【正文】 n facility design, cleanroom operations, and control of the chapter discussing pharmaceutical water systems is included. Key quality attributes of sterile dosage forms are discussed, including particulate matter, endotoxin, and sterility testing. The most widely used sterilization techniques as well as processing technologies are presented. Volume 2 concludes with an indepth chapter on lyophilization. Volume 3 focuses on regulatory requirements, riskbased process design, specifications, QbD, and extractables/leachables. In addition, we have included chapters on parenteral administration devices, siRNA delivery systems, injection site pain assessment, and control, PAT, and rapid microbiology test methods. Volume 3 concludes with a forwardlooking chapter discussing the future of parenteral product manufacturing. These three volumes differ from other textbooks in that they provide a learned review on developing parenteral dosage forms for both small molecules and biologies. Practical guidance is provided, in addition to theoretical aspects, for how to bring a drug candidate forward from discovery, through preclinical and clinical development, manufacturing, validation, and eventual registration. The editors wish to thank Judy Clarkston and Lynn OTooleBird (Pfizer, Inc.) for their invaluable assistance and organizational support during this project, and Sherri Niziolek and Bianca Turnbull (Informa Healthcare) for patiently leading us through the publishing process. PREFACE We also acknowledge the assistance of Pfizer, Inc. colleagues Lin Chen and Min Huang for reviewing several of the chapters. We would like to express special gratitude to the late Kenh E. Avis (University of Tennessee College of Pharmacy) for his dedication to teaching and sharing practical knowledge in the area of parenteral medications to so many students over the years, including us. Finally, we acknowledge the contributions of Dr Avis, Leon Lachman, and Herbert A. Lieberman who edited the earlier editions of this book series. Sandeep Netna John D. LudwigContents Foreword Michael J. Akers vii Preface ix Contributors xiii 1. Aseptic manufacturing facility design 1 Mark Caldwell, Bob Helt, Beth Holden, Francesca McBride, and Kevin Schreier 2. Personnel and their impact on clean room operations 56 Jeanne Moldenhauer 3. The fundamentals of an environmental control program 80 William H. Miele 4. Water systems for parenteral facilities 91 Joseph /. Manfredi 5. Particulate matter: subvisible 114 D. Scott Aldrich 6. Endotoxin testing 146 Michael E. Dawson 7. The pendial sterility tests 187 Scott . Sutton 8. Industrial sterilization technologies: principles and overview 195 Anne F. Booth 9. Steam sterilization 221 James AgaHoco 10. Gas, vapor, and liquid chemical sterilization 241 fames Agalloco 11. Dry heat depyrogenation and sterilization 255 Deborah Havlik and Kevin Trupp 12. Radiation sterilization 268 Barry P. Fairand and Dusan Razemxii CONTENTS 13. Filters and filtration 297 Maik \N. Jornitz and Theodore H. Meltzer 14. Processing of small volume parenterals and large volume parenterals 334 Donald A. Eiseiihauer, Roland Schmidt, Christine Martin, and Steven G. Schultz 15. Freezedrying: principles and practice 353 Steven L. Nail and Larri/ A. Gatlin Index 383Contributors James Agalloco Agalloco amp。 Co. KG, Ludwigshafen, Germany Kevin Schreier Jacobs Engineering Group, Inc., Conshohocken, Pennsylvania, . Steven G. Schultz Abbott Laboratories, North Chicago, Illinois, . Scott V. W. Sutton Microbiology Network, Inc., Rochester, New York, . Kevin Trupp Global Sterilization Engineering, Hospira, Inc., Lake Forest, Illinois, .1 Aseptic manufacturing facility design Mark Caldwell, Bob Helt, Beth Holden, Francesca McBride, and Kevin Schreier INTRODUCTION Sterile products may be in liquid or powder form (among others) as drug products and may be presented in formats including ampoules, vials, prefilled syringes, presterilized bottles, and blowfil 1seal containers. Product form and presentation influence processing conditions, equipment selection, and therefore, facility design. The sterile envelope refers to all the steps carried out during and following the final sterile filtration step through process pletion, which occurs after filled product containers are sealed and a risk of environmental contamination to the product is eliminated. These steps include: ? Adjuvant, buffer and media formulation ? Addition of excipients ? Adjustment of concentration to achieve target potency ? Sterile filtration ? Component preparation ? Filling, stoppering/plugging, and sealing of product in final dosage containers The design of the facility must meet all applicable regulatory guidelines, and meet GMP and safety guidelines. Current Good Manufacturing Practice (GMP) requires that areas of operation used for aseptic processing must prevent contamination from particles and microbes that may be present in the air, on product contact surfaces, or shed from personnel (15). When processing biological products, such as live virus vaccines, attenuated vaccines and viral vectors, the Giohazard nature of these products place extra demands on the facility. Potent pounds, like some biological products, also pose a risk to the operator and environment. Therefore, the facility and process design must also ensure both product and personnel safety. This chapter establishes a basis for pliance with the global regulatory expectations for facility design, equipment interfaces, and utility requirements applicable to sterile processing and the manufacture of sterile products (610). FACILITY DESIGN DRIVERS As each facility is being designed, process requirements specific to each product must be considered. Each different type of product has different facility needs. Also, the