, and Seal Bottles . . . . . . . . . . . . . . . . . . . . . . . . 336Plastic Tubes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339Laminated Tubes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3429. Sterilization Technology . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345Overview of Sterilization Requirements . . . . . . . . . . . . . . . . . . . 346 13. Contents xiiiHeat Sterilization Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . 352Sterilization Using Steam and Pressure (Autoclave) . . . . . . . 352Sterilization by Boiling . . . . . . . . . . . . . . . . . . . . . . . . . . . 355Dry Heat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356Other Heat Sterilization Methods . . . . . . . . . . . . . . . . . . . . 356Chemical Sterilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357EtO Sterilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357Other Chemical Sterilants . . . . . . . . . . . . . . . . . . . . . . . . . 365Radiation Sterilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368g-Ray Sterilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368X-Rays and Electron Beam (E-Beam) Sterilization . . . . . . . . 373UV Light . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375Sterile Filtration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376Regulatory Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376Monitoring Sterilization Processes . . . . . . . . . . . . . . . . . . . . . . 382Mechanical, Chemical, and Biologic Indicators . . . . . . . . . . 382Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38510. Container Closure Systems: Completing All Types of FilledPharmaceutical Containers . . . . . . . . . . . . . . . . . . . . . . . . . . 387Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387Closure Functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389Protection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390Containment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390Complete and Positive Sealing . . . . . . . . . . . . . . . . . . . . . . 390Access (The Ability to Open and Close a Package Repeatedlyand Safely) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390Consumer Communication . . . . . . . . . . . . . . . . . . . . . . . . . 391Display . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391Metering and Measuring . . . . . . . . . . . . . . . . . . . . . . . . . . 392Types of Closures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393Closures for Metal Cans . . . . . . . . . . . . . . . . . . . . . . . . . . 393Bottles and Jars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395Threaded Closures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395Friction-Fit Closures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399Crown Closures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399Snap-Fit Closures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400Press-on Vacuum Caps . . . . . . . . . . . . . . . . . . . . . . . . . . . 400Vial Stoppers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401Flanged Plug Elastomeric Stoppers . . . . . . . . . . . . . . . . . . . 401Flanged Hollow Plug with Cutouts for Lyophilized Products . . 402Flanged Elastomeric Plug with Plastic Overseal . . . . . . . . . . 403Metal Closure with an Elastomeric Disk . . . . . . . . . . . . . . . 403Elastomeric Closure Performance . . . . . . . . . . . . . . . . . . . . 403Tube Closures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405Specialty Closures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405Dispensing Closures and Closures with Applicators . . . . . . . 406Fitment Closures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407 14. xiv ContentsSpray and Pump Dispensers . . . . . . . . . . . . . . . . . . . . . . . . . . . 407Single-Dose Closures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408Compliance (Adherence) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409Closure Liners . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410Composition of Closure Liners . . . . . . . . . . . . . . . . . . . . . . . . . 411Linerless Closures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412Child-Resistant Closures . . . . . . . . . . . . . . . . . . . . . . . . . . 412Child-Resistant Testing of ClosuresAn Overview . . . . . . . . . . 417Design of Child-Resistant Closures . . . . . . . . . . . . . . . . . . . . . . 420Combination Closures . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421Aerosol Closures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421Non-reclosable Packages . . . . . . . . . . . . . . . . . . . . . . . . . . 421Pouches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421Tamper-Evident Packaging Closures . . . . . . . . . . . . . . . . . . 422Ease of Opening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425Capsule Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425Heat Sealing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426Peelable Seals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43011. Labels and Labeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433History of Drug Labels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435Labeling Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435Prescription Drug Labeling . . . . . . . . . . . . . . . . . . . . . . . . 435Label Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437Drug Facts LabelingOTC Pharmaceutical Products . . . . . 443NDC NumberThe National Drug Code . . . . . . . . . . . . . . . . . 447Label Construction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448Types of Labels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448Label and Package Printing . . . . . . . . . . . . . . . . . . . . . . . . 454Overview of Bar Code Administration: GS1 Designations . . . . . . 469Universal Product Code Numbers . . . . . . . . . . . . . . . . . . . . . . 470The Global Trade Item Number . . . . . . . . . . . . . . . . . . . . . . . . 472Bar Codes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 474GS1 Standards Organization . . . . . . . . . . . . . . . . . . . . . . . . . . 477EAN International Article Numbering Associationand UCC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477Two Dimensional Codes (2-D Data Matrix and otherMatrix Codes) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479RSS Codes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484RSS-14 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485RSS Limited . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486RSS Expanded . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486Composite Components of the Codes . . . . . . . . . . . . . . . . . 487Composite Code A (CC-A) . . . . . . . . . . . . . . . . . . . . . . . . 487 15. Contents xvComposite Code B (CC-B) . . . . . . . . . . . . . . . . . . . . . . . . . 487Composite Component C (CC-C) . . . . . . . . . . . . . . . . . . . . 487Code Category Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 488Narrow-Width Bar Code Symbologies . . . . . . . . . . . . . . . . 488Pulse-Width Modulated Bar Code . . . . . . . . . . . . . . . . . . . 489Multi-Width Modular Codes . . . . . . . . . . . . . . . . . . . . . . . 489References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49012. Issues Facing Modern Drug Packaging . . . . . . . . . . . . . . . . . 493Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493Compliance or Adherence to Drug Regimens . . . . . . . . . . . . . . 496Unit Dose Packaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501Anticounterfeiting Packaging . . . . . . . . . . . . . . . . . . . . . . . . . . 505Detailed Product Information . . . . . . . . . . . . . . . . . . . . . . 510Transaction Details . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 510Environmental Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 511Packaging and the Environment . . . . . . . . . . . . . . . . . . . . . 512United States Recycling Programs . . . . . . . . . . . . . . . . . . . 516Collection Methods for Recycling . . . . . . . . . . . . . . . . . . . . 518European Recycling Programs . . . . . . . . . . . . . . . . . . . . . . 521Plastic Packaging and the Environment . . . . . . . . . . . . . . . . 523Recycling Rates for Plastic Packaging . . . . . . . . . . . . . . . . . 523U.S. Municipal Solid Waste: An Overview . . . . . . . . . . . . . 524Infectious Waste . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524Biodegradable Plastics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525Biodegradable Materials . . . . . . . . . . . . . . . . . . . . . . . . . . 527Starch-Based Plastics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 527Lactic Acid Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . 528Polyesters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 529Other Biodegradable Polymers . . . . . . . . . . . . . . . . . . . . . . 530Naturally Occurring Biodegradable Polymers . . . . . . . . . . . 531Other Pharmaceutical Packaging Issues . . . . . . . . . . . . . . . . . . . 532References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 534Glossary of Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 537Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 561Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 565 16. 1Introduction to the PharmaceuticalIndustry: An OverviewINTRODUCTIONGeneral Aspects of Drug PackagingPackaging pharmaceutical products is a broad, encompassing, and multi-facetedtask. It differs substantially from food packaging and is equally as challenging. Itrequires the application of a large amount of scientific and engineering expertiseto deliver a product for a world market. Its practice focuses on information andknowledge from a wide range of scientific disciplines, including chemistry,engineering, material science, physical testing, sales, marketing, environmentalscience, and regulatory affairs to name just a few. This broad general backgroundis needed for the design and development of each and every product produced bythe pharmaceutical industry. Packaging is responsible for providing life-savingdrugs, medical devices, medical treatments, and new products like medicalnutritionals (nutraceuticals) in every imaginable dosage form to deliver every typeof supplement, poultice, liquid, solid, powder, suspension, or drop to people theworld over. It is transparent to an end user when done well and is open to criticismfrom all quarters when done poorly. Everyone is a packaging expert, and this isparticularly true when one evaluates how something designed to help a personhinders his or her ability to use the product. This book will discuss in detail themany forms of pharmaceutical packaging. It wont describe each and every one,but it will describe the broad families of packaging designed to deliver the manydifferent and unique forms of a product or products to a patient. It will provide anintroduction to some of the chemistry of pharmaceutically active molecules andhow they must be protected from the environment and from the package itself. Itwill touch upon the packaging of nutritional products and supplements that are1 17. 2 Chapter 1slightly removed from the normal realm of pharmaceutical products but arebeginning to play a bigger role in the overall treatment of disease.Packaging for biologic products can involve a slightly different set ofrequirements, and some of the unique differences and problems for packaginggenetically modified biologically produced products are noted.Pharmaceuticals use a wide variety of sterilization techniques that varysignificantly from those used for foods. An introduction to some of these con-ceptswill touch upon the multiple sterilization processes and the problems theypresent to the design of drug and device packaging.Distribution of products is now more global than ever. Mass customizationof packaging to permit its use in multiple markets is a topic that needs expositionand discussion.Environmental issues, including sustainability, will always be a subjectivedimension to any packaging design. These topics and many others highlight thebreath of knowledge a packaging engineer must master when developing andproducing a widely acceptable product.This is a lot of ground for any book to cover. Hopefully it will provide youwith a ready reference replete with examples that provide a starting point for design,development, testing, and execution of a new package for any pharmaceutical product.The book also provides an introduction to over-the-counter (OTC) pack-agesand products. These are the medicines we keep in our homes and manytimes carry with us to relieve unpleasant symptoms of things we think of asannoyances to everyday life, like the common cold, or for treatment of commonconditions, including rashes, cold sores, dry eyes, and other minor problems.It will discuss labeling, and how copy and artwork are prepared for alltypes of packaging. Artwork typically sells a product in the OTC context; art-workcreates a feeling about a product, an identity, and in some cases creates inthe consumers mind a reason to choose one product over another.Amazing, isnt it? So many different requirements, so many facets topackaging, so many scientific, cultural, sociological, and environmental needs.Oh, and by the way, it also has a large regulatory and legal requirement that isoutside all of the things mentioned above.Packaging is an emerging science, an emerging engineering discipline, anda success contributor to corporations. Surprisingly it is something that fewcorporations have singled out as a stand-alone department or organization.Packaging can reside, or report through research and development (R&D),engineering, operations, purchasing, marketing, or the general administrativedepartment of a company. For the majority of products produced in the food andpharmaceutical industries it is probably the single largest aggregate purchasemade by a company of materials critical to the protection, distribution, and saleof the product. Hopefully the contents of this text will provide a new appreci-ationof how important and complex pharmaceutical packaging is, not just thetraditional expectations of product protection. 18. Introduction to the Pharmaceutical Industry: An Overview 3BRIEF HISTORYThe global pharmaceutical business is one of the most dynamic, research-intensive,and innovative businesses in the world. Todays pharmaceuticalindustry began to emerge in the mid to late 19th century as a small and uniquesubset of the chemical industry. For most of the 20th century, the pharmaceuticalbusiness paralleled developments in synthesis, catalysis, and manufacturing thatwere outgrowths of the larger chemical business. Before World War II, advancesin chemistry and chemical engineering from Europe, particularly from Germany,drove both the worldwide chemical industry and the smaller pharmaceuticalcompanies. The United States developed its own group of companies that, withonly a few notable exceptions, concentrated on the U.S. market, while theEuropeans, particularly the Germans, expanded abroad and also set up operationsin the United States. The United States and Europe became the two centers of thechemical industry and developed in parallel, as they expanded to meet thegrowing demand for chemical products in the markets of concentration. Twoexamples of European influence on U.S. pharmaceutical companies are Pfizerand Merck, both of which have German heritage. Another example of Europeaninfluence is seen in one of the largest, best-known products in the United States,aspirin, which came from Bayer1, another German company. In fact, aspirin wasprobably the first of what we would today call a blockbuster drug.At the end of World War II, the American chemical industry emerged asthe dominant force in the world. The U.S. companies exploited the wealth ofnatural resources available in the United States, and the large volume ofknowledge gained from wartime research into rubbers, plastics, and other relatedchemical and engineering technologies and used that knowledge to expandworldwide.The pharmaceutical companies followed the same path of expansion, whilebeginning to develop the unique chemical, chemical engineering, and manu-facturingknowledge necessary to produce pharmaceutical ingredients and bringthese unique products to market. The world war also produced a burst ofknowledge about the production and manufacture of biologic products, notablypenicillin. During this period, the United States also began to produce world-classscientific talent necessary to build and sustain the pharmaceutical industryand develop world-class facilities for the development of scientific knowhow inboth industry and the universities. The talent was augmented by many emigresfrom Europe.The pharmaceutical industrys strength and reliance on chemistry alonebegan to change in the 1970s when an entirely new way of developing phar-maceuticalsemerged. The new technology was a combination of biology,chemistry, biochemistry, and new cell modification and manufacturing tech-nologiescalled biotech. This breakthrough technology challenged the traditionalway of identifying and developing pharmaceutical products. Genentech was thefirst company to establish an identity in biotech. It was founded by a geneticist, 19. 4 Chapter 1Herb Boyer, and began operations in the San Francisco Bay Area during the mid-1970s. Amgen, located in Thousand Oaks California, followed shortly after andwas the first of the new biotech companies to introduce a biologically derivedpharmaceutical product. These two early leaders not only changed the waypharmaceuticals were developed, they also ushered in a new way of developingpharmaceutical products using genetics, molecular biology, and biochemistrythat when combined produced a genetic engineering approach to the treatment ofdisease. This change in approach has produced a fast and remarkable change inthe pharmaceutical companies core competencies. They have transformedthemselves into biopharmaceutical companies.The primary method the pharmaceutical industry used for drug devel-opmentduring most of the 20th century was to study the chemical reactions ofvarious chemical molecules within the body. The molecules under study camefrom a variety of sources, both natural and synthetic. Extraction of activechemical ingredients from plants and animals known or identified to exhibitbiologic activity is one way the development process progressed. Modifyingnew or existing chemical entities with human biologic activity was anotherway the pharmaceutical manufacturers produced compounds and then studiedthem for their effects in the body to determine efficacy against a disease. Mostof the identifications of biologic reactions were carried out in cell cultureexperiments and in animal studies. This approach relied on chemistry andbiochemistry and served the companies well. This approach and method ofdiscovery produced the remarkable array of chemical products we take forgranted today.Going back to the World War II timeframe (19421945) another form ofproduct development was taking shape for pharmaceutical products. The type ofdevelopment was the growth and harvesting of a biologic agent that was thenconverted to a pharmaceutical product. The best example of this development ispenicillin, a product produced from a mold and became the worlds first greatantibiotic. Penicillin required the development of many of the biologic manu-facturingprocesses needed to grow the mold that produces the active pharma-ceuticalingredient. It then required the development of unique chemistries,chemical engineering, and manufacturing skills to extract, purify, and producethe product. These traditional chemical methods and processes, which were thecore strengths of the pharmaceutical companies, were applied to turn the raw,dilute material into the injectable and later the oral penicillin product we knowtoday. This traditional path of product development was superseded in the lasttwo decades of the 20th century by biotechnology.Biotechnology is the term applied to developments that come from thecombining of biochemistry, molecular biology, genetics, and immunology intopharmaceutical product development and manufacturing. This merging of twodistinct sets of scientific disciplines, chemistry and molecular biology, hasproduced a powerful research engine that creates treatments for disease unknownonly a few years ago. This merger of disciplines has changed the way traditional 20. Introduction to the Pharmaceutical Industry: An Overview 5pharmaceutical companies approach drug research. Biotech permits a targetedapproach to the development of products, and when combined with computa-tionalchemistry, computer assisted synthesis, and a wide range of analyticaltools, it gives pharmaceutical companies the ability to study compounds, pro-teins,enzymes, and other biologically active materials in the minutest detail. Allof the major pharmaceutical companies now have their own biotechnologycapabilities or have partnered with others to acquire this competency. Thiscombination of scientific methods has opened many exciting opportunities forthem and has enhanced the investments made in R&D of their core strengths ofchemistry, chemical engineering, and manufacturing. The real name for theindustry, and one that it is beginning to adopt in its trade literature, is thebiopharmaceutical industry.It is interesting to note that both Genentech and Amgen see themselves aspharmaceutical companies, not biologic companies. Amgen brought to marketthe first genetically derived drugs, and Genentech has a major drug pipeline ofnew products in various stages of development. Eli Lilly and Company led thetraditional pharmaceutical companies when they introduced their first bio-technologyproducts in the early 1990s. Lilly introduced the first human healthcare product using recombinant DNA technology. The modern pharmaceuticalindustry and parts of the chemical industry now rely on the many advances in thebiologic sciences and other key related technologies being led by pharmaceuticalcompany investments in basic science, disease specific research, genetics,computer technology, and other supporting technologies, including packaging,that enable the laboratory discoveries to proceed to commercial products.The U.S. government also funds R&D at the National Institutes of Healthas part of the drug discovery effort [Fig. 1 graph). These funds are in addition tothe R&D dollars spent by pharmaceutical companies.Pharmaceutical companies break their research budgets into two parts:basic research and applied R&D. Research spending by U.S. domestic phar-maceuticalcompanies (Table 1) is indicative of pharmaceutical researchworldwide. In 2003, 38% of their budgets went into the basic research and 58%went into applied R&D.The reach of the pharmaceutical industry is enormous and its impact on apeoples lives everywhere is profound. Today diseases that killed millions areroutinely treated with antibiotics. Death sentences from diseases like AIDS andleukemia have been put off to the point that these diseases are now treated aslong-term chronic problems because modern pharmaceutical products put theminto long-term remission. The U.S. death rate from AIDS has fallen by 70%since the mid-1990s with the introduction of protease inhibitors (1). Over thepast two decades, the chances of surviving cancer for five years after diagnosishas improved by 10% and stands at 62% today (2). Our understanding of thesediseases, resulting from the science that underpins all of the pharmaceuticalindustry, will continue to lead the way to a brighter, longer-lived, and healthierfutures for countless people. 21. 6 Chapter 1Figure 1 Drug discovery from laboratory to patient.Table 1 Domestic R&D Spending by Type PhRMA Member Companies: 2003Type Expenditure ($) Share (%)Basic and applied research 10,382.6. 38.4Development 15,766.2 58.3Uncategorized 916.1 3.4Domestic R&D total 27,064.9 100.0Source: From Ref. 8.GENERAL BUSINESS OVERVIEW OF THE PHARMACEUTICAL INDUSTRYPharmaceutical products are a very big business. Global sales reached $491.8 billionin 2003 (3). More than 400,000 people go to work each day for a pharmaceuticalcompany in the United States (4). Pharmaceutical companies, or, more correctly,biopharmaceutical companies have a significant impact on our nations economy.Each job in the pharmaceutical industry produces many others. Economistsapplying the normal multiplicative effect on the jobs number, estimate the totalreach of the pharmaceutical industry was 2.7 million jobs and $172 billion in realoutput to the U.S. economy in 2003 (4). This output with these related jobs createsa significant addition of 2.1% of total employment in the U.S. economy (4).Scientists in the United States lead the world in the discovery and devel-opmentof new medicines. This is due in no small part to the tremendousinvestments the pharmaceutical companies make in research and development(Table 2). Research spending by the Pharmaceutical Research and ManufacturersAssociation (PhRMA) companies totaled $39 billion in a 2004 estimate made bythis trade organization. It also estimates the total research spending for 22. Table 2 Research and Development Spending Worldwide 19702004 (PharmaceuticalResearch and Manufacturers of America [PhRMA] Member Companies Domestic R&Dand R&D Abroad Total Spending)YearDomesticR&D ($ inmillions)AnnualpercentagechangeR&DabroadbAnnualpercentagechangeTotalR&D($ in millions)Annualpercentagechangea2004 30,643.9 13.2 8,150.3 10.3 38,794.2 12.62003 27,407.1 6.8 5,808.3 8.4 33,215.4 7.12002 25,655.1 9.2 5,357.2 13.9 31,012.2 4.22001 23,502.0 10.0 6,220.6 33.3 29,772.7 14.42000 21,363.7 15.7 4,667.1 10.6 26,030.8 14.71999 18,471.1 7.4 4,219.6 9.9 22,690.7 8.21998 17,127.9 11.0 3,839.0 9.9 20,996.9 10.81997 15,466.0 13.9 3,492.1 6.5 18,958.1 12.41996 13,627.1 14.8 3,278.5 1.6 16,905.6 11.21995 11,874.0 7.0 3,333.5 c 15,207.4 c1994 11,101.6 6.0 2,347.8 3.8 13,449.4 5.61993 10,477.1 12.5 2,262.9 5.0 12,740.4 11.11992 9,312.1 17.4 2,155.8 21.3 11,467.9 18.21991 7,928.6 16.5 1,776.8 9.9 9,705.4 15.31990 6,802.9 13.0 1,617.4 23.6 8,420.3 14.91989 6,021.4 15.0 1,308.6 0.4 7,330.0 12.11988 5,233.9 16.2 1,303.6 30.6 6,537.5 18.81987 4,504.1 16.2 998.1 15.4 5,502.2 16.11986 3,875.0 14.7 865.1 23.8 4,740.1 16.21985 3,378.7 13.3 698.9 17.2 4,077.6 13.91984 2,982.4 11.6 596.4 9.2 3,578.8 11.21983 2,671.3 17.7 546.3 8.2 3,217.6 16.01982 2,268.7 21.3 505.0 7.7 2,773.7 18.61981 1,870.4 20.7 469.1 9.7 2,339.5 18.41980 1,549.2 16.7 427.5 42.8 1,976.7 21.51979 1,327.4 13.8 299.4 25.9 1,626.8 15.91978 1,166.1 9.7 237.9 11.6 1,404.0 10.01977 1,063.0 8.1 213.1 18.2 1,276.1 9.71976 983.4 8.8 180.3 14.1 1,163.7 9.61975 903.5 13.9 158.0 7.0 1,061.5 12.81974 793.1 12.0 147.7 26.3 940.8 14.01973 708.1 8.1 116.9 64.0 825.0 13.61972 654.8 4.5 71.3 24.9 726.1 6.21971 626.7 10.7 57.1 9.2 683.8 10.61970 566.2 52.3 618.5 Average 12.5 16.1 13.0Note: All figures include company-financed R&D only. Total values may be affected by rounding.aEstimatedbR&D abroad includes expenditures outside the United States by U.S.-owned PhRMA membercompanies and R&D conducted abroad by the U.S. divisions of foreign-owned PhRMA membercompanies. R&D performed abroad by the foreign divisions of foreign-owned PhRMA membercompanies is excluded. Domestic R&D, however, includes R&D expenditures within the UnitedStates by all PhRMA member companies.cR&D abroad affected by merger and acquisition activity.Source: From Ref. 8. 23. 8 Chapter 1pharmaceutical and biotech research to be $49.3 billion when the estimates fornon-PhRMA members are added to the members total. As a percentage of sales,the total for PhRMA members is 18.3% of U.S. domestic sales and 15.9% ofsales worldwide (Table 3) (5).Table 3 R&D as a Percentage of Sales PhRMA Member Companies: 19702004YrDomestic R&D as a percentageof domestic sales (%)Total R&D as a percentageof total sales (%)2004a 18.3 15.92003 18.3 15.72002 18.4 16.12001 18.0 16.72000 18.4 16.21999 18.2 15.51998 21.1 16.81997 21.6 17.11996 21.0 16.61995 20.8 16.71994 21.9 17.31993 21.6 17.01992 19.4 15.51991 17.9 14.61990 17.7 14.41989 18.4 14.81988 18.3 14.11987 17.4 13.41986 16.4 12.91985 16.3 12.91984 15.7 12.11983 15.9 11.81982 15.4 10.91981 14.8 10.01980 13.1 8.91979 12.5 8.61978 12.2 8.51977 12.4 9.01976 12.4 8.91975 12.7 9.01974 11.8 9.11973 12.5 9.31972 12.6 9.21971 12.2 9.01970 12.4 9.3aEstimated.Source: From Ref. 8. 24. Introduction to the Pharmaceutical Industry: An Overview 9Table 4 Size of Pharmaceutical MarketsCountrySales to June 2005($ billions)Share of globalsales (%)12-mochangea(%)United States 246.4 44.7 7Japan 60.0 10.9 3Germany 31.2 5.7 6France 30.3 5.5 7United Kingdom 20.3 3.7 3Italy 19.4 3.5 0Spain 14.8 2.7 8Canada 12.7 2.3 10China 8.6 1.6 30Mexico 6.9 1.3 11Top 10 markets 450.6 81.9 6Note: Sales in the United States are for the 12 months ending in June 2005.aBased on local currencies.Source: Ref. 10.Pharmaceuticals are extremely cost efficient when compared with otherforms of treatment for disease. Every dollar spent on new medicines reduces thecost of hospitalizations by $4.44 (5) (Table 4). These new medicines alsoaccounted for over 40% of the two-year gain in life expectancy achieved in52 countries between 1986 and 2000 (6). The next time you wonder about whatthe pharmaceutical industry is doing for you, ask yourself the following question:What is the value of those two additional years of life?General Industry Challenges and TrendsThe pharmaceutical industry is facing many challenges. The cost of developingnew drugs continues to grow. During the 1970s, the cost of bringing a new drugto approval by the U.S. Food and Drug Administration (FDA) was approximately$138 million. Today the cost of bringing a drug to approval by the FDA is morethan $800 million (7). A diagram of the cost and timing to bring a drug to markethighlights how difficult this process can be (Fig. 2). The potential legal liability,particularly in the United States, when something goes wrong is another enor-mousproblem all of the companies face. Wyeth faced billion-dollar liabilities forits diet drugs Pondamin1 and Redux1, and Merck faced large liabilities from itswithdrawal of Vioxx1 in 2004.THE EVOLUTION AND STRUCTURE OF THE PHARMACEUTICALBUSINESSThe structure of the industry and the makeup of companies have undergone a rapidtransformation in the last decade, and this process continues at an accelerated pacetoday. Companies have merged or have been acquired to form significantly larger 25. 10 Chapter 1Figure 2 Biopharmaceutical expenditures and the NIH budget.companies that may be newly named or may retain their traditional name.Remarkably, even after all the merger activity and changes in the shape of thepharmaceutical business landscape the largest company, Pfizer, only controlsabout 10% of the total U.S. market (based on 2003 sales) (Table 5) (9).Another market force changing the appearance and development of phar-maceuticalsis generic drug products. These products, the same chemical entity oractive pharmaceutical ingredient (API) developed by the innovating company, areproduced by many companies after the original innovators patents have expired.Without the high cost of R&D, the competitor can offer the products for sale atsignificantly reduced prices. The number of new products with profiles that showsignificant improvement over older drugs is slowing; so generic products in manycases remain the standard of care for the treatment of many ills. A number of themajor pharmaceutical companies actively support a dual strategic approach toproduct offerings and complement their new drug development with a genericdrug supply strategy. These products not only produce significant revenues, they 26. Introduction to the Pharmaceutical Industry: An Overview 11Table 5 Top 10 Pharmaceutical Companies: Five-Year Merger HistoryCompany Market ShareBased on 2003sales (%)Based on 1998sales (proforma) (%) Major component companiesPfizer 10.1 9.0 Pfizer, Pharmacia, Upjohn,also provide the volume manufacturing needed for many raw materials andstarting ingredients, used in both new and generic products, to maintain manu-facturingcosts at a reasonable level. The products also provide significant volume,which is needed in most investment models to pay for the expansion or mainte-nanceof existing manufacturing capacity.Therapeutic Areas of ConcentrationWhat are the disease-specific areas now receiving the most concentratedinvestigation? What areas of treatment have produced the most successfulproducts? What ills touch the majority of people in the world, and because of thelarge patient populations, attract the research and capital needed to understandand treat them? The top 10 therapies based on dollar sales encompass aremarkable set of problems (Table 6). Listed below are the conditions that havemajor effects on peoples health. The top 10 therapeutic treatments based onsales fall into these categories (9):1. Cholesterol and triglyceride reducers2. Antiulcerants3. Antidepressants4. Antipsychotics5. Antirheumatic nonsteroidalsWarner-Lambert, SearleGlaxoSmithKline 6.6 7.2 Glaxo, Wellcome, SmithKlineFrench, BeechamSanofiAventis 5.4 5.8 Sanof, Synthelabo, Hoechst,RhonePoulenc, FisonsMerck & Co. 4.8 4.2Johnson & Johnson 4.8 3.6Novartis 4.3 4.2 Ciba-Geigy, SandozAstraZeneca 4.1 4.3 Astra, ZenecaBristolMyersSquibb3.4 4.2 BristolMyers Squibb,Dupont PharmaRoche 3.3 3.1Abbott 2.8 3.3 Abbott, BASF Pharma (Knoll)Top 10 corporations 49.6 48.9Source: Ref. 11. 27. 12 Chapter 1Table 6 Top 10 Therapies Based on Global Sales of the Pharmaceutical ClassTherapeutic typeSales to June 2005($ billions)Cholesterol andtriglyceride reducersAntiulcerants 26.3 4.8 3Antidepressants 20.1 3.6 3Antipsychotics 15.5 2.8 11AntirheumaticnonsteroidalsCalcium antagonists,plainErythropoietins 11.7 2.1 9Antiepileptics 11.4 2.1 15Oral antidiabetics 10.4 1.9 6Cephalosporins 9.9 1.8 30Top 10 therapies 160.9 29.2 5Note: All therapy classes are World Health Organization code groups. Sales are US dollars for the12 months ending June 2005.Source: Ref. 10.6. Calcium antagonists, plain7. Erythropoietins8. Antiepileptics9. Oral antidiabetics10. CephalosporinsShare ofglobal sales (%)12-mochange (%)31.6 5.7 1012.1 2.2 611.9 2.2 2As the list clearly shows, a large number of people have debilitatingconditions that, when left untreated, significantly reduce the quality of life andlife expectancy. Drugs targeted at heart disease are number 1 on the list. Thetherapies created for these disease-states and those not on the list permit all of usto lead functional productive lives that would not be possible without them.The top 10 drugs had sales in excess of $55 billion. Seven of the top fiftyproducts were biotechnology products with combined sales of $15.1 billion. (10)GENERAL WORLDWIDE PHARMACEUTICAL TRENDSPossibly the biggest challenge facing the pharmaceutical and the health careindustries in general is the role the government will play in determining the costof pharmaceuticals, devices, and treatments for diseases. The United States is theonly market in the world that does not have general government price controls. Itis also the most heavily regulated market, and the market pharmaceuticalcompanies typically target their drug-approval strategy and development foracceptance and approval by the FDA. 28. Introduction to the Pharmaceutical Industry: An Overview 13Cost and Pricing TrendsEurope and Japan have led the way in restricting and regulating the cost ofpharmaceuticals. This has created problems for pharmaceutical companies intheir countries, which if emulated, may also create problems in the United States.Japan has taken a number of steps to restrain drug prices and has been able toreduce total government spending on pharmaceuticals. This restraint has reducedtotal health care spending in Japan on pharmaceuticals from 30% of the total costof health care in the early 1990s to approximately 20% today (9). The Japaneseimpose biennial price cuts on all products to limit annual cost growth of phar-maceuticalsin Japan to 3% annually.Europe has a number of plans and schemes to limit the cost of pharma-ceuticals.With the formation of the European Union (EU), the concept of paralleltrade has created problems for the pharmaceutical manufacturers. Parallel trade isthe practice of purchasing goods in the cheapest countries and selling them in themost expensive. European commission laws permit the movement of goods fromone member state to another without restriction. This means that drugs priced inthe lowest-cost countries (Eastern Europe) can be moved to the higher-costcountries, i.e., the United Kingdom, Germany, France, and Scandinavia. The EUexpanded by 10 countries in May 2004, and many of these countries had stronggeneric pharmaceutical industries that will take advantage of these higher-costmarkets. Germany is the largest market for drugs in the EU. During 2004, theyimposed a compulsory discount of 16% on all manufacturers. That discount wasup from 6% in 2003. The move applied to all drugs not part of the countrysreference price scheme. This is one example of variants being enacted in the othercountries. The most notable feature of the controls limits the price of a brand nameor patented drug to the same cost as nonpatent medications if the new products arejudged equal in treatment or outcome to their generic product equivalents. Anexample of this method of classifying patented and generic products is a ruling onthe overall effectiveness of drugs called statins, which are used for treatment andreduction of cholesterol levels. As one statin loses patent protection, all otherproducts, including all products still on patent, lose it as well in terms of productpricing. All of these schemes have caused most of the companies in Europe torethink their research strategies, and a number have relocated research to theUnited States or have canceled expansions in Europe to focus on producingproducts for markets that pay for the cost of discovery (11).Generic ProductsAnother major trend that will affect the pharmaceutical companies and phar-maceuticalpackaging is the growing use of generic drugs. One of the Europeanpharmaceutical companies, Novartis, has adopted a generic strategy, betting thatdollar volume and manufacturing volume will increase more in this area than inthe development of new blockbuster products. Generic drug introductions areat an all-time high, and this trend will continue. 29. 14 Chapter 1Generics account for approximately 30% of the total volume of drugsdispensed for use but only produce 10% of the global sales revenues (9). Brandedproducts lose sales very rapidly after a generic analogue is introduced. This andthe fact that so many blockbuster drugs from the 1990s are losing patent pro-tectionin the next few years means generics will be a bigger and bigger part ofthe prescription drug landscape.For packaging, the updating and maintaining of materials and labeling forgenerics will become more and more prominent in the mix of responsibilities.Packaging will work with marketing and sales to begin to develop genericidentities for the off-patent products.OTC ProductsThe pharmaceutical companies have also pushed for and accepted the fact thatmany products that require a prescription at introduction will eventually beoffered over the counter at pharmacies. In the United States, a wide range ofproducts, from prescription painkillers to female hygiene products, have madethe transition from prescription (Rx Only on new labeling in the United States)to OTC items. Both generic and branded products will be part of this trend toOTC sales. The trend toward OTC presentations of products is not limited to theUnited States. Merck and JohnsonJohnson pursued a joint venture in theUnited Kingdom for OTC sales of the drug Zocor1. This product, a prescription-onlydrug called a statin and used for lowering cholesterol, was launched as anOTC item in July 2004. Packaging a prescription (Rx) product for OTC saleswill be a major responsibility for packaging departments, and as volume growsmore emphasis will be placed on designing, developing, and delivering theseformerly doctor-directed drugs as consumer products. The responsibility ofpackaging will be twofold. First, it must convey and provide a simple commu-nicationto the user on how to use the product. This may be in the form of howthe drug is presented to the consumer on a numbered blister or some moreelaborate symbolic presentation for the user that transcends language. Second,packaging will become increasingly involved in the labeling and attendant lit-eraturethat is needed for OTC products. This labeling and the methods needed toupdate its content is a major new responsibility that is outside standard structuralpackaging development.DEFINITION OF A DRUGThe FDA is very specific about what constitutes a drug. This level of control isevident in the way biologic products, originally regulated by the Center forBiologic Evaluation and Research (CBER), was moved under the jurisdiction ofthe Center for Drug Evaluation and Research (CDER). These two branches ofthe FDA work in tandem with each other to evaluate, review, and ultimatelyapprove a drug or biologic product for human use. The fact that the biologic 30. Introduction to the Pharmaceutical Industry: An Overview 15product has therapeutic activity makes it subject to the strict interpretation of theFederal Food Drug and Cosmetic Act of 1938, which has been and continues tobe amended as needs and technology change. The Act (12) defines a drug asfollows:A. Articles recognized in the official United States Pharmacopoeia (USP),Official Homeopathic Pharmacopoeia of the United States or the officialNational Formulary or any supplement to any of them.B. Articles intended for use in the diagnosis, cure, mitigation, treatment, orprevention of disease in man or other animals: andC. Articles (other than food) intended to affect the structure or any function ofthe body of man or other animals; andD. Articles intended for use as a component or any article specified in clause(A), (B), or (C); but does not include devices or their components, parts, oraccessories.Medical devices, another large portion of the medical industry, are treatedin a separate chapter in this book. They have their own packaging and technicalchallenges that are in many ways similar but distinct in their treatment andevaluation by the agency. Food products with pharmaceutical claims and thosethat require review and approval by the FDA also must meet the review processalbeit at different levels, depending on the claims being made.Unique food products such as infant formula and medical nutritional foodsand food supplements that help manage certain diseases receive high levels ofscrutiny. Other products covered in the Act are cosmetics, and these products aremaking claims that in some cases are becoming more like drugs. Cosmeticproducts are not discussed in this book.Throughout this book, the terms pharmaceutical and drug are treated assynonyms, although they are not. A drug is really an active pharmaceutical ingre-dient(API) and a pharmaceutical product is an API in combination with otheringredients that are blended or compounded to make the finished product. In somecases, the word drug is used in this book as a synonym for pharmaceutical andvice versa. The term API is always applied to the active ingredient only.THE DIFFERENCES BETWEEN PHARMACEUTICALAND FOOD PACKAGINGFood and pharmaceutical packaging are both equally difficult to do well. Foodpackaging is far more diverse than pharmaceutical packaging, while pharma-ceuticalpackaging operates in a much more regulated environment. Someunderstanding of the differences is useful, and for crossover products such asmedical nutritional foods, essential. As more and more foods are enhanced withingredients that can impart a change in the body, or as manufacturers makeclaims regarding the benefits of food products, which may be considered drug 31. 16 Chapter 1claims by the FDA or the Federal Trade Commission, the amount or regulationand the amount of testing necessary to gain approval of the products increasesexponentially. These products will be supplied in familiar food containersappropriate for the type of food product; however, the containers will be requiredto meet pharmaceutical regulations that were not required when the product wasstrictly a food. It will become harder and harder to determine if the packagingmust follow food or drug regulations.Food and pharmaceutical packaging follow two different paths in pack-agingdevelopment that not only have many similarities but also have majordifferences. Food is rarely toxic even when consumed in huge quantities. Nauseaand bloating will normally stop someone from overingesting food well before thecondition becomes harmful or life threatening. With drugs, overdose is easy andcan be fatal. This difference is the reason why labeling is so stringent and therequirements for labeling, discussed in chapters 5 and 11, are so precise. TheFDA takes a very dim view of mislabeled pharmaceutical products, so manu-facturersare extremely careful about controlling the labeling that goes on anypharmaceutical package.Drugs, being so toxic, also come under poison-control regulationsadministered by the U.S. Consumer Product Safety Commission (CPSC). Therequirement for child-resistant closures on pharmaceutical products is related tothe highly toxic nature of most pharmaceutical products. This requirement cre-atesa great deal of problems for the elderly, who are the major users of drugs.Many elderly patients complain that it is too hard to open or get into a package,and that they must go to great lengths to open the package. Child resistantclosures are designed to protect children from poisoning. Unfortunately, manyseniors after opening a package with a child-resistant closure only partiallyreplace the closure back on the package and do not engage the closure to thepoint where it is effective in preventing an inquisitive child from becomingharmed by the containers contents.Foods dont look alike and certainly dont smell alike. In fact, the appealto the senses is a primary determinant of which foods we like. We are con-cernedabout the nutritional value of the food we eat, and in recent years, theFDA has promoted new food labeling to detail exactly what the food we eatpresents to our bodies in the form of nutrition. This is not the case with drugs.Most pharmaceuticals look alike. Most drugs are packaged in opaque con-tainersthat dont permit easy viewing of the contents. There is no sensorycomponent of smell or flavor. This makes labeling of drugs even more crucial.The contents must be accurately described on the labeling. Even with the minorvariations in shape and the use of impressed symbols or printing on the outsideof a tablet, it can be hard to distinguish between multiple drugs that are partof a patients regimen. Color helps, but the main way that people can distin-guishone tablet from another is through labeling. Accurate labeling is essentialfor the patient in the use of any prescription product to produce the therapeuticresult. 32. Introduction to the Pharmaceutical Industry: An Overview 17This is especially critical with OTC drugs that have undergone multipleupdates to their labeling mandated by new FDA standards to help improve thelabels ability to easily communicate to consumers. OTC packaging of phar-maceuticalproducts has become one of the most difficult forms of packaging.Packaging and labeling of OTC products communicate to the consumer in muchthe same way they do for food. They have the dual purpose of building brandrecognition and communicating the proper use of the product. Many peopledont realize how dangerous OTC medicines can be and misuse of these prod-ucts;or, more properly stated, the improper use or dosage with these products ishigh. The labeling, with its prominent warnings, alerts even the most casualconsumer to the dangers of an OTC product and helps distinguish it from foodor candy.All food is taken or ingested orally. The mouth is a non-sterile orifice, andour digestive systems are structured to kill the majority of harmful organismsthat can enter our bodies with food. We do get sick from foodborne pathogens,and in some case severely sick, with Escherichia coli or, in extreme cases,botulism. When this happens, it creates headlines and is extensively reportedbecause the occurrence is very rare. Drugs, on the other hand, can not only betaken orally, but can also be administered directly into the circulatory system(parenteral), under the skin (subcutaneous), or across mucous membranes in thenose, throat, and rectum, as well as through the skin with patches or highpressure injections. These methods of ingestion are quite different from anyfood, and provide the opportunity to introduce harmful or fatal micro-organismsdirectly into a patient. Drugs and devices must be completely sterile, as opposedto commercially sterile, the term applied to many retorted (processed) foodslike meat, vegetables, soups, and canned products. For food, a complete steril-ization,equal to the sterilization required for a drug, would render it tasteless,texture-less, and totally unpalatable.Drugs are repackaged to a very large degree. This is changing, and in someparts of the world, unit-dose packaging is more common than in the UnitedStates. Even so, the pharmacist repackages a large number of products for thepatient. This is a requirement that doesnt touch food to a large degree. Pack-agingmust protect the product both in the large containers used for generaldistribution and in the small containers a pharmacist uses for the repackagedproduct when it is dispensed from the pharmacy. These same packages must alsoprotect a pharmaceutical product after it gets to the patients home. Products areheld and dispensed from the pharmacy container in which they are supplied farlonger than most foods after they are opened.In many cases, the package not only protects the product but also providesa method for tracking its use or compliance. Compliance is a term that isbecoming more and more critical; and, for a pharmaceutical, it means the patientfollows the dosage regimen specified by the doctor. The term adherence is alsoused in this connotation. Compliance can result in reduced health care costsbecause the patient gains control over a condition before it becomes much more 33. 18 Chapter 1serious. A good example of a chronic problem that requires constant complianceis hypertension or high blood pressure. Surprisingly, patients typically have arelatively low rate of compliance for these products even though hypertensioncan cause stroke or heart attack.DRUG REGULATIONSPackaging of drugs is highly regulated when compared with food packaging. TheUSP lists approved packaging for drugs, and this recommendation carries theforce of law. There is no single reference for food products. Pharmaceuticalproducts come under a number of specific parts of Title 21 of the Code ofFederal Regulations (CFR) that mandate specific procedures for developing,proving, and changing previously approved packaging. The regulation slows andsometimes stops innovation.Drug packaging is slow to change. The cost of stability studies needed toprove long term packaging safety is extremely high and can take two to fiveyears. Drugs, with packaging defined and approved many years ago, and genericdrug packaging is particularly hard to change. Many times the sales dollars andprofits generated by a generic drug do not justify the cost of qualifying a newmaterial or a new dosage form. This situation is improving and a good exampleof the improvement is found when qualifying a new plastic resin. The FDA hasalways interpreted the same container closure system to mean the same plasticresin formulation identified in the original application, or from a suppliers pointof view, the same material produced at the same manufacturing facility of theresin manufacturer. The FDA has developed procedures that permit the changeof plastic resins if they meet the approval procedures developed by the USP.These protocols permit the establishment of equivalence between two similartypes of resinan example would be high-density polyethylene from two dif-ferentmanufacturers. The procedures permit the qualification and changewithout prior approval. This approval is always conditional to the materialpassing real time stability testing with the actual product. More on this topic willbe discussed and included in the chapter on regulatory affairs.Tamper evidence built into the packaging is a much more important issuefor drugs than it is for food. This is a direct outgrowth of a tampering problem inChicago that caused a number of deaths in the mid-1980s. Tylenol1 (acet-aminophen)packages were tampered with and a poison was introduced. A numberof people died. This sparked a major change in how drugs, particularly OTC drugs,were packaged. Tamper evidence is typically costly and requires one or moresteps, either in the container-manufacturing process or in the assembly of thecontainer during filling to put the safeguards into place. It also requires educationof the public about what to look for and how to identify a package that has beenaltered or changed. Food products are every bit as vulnerable; however, no reg-ulationsnow mandate tamper evidence on food products. Food packaging is farmore diverse than drug packaging and carries a much smaller profit margin. These 34. Introduction to the Pharmaceutical Industry: An Overview 19two facts make it far more difficult for manufacturers to change food productspackaging by adding tamper-evident features, although when possible, these areincluded in the package design. A good food example is the use of the breakawayring on soda and water bottles. Tampering with foods has every bit as muchpotential to harm the general public as does tampering with OTC products.The cost of packaging is the last aspect of the differences between drugand food packaging. Food products typically carry a much smaller profit margin,and most food products are produced in much greater volume than pharma-ceuticals.The constant pressure on cost, the fact that packaging costs are a muchmore significant contributor to the cost of a food product compared with phar-maceuticals,and the volume of material used to make a package drives the foodpackager to be more cost conscious than the pharmaceutical packager. Volume,in this case, is the higher number of units produced for a food product comparedwith that produced for a pharmaceutical. Pharmaceuticals are costlier than food,and as a result, the percentage that packaging contributes to the total cost of theproduct is significantly less. The crossover products, such as medical nutritionalfoods, infant formulas, energy bars, and other similar products, are typicallydeveloped and their packaging costs are managed in the same way food productsare scrutinized and controlled. Crossover products are the one exception to thegeneral rule regarding the cost of pharmaceutical packaging.THE FUNCTION OF PACKAGINGAll packaging is required to perform two functions, containment and protection.Containment is the first role that any package must play in conjunction with aproduct. Containment means that the package prevents the product fromtouching or being exposed to the environment. For a drug package, this meansthe container completely separates the product from its surrounding physicalenvironment. The package is sealed, preventing the product from entering theenvironment and the environment from entering the product. It also means thepackage does not become part of the product or vice versa. The package mustremain functionally inert to its contents.Protection is the second aspect that any package is expected to perform.Protection within the package means the product inside does not sustain physicaldamage. This could take the form of broken tablets or chemical breakdowncaused by light, heat, oxygen, and water vapor.Along with these two primary functions, a drug package must also providea number of other features. A short list of some of these protective functionsincludes:1. Sterility2. Reclosure3. Communication (via the label)4. Compliance 35. 20 Chapter 15. Tamper evidence6. Temperature controlEach of these items will be addressed in greater detail in various chaptersof this book.Trends in Pharmaceutical PackagingPharmaceutical packaging is a demanding and diverse area of package design,development, and engineering. It is undergoing significant change and re-alignmentjust as the pharmaceutical companies are undergoing change. Emphasis on many ofthe key aspects of packaging is changing and moving directly into the spotlight ofgovernment and consumer scrutiny. This is highlighted by the trends that areaffecting packaging directly and howpackaging is viewedwithin the companies andby the users of the products.Current Trends in PackagingPackaging is being required to do more and more in many areas within andoutside a pharmaceutical company. In the past, its essential roles were con-tainmentand protection of the product. In many cases, the company and theconsumer paid little attention to the package. Today, packagings role is beingexpanded to include branding, communication, distribution control, anti-counterfeiting,poison protection, and much more.Packaging has emerged as both a science and an engineering discipline thathas influence on a product, both within the producing company and with theconsumer outside the company. The science portion of this mix is a broadcombination of disciplines. It includes polymer science, material science, andanalytical chemistry to name a few. These scientific aspects of packagingdevelopment are used along with the science of drug discovery as two integralparts of pharmaceutical product development. It has assumed an engineering roleby taking laboratory prototypes and in many cases stability sample packagingand converting it into a product and package entity that can be manufactured,filled, sealed, labeled, and distributed safely. It has also assumed the role of amanagement tool in the manufacturing process. Packaging is the only scientificand engineering discipline within a pharmaceutical company that touches aproduct from conception to the complete end of a products life or use, includingthe recycling or disposal of used packaging.Packaging is involved in and required to provide guidance and recom-mendationsto researchers and in some case