HANDBOOK OF Pharmaceutical Manufacturing …

1 HANDBOOK OFPharmaceuticalManufacturingFormulation sSterile ProductsVOLUME 6 2004 by CRC Press LLC HANDBOOK ofPharmaceutical Manufacturing FormulationsVolume SeriesVOLUME 1 Volume 1 HANDBOOK of Pharmaceutical Manufacturing Formulations:Compressed Solid ProductsVolume 2 HANDBOOK of Pharmaceutical Manufacturing Formulations:Uncompressed Solid ProductsVolume 3 HANDBOOK of Pharmaceutical Manufacturing Formulations:Liquid ProductsVolume 4 HANDBOOK of Pharmaceutical Manufacturing Formulations:Semisolid ProductsVolume 5 HANDBOOK of Pharmaceutical Manufacturing Formulations:Over-the-Counter ProductsVolume 6 HANDBOOK of Pharmaceutical Manufacturing Formulations:Sterile ProductsSarfaraz K. Niazi 2004 by CRC Press LLC CRC PRESSBoca Raton London New York Washington, OFPharmaceuticalManufacturingFormulation sSterile ProductsSarfaraz K. NiaziVOLUME 6 2004 by CRC Press LLC This book contains information obtained from authentic and highly regarded sources.

2 Reprinted material is quoted with permission, andsources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information,but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, includingphotocopying, microfilming, and recording, or by any information storage or retrieval system, without prior permission in writing fromthe consent of CRC Press LLC does not extend to copying for general distribution, for promotion, for creating new works, or for permission must be obtained in writing from CRC Press LLC for such all inquiries to CRC Press LLC, 2000 Corporate Blvd.

3 , Boca Raton, Florida 33431. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification andexplanation, without intent to infringe. Visit the CRC Press Web site at 2004 by CRC Press LLC No claim to original Government worksInternational Standard Book Number 0-8493-1751-7 Library of Congress Card Number 2003051451 Printed in the United States of America 1 2 3 4 5 6 7 8 9 0 Printed on acid-free paperLibrary of Congress Cataloging-in-Publication Data Niazi, Sarfaraz, 1949 HANDBOOK of Pharmaceutical Manufacturing formulations / Sarfaraz K. bibliographical references and : Sterile 0-8493-1751-7 (alk. paper)1. Drugs Dosage forms Handbooks, manuals, etc. I. 2004615'19 dc212003051451 2004 by CRC Press LLC Dedication To Professor Shamsuz Zoha, my first pharmacy teacher, who inspired many with his passion for the profession and for science 2004 by CRC Press LLC Preface to the Series No industry in the world is more highly regulated thanthe Pharmaceutical industry because of potential threat toa patient s life from the use of Pharmaceutical cost of taking a new chemical entity (amortized overthe cost of all molecules racing) to final regulatoryapproval is a staggering $800 million, making the phar-maceutical industry one of the most research-intensiveindustries in the world.

4 In the year 2004, it is anticipatedthat the industry will spend about $20 billion on researchand development. The generic market of drugs as the newentities come off patent is one of the fastest growingsegments of the Pharmaceutical industry, with every majormultinational company having a significant presence inthis many stages of new drug development areinherently constrained with time, the formulation of drugsinto desirable dosage forms remains an area where expe-diency can be practiced with appropriate knowledge bythose who have mastered the skills of Pharmaceutical for-mulations. The HANDBOOK of Pharmaceutical Manufactur-ing Formulations is the first major attempt to consolidatethe available knowledge about formulations in a compre-hensive, and by nature a rather voluminous, book is divided into six volumes, based strictlyon the type of formulation science involved in the devel-opment of these dosage forms: sterile products, com-pressed solids, uncompressed solids, liquid products,semisolid products, and OTC products.

5 The separation ofOTC products even though they may easily fall into oneof the other five categories is made to comply with theindustry norms of separate research divisions for OTCproducts. Sterile products require skills related to steril-ization of product, and of less importance is the bioavail-ability issue, which is an inherent problem of compresseddosage forms. These types of considerations have led tothe classification of products into these six volume includes a description of regulatory fil-ing techniques for the formulations described. Alsoincluded are the current regulatory guidelines on cGMPcompliance specific to the dosage form. Advice is offeredon how to scale up the production is expected that formulation scientists will use thisinformation to benchmark their internal development pro-tocols and cut the race to file short by adopting formulaethat have survived the test of time.

6 Many of us who haveworked in the Pharmaceutical industry suffer from a closeparadigm when it comes to selecting formulations notinvented here perhaps reigns in the mind of many sea-soned formulations scientists subconsciously when theyprefer to choose only a certain platform for is expected that with the quick review of possibilitiesavailable to formulate made available in this book, scien-tists will benefit from the experience of the teachers of formulation sciences, this seriesoffers a wealth of information. Whether it is a selectionof a preservative system or the choice of a disintegrant,the series offers a wide choice to study and have assisted me in the development of thiswork that has taken years to compile, and I thank scoresof my graduate students and colleagues for their help.

7 Awork of this size cannot be produced without errors,although I hope that these errors do not distract the readerfrom the utility of the book. I would sincerely appreciateif readers point out these mistakes for corrections in futureeditions. Sarfaraz K. Niazi, Deerfield, Illinois 2004 by CRC Press LLC Preface to the Volume The HANDBOOK of Pharmaceutical Manufacturing Formu-lations: Sterile Products (HPMF/SP) is written for thepharmaceutical scientist and others involved in the regu-latory filing and Manufacturing of new sterile other area of regulatory compliance receives moreattention and scrutiny by regulatory authorities than theregulation of sterile products, for obvious reasons. Withthe increasing number of potent products, particularly thenew line of small protein products, joining the long listof proven sterile products mainly parenteral and oph-thalmic products the technology of Manufacturing ster-ile products has evolved into a very sophisticated entry barrier to this technology is much higher com-pared with those for other dosage forms.

8 Consequently,the cost of production remains high as well. In recentyears, regulatory agencies around the world have takenvery serious notice of the deficiencies in the manufactur-ing specifications of the active raw material intended forparenteral administration. New guidelines for the API andaseptic processing of sterile products are the main issuesof concern today for manufacturers. This volume of HPMF/SP does not delve into details related to startingmaterial issues. Of interest in this issue are formulationsof sterile dosage forms, regulatory filing requirements ofsterile preparations, and cGMP compliance , all of whichare tied together in the final preparation of the Chemistry, Manufacturing , and Control (CMC) sections of 1 describes the specifications of a manufac-turing facility to manufacture compliant sterile 2 outlines the New Drug Application (NDA) orANDA (Abbreviated New Drug Application) filingrequirements of sterile products.

9 Chapter 3 describes indetail the layout of formulations provided in the chapter must be thoroughly examined to make thebest use of this book. Because the intent of the informationprovided in this book is to help the formulator develop aproduct for regulatory filing, boilerplate details are leftout. Chapter 3 provides these details and also makes strongrecommendations on how the formulator can benefit fromthe information available from suppliers of componentsand chemicals used in the three chapters are followed by the body of thebook, which provides an alphabetical presentation of for-mulations of Pharmaceutical products based on theirgeneric names. There are three types of formulationentries. In the first type, both the bill of materials andmanufacturing directions are provided. This type is furthercomposed of two types, wherein greater detail is providedfor some products.

10 This differentiation is intentionalbecause the common details are often omitted in subse-quent presentations. The second type of formulations isprovided with bill of materials only. This may includeproducts for which the Manufacturing directions are obvi-ous to a prospective manufacturer, particularly in light ofthe details already provided for similar products elsewherein the book, and also those products for which such infor-mation is not readily available. The third category of for-mulations includes experimental formulations, which maynot yet have been commercialized or received regulatoryapprovals. These formulations are included to show to theformulation scientist unique opportunities that exist forthe chemical entity in of biotechnology-derived drugs areprovided with some additional details and remainrestricted to declaration of composition, yet they providea good overview of the complexities involved in consolidating the details of formulations, effortshave been made to present them in as unified a form aspossible; nevertheless, some nonuniformities existbecause of the large variety of presentations possible forthe wide diversity of formulations presented in the limited number of products intended for veterinary useare also included.