【正文】 fessionals strictly as a supplement to the medical professionars own judgement, knowledge of the patient39。 Co. KG, Ludwigshafen, Germany Francesca McBride Jacobs Engineering Group, Inc., Conshohocken, Pennsylvania, Theodore H. Meltzer Capitola Consultancy, Bcthcsda, Maryland, . William H. Miele Pfizer Global Manufacturing, Kalamazoo, Michigan, . Jeanne Moldenhauer Excellent Pharma Consulting, Mundelein, Illinois, . Steven L. Nail Baxter Pharmaceutical Solutions, Bloomington, Indiana, . Dusan Razem Ruder Boskovic Institute, Zagreb, Croatia Roland Schmidt Abbott GmbH amp。 For foreign rights please contact: For reprint permissions please contact: Typeset by MPS Limited, A Macmillan Company Printed and bound in India We dedicate this work to those who have inspired us. To my parents Walter and Ruth Ludwig and my wife Sue Ludwig To my parents Hari and Pratiblm Nema and my wife Tina BuschNemaThis page intentionally left blankForeword I was a faculty member at the University of Tennessee and a colleague of Dr. Kenh Avis when he conceived, organized, and edited (along with . Lieberman and L. Lachman) the first edition of this book series that was published in 1984. It was so well received by the pharmaceutical science munity that an expanded threevolume second edition was published in 1992. Dr. Avis did not survive long enough to oversee a third edition, and it was questionable whether a third edition would ever be published until two of his graduate students, Drs. Nema and Ludwig, took it upon themselves to carry on Dr. Avis39。) revise the text with current and emerging sterile product development and manufacturing science and (ii) maintain the high standard of quality the readers expect. The third edition not only reflects enhanced content in all the chapters, but also more than half of the chapters are new underscoring the rapidly advancing technology. We have divided the volumes into logical subunits—volume 1 addresses formulation and packaging aspects。 Associates, Belle Mead, New Jersey, . D. Scott Aldrich Ultramikro, LLC, Richland, Michigan, . Anne F. Booth Booth Scientific, Inc., Hendersonville, North Carolina, . Mark Caldwell Jacobs Engineering Group, Inc., Conshohocken, Pennsylvania, . Michael E. Dawson Associates of Cape Cod, Inc., Falmouth, Massachusetts, . Donald A. Eisenhauer Abbott Laboratories, North Chicago, Illinois, . Barry P. Fairand Sterigenics International, Dublin, Ohio, . Larry A. Gatlin PK, LLC, Groton, Connecticut, . Deborah Havlik Ramp。s medical history, relevant manufacturer39。 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 number of products to be manufactured and the xiv CONTRIBUTORS production campaign strategy will impact the facility design. Product Types Chemical Bulk Drug Substances (API) Sterile chemical bulk drug substances are derived from chemical reactions. Facilities producing sterile API will be required to provide protection of the product during synthesis, isolation, and bulk filling. An adjuvant produced by precipitation is an example of a sterile API. Potent Compounds Potent pounds are classified as those chemical drug substances that are considered to be toxic to human s when exposure limits are exceeded, and may cause allergic reactions, birth defects, cancer, or other conditions. For this reason, it is required to ensure protection of operators working with potent pounds, ensure containment o