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`Exhibit 1024
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`AMGEN INC.
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`a
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`Ex. 1024 - Page 1 of 7
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`AMGEN INC.
`Exhibit 1024
`
`Ex. 1024 - Page 1 of 7
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`Ex. 1024 - Page 2 of 7
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`Ex. 1024 - Page 2 of 7
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`

`

`
`
`Remington: The
`Science and ~
`Practice
`of Pharmacy
`
`ALFONSO R GENNARO
`
`Chairman of the Editorial Board
`
`and Editor
`
`Ex. 1024 - Page 3 of 7
`
`

`

`
`
`Editor: Daniel Limmer
`Managing Editor: Matthew J. Hauber
`Marketing Manager: Anne Smith
`
`Lippincott Williams & Wilkins
`
`351 West Camden Street
`Baltimore, Maryland 21201—2436 USA
`
`227 East Washington Square
`Philadelphia, PA 19106
`
`All rights reserved. This book is protected by copyright. No part of this book may
`be reproduced in any form or by any means, including photocopying, or utilized
`by any information storage and retrieval system without written permission
`from the copyright owner.
`
`The publisher is not responsible (as a matter of product liability, negligence or
`otherwise) for any injury resulting from any material contained herein. This
`publication contains information relating to general principles of medical care
`which should not be construed as specific instructions for individual patients.
`Manufacturers’ product information and package inserts should be reviewed for
`current information, including contraindications, dosages and precautions.
`
`Printed in the United States of America
`
`Entered according to Act of Congress, in the year 1885 by Joseph P Remington,
`in the Office of the Librarian of Congress, at Washington DC
`
`Copyright 1889, 1894, 1905, 1907, 1917, by Joseph P Remington
`
`Copyright 1926, 1936, by the Joseph P Remington Estate
`
`Copyright 1948, 1951, by the Philadelphia College of Pharmacy and Science
`
`Copyright 1956, 1960, 1965, 1970, 1975, 1980, 1985, 1990, 1995, by the Phila-
`delphia College of Pharmacy and Science
`
`Copyright 2000, by the University of the Sciences in Philadelphia
`
`All Rights Reserved
`Library of Congress Catalog Card Information is available
`ISBN 0—683-306472
`
`The publishers have made every effort to trace the copyright holders for borrowed
`material. If they have inadvertently overlooked any, they will be pleased to make
`the necessary arrangements at the first opportunity.
`
`The use of structural formulas from USAN and the USP Dictionary of Drug
`Names is by permission of The USP Convention. The Convention is not respon-
`sible for any inaccuracy contained herein.
`Notice—This text is not intended to represent, nor shall it be interpreted to be, the
`equivalent of or a substitute for the official United States Pharmacopeia (USP)
`and/or the National Formulary (NF). In the event of any difference or discrep-
`ancy between the current official USP or NF standards of strength, quality,
`purity, packaging and labeling for drugs and representations of them herein, the
`context and effect of the official compendia shall prevail.
`
`To purchase additional copies of this book call our customer service department
`at (800) 638-3030 or fax orders to (301) 824-7390. International customers
`should call (301) 714-2324.
`
`02 03 O4
`2 3 4 5 6 7 8 9 10
`
`Ex. 1024 - Page 4 of 7
`
`Ex. 1024 - Page 4 of 7
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`

`

`. A treatise on the theory
`.
`Remington: The Science and Practice of Pharmacy .
`and practice of the pharmaceutical sciences, with essential
`information about pharmaceutical and medicinal agents; also, a
`guide to the professional responsibilities of the pharmacist as the
`drug information specialist of the health team .
`.
`. A textbook and
`reference work for pharmacists, physicians, and other practitioners of
`the pharmaceutical and medical sciences.
`
`EDITORS
`
`Alfonso R Gennaro, Chair
`
`Nicholas G Popovich
`
`Ara H Der Marderosian
`
`Roger L Schnaare
`
`Glen R Hanson
`
`Joseph B Schwartz
`
`Thomas Medwick
`
`H Steve White
`
`AUTHORS
`
`The 1 19 chapters of this edition of Remington were written by the
`
`editors, by members of the Editorial Board, and by the authors
`
`listed on pages viii to X.
`
`Managing Editor
`
`John E Hoover, BSc (Pharm)
`
`Editorial Assistant
`
`Bonnie Brigham Packer, RNC, BA
`
`Director
`
`Philip P Gerbino 1995—2000
`
`. Twentieth Edition—2000
`
`Published in the 180th year of the
`PHILADELPHIA COLLEGE OF PHARMACY AND SCIENCE
`
`EX. 1024 - Page 5 of 7
`
`Ex. 1024 - Page 5 of 7
`
`

`

`
`Types of Vehicles
`
`AQUEOUS VEHICLES—Certain aqueous vehicles are
`recognized officially because of their valid use in parenterals.
`Often they are used as isotonic vehicles to which a drug may be
`added at the time of administration. The additional osmotic
`effect of the drug may not be enough to produce any discomfort
`when administered. These vehicles include Sodium Chloride
`Injection, Ringer’s Injection, Dextrose Injection, Dextrose and
`Sodium Chloride Injection, and Lactated Ringer’s Injection.
`WATER-MISCIBLE VEHICLES—A number of solvents
`that are miscible with water have been used as a portion of the
`vehicle in the formulation of parenterals. These solvents are
`used primarily to affect the solubility of certain drugs and to
`reduce hydrolysis. The most important solvents in this group
`are ethyl alcohol, liquid polyethylene glycol and propylene gly—
`col. Ethyl alcohol is used particularly in the preparation of
`solutions of cardiac glycosides and the glycols in solutions of
`barbiturates, certain alkaloids and certain antibiotics. Such
`preparations usually are given intramuscularly. These sol-
`vents, as well as nonaqueous vehicles, have been reviewed by
`Spiegel and Noseworthy.6
`NONAQUEOUS VEHICLES—The most important group
`of nonaqueous vehicles are the fixed oils. The USP provides
`specifications for such vehicles, indicating that the fixed oils
`must be of vegetable origin so that they will be metabolized,
`will be liquid at room temperature, and will not become rancid
`readily. The USP also specifies limits for the degree of unsat-
`uration and free fatty acid content. The oils most commonly
`used are corn oil, cottonseed oil, peanut oil, and sesame oil.
`Fixed oils are used particularly as vehicles for certain hormone
`preparations. The label must state the name of the vehicle so
`that the user may beware in case of known sensitivity or other
`reactions to it.
`
`
`SOLUTES
`
`Care must be taken in selecting bulk active chemicals and excipi—
`ents to ensure that their quality is suitable for parenteral admin—
`istration. A low microbial level will enhance the effectiveness of
`either the aseptic or terminal sterilization process used for the
`drug product. Likewise, nonpyrogenic ingredients enhance the
`nonpyrogenicity of the finished injectable product. Chemical im-
`purities should be virtually nonexistent in bulk substances for
`parenterals, because impurities are not likely to be removed by
`the processing of the product. Depending on the chemical in-
`volved, even trace residues may be harmful to the patient or cause
`stability problems in the product. Therefore, the compounder
`should use the best grade of chemicals obtainable and use its
`analytical profile to determine that each lot of chemical used in
`the formulation meets the required specifications.
`Reputable chemical manufacturers accept the stringent
`quality requirements for parenteral products and, accordingly,
`apply good manufacturing practices to their chemical manufac-
`turing. Examples of critical bulk manufacturing precautions
`include using dedicated equipment or properly validated clean-
`ing to prevent cross-contamination and transfer of impurities,
`using WFI for rinsing equipment and for bulk manufacturing
`steps not followed by further purification, using closed systems
`wherever possible, and adhering to specified endotoxin and
`bioburden testing limits for the substance.
`ADDED SUBSTANCES—The USP includes in this cate—
`gory all substances added to a preparation to improve or safe-
`guard its quality. An added substance may
`
`Effect solubility, as does sodium benzoate in Caffeine and Sodium
`Benzoate Injection.
`Provide patient comfort, as do substances added to make a solution
`isotonic or near physiological pH.
`Enhance the chemical stability of a solution, as do antioxidants,
`inert gases, chelating agents, and buffers.
`
`PARENTERAL PREPARATIONS
`
`785
`
`Protect a preparation against the growth of microorganisms. The
`term preservative sometimes is applied only to those substances that
`prevent the growth of microorganisms in a preparation. However, such
`limited use is inappropriate, being better used for all substances that
`act to retard or prevent the chemical, physical, or biological degradation
`of a preparation.
`
`While added substances may prevent a certain reaction
`from taking place, they may induce others. Not only may visible
`incompatibilities occur, but hydrolysis, complexation, oxida-
`tion, and other invisible reactions may decompose or otherwise
`inactivate the therapeutic agent or other added substances.
`Therefore, added substances must be selected with due consid-
`eration and investigation of their effect on the total formulation
`and the container—closure system.
`ANTIMICROBIAL AGENTS—The USP states that anti—
`microbial agents in bacteriostatic or fungistatic concentrations
`must be added to preparations contained in multiple—dose con—
`tainers. They must be present in adequate concentration at the
`time of use to prevent the multiplication of microorganisms
`inadvertently introduced into the preparation while withdraw-
`ing a portion of the contents with a hypodermic needle and
`syringe. The USP provides a test for Antimicrobial Preserva—
`tive Effectiveness to determine that an antimicrobial substance
`or combination adequately inhibits the growth of microorgan-
`isms in a parenteral product. Because antimicrobials may have
`inherent toxicity for the patient, the USP prescribes concentra-
`tion limits for those that are used commonly in parenteral
`products, eg
`
`Phenylmercuric nitrate and thimerosal 0.01%.
`Benzethonium chloride and benzalkonium chloride 0.01%.
`Phenol or cresol 0.5%.
`Chlorobutanol 0.5%.
`
`The above limit rarely is used for phenylmercuric nitrate, most
`frequently employed in a concentration of 0.002%. Methyl p—
`hydroxybenzoate 0.18% and propyl p-hydroxybenzoate 0.02%
`in combination, and benzyl alcohol 2% also are used frequently.
`In oleaginous preparations, no antibacterial agent commonly
`employed appears to be effective. However, it has been reported
`that hexylresorcinol 0.5% and phenylmercuric benzoate 0.1%
`are moderately bactericidal. A few therapeutic compounds
`have been shown to have antibacterial activity, thus obviating
`the need for added agents.
`Antimicrobial agents must be studied with respect to com-
`patibility with all other components of the formula. In addition,
`their activity must be evaluated in the total formula. It is not
`uncommon to find that a particular agent will be effective in
`one formulation but ineffective in another. This may be due to
`the effect of various components of the formula on the biological
`activity or availability of the compound; for example, the bind-
`ing and inactivation of esters ofp—hydroxybenzoic acid by mac—
`romolecules such as Polysorbate 80 or the reduction of phe-
`nylmercuric nitrate by sulfide residues in rubber closures. A
`physical reaction encountered is that bacteriostatic agents
`sometimes are removed from solution by rubber closures.
`Single—dose containers and pharmacy bulk packs that do not
`contain antimicrobial agents are expected to be used promptly
`after opening or to be discarded. Large—volume, single-dose
`containers may not contain an added antimicrobial preserva—
`tive. Therefore, special care must be exercised in storing such
`products after the containers have been opened to prepare an
`admixture, particularly those that can support the growth of
`microorganisms, such as total parenteral nutrition (TPN) solu-
`tions and emulsions. It should be noted that while refrigeration
`slows the growth of most microorganisms, it does not prevent
`their growth.
`Buffers are used primarily to stabilize a solution against
`the chemical degradation that might occur if the pH changes
`appreciably. Buffer systems employed should normally have as
`low a buffering capacity as feasible so as not to disturb signif-
`icantly the body’s buffering systems when injected. In addition,
`the buffer range and effect on the activity of the product must
`
`Ex. 1024 - Page 6 of 7—
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`Ex. 1024 - Page 6 of 7
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`

`

`786
`
`CHAPTER 41
`
`be evaluated carefully. The acid salts most frequently em-
`ployed as buffers are citrates, acetates, and phosphates.
`Antioxidants are required frequently to preserve products
`because of the ease with which many drugs are oxidized.
`Sodium bisulfite 0.1% is used most frequently. The use of
`sulfites has been reviewed by Schroeter.7 Acetone sodium bisul—
`fite, sodium formaldehyde sulfoxylate, and thiourea also are
`used sometimes. The sodium salt of ethylenediaminetetraace-
`tic acid has been found to enhance the activity of antioxidants
`in some cases, apparently by chelating metallic ions that would
`otherwise catalyze the oxidation reaction.
`Displacing the air (oxygen) in and above the solution by
`purging with an inert gas, such as nitrogen, also can be used as
`a means to control oxidation of a sensitive drug. Process control
`is required for assurance that every container is deaerated
`adequately and uniformly.
`Tonicity agents are used in many parenteral and ophthalmic
`products to adjust the tonicity. However, not all preparations
`need to be isotonic. The agents most commonly used are elec—
`trolytes and mono- or disaccharides. This subject is considered
`much more extensively in Chapter 18.
`,.
`A recent publication surveys excipients being used today in
`parenteral formulations in the United States.8
`
`
`
`
`
`PYROGENS (ENDOTOXINS) ‘_—
`
`Pyrogens are products of metabolism of microorganisms. The
`most potent pyrogenic substances (endotoxins) are constituents
`of the cell wall of gram—negative bacteria. Gram—positive bac-
`teria and fungi also produce pyrogens but of lower potency and
`of different chemical nature. Endotoxins are high—molecular-
`weight (about 20,000 daltons) lipopolysaccharides. Studies
`have shown that the lipid portion of the molecule is responsible
`for the biological activity. Since endotoxins are the most potent
`pyrogens and gram—negative bacteria are ubiquitous in the
`environment, this discussion focuses on endotoxins and the
`risk of their presence as contaminants in sterile products.
`Pyrogens, when present in parenteral drug products and
`injected into patients, can cause fever, chills, pain in the back
`and legs, and malaise. While pyrogenic reactions are rarely
`fatal, they can cause serious discomfort and, in the seriously ill
`patient, shock—like symptoms that can be fatal. The intensity of
`the pyrogenic response and its degree of hazard will be affected
`by the medical condition of the patient, the potency of the
`pyrogen, the amount of the pyrogen, and the route of adminis—
`tration (intrathecal is most hazardous followed by intravenous,
`intramuscular, and subcutaneous). When bacterial (exogenous)
`pyrogens are introduced into the body, leukocytic phagocytosis
`is believed to occur, and endogenous pyrogen is produced. The
`endogenous pyrogen then produces the familiar physiological
`effects. Space does not permit further elaboration of these
`matters here; the reader is referred to the work by Pearson9 if
`more information is needed.
`’
`
`CONTROLOF PYROGENS—Pyrogens are contaminants
`if present in parenteral drug products and should not be there.
`In general, it is impractical, if not impossible, to remove pyro-
`gens once present without adversely affecting the drug product.
`Therefore, the emphasis should be on preventing the introduc—
`tion or development of pyrogens in all aspects of the compound-
`ing and processing of the product.
`Pyrogens may enter a preparation through any means that
`will introduce living or dead microorganisms. However, current
`technology generally permits the control of such contamina-
`tion, and the presence of pyrogens in a finished product indi—
`cates processing under inadequately controlled conditions. It
`also should be noted that time for microbial growth to occur
`increases the risk for elevated levels of pyrogens. Therefore,
`compounding and manufacturing processes should be carried
`out as expeditiously as possible, preferably planning comple-
`tion of the process, including sterilization, within one work day.
`
`Pyrogens can be destroyed by heating at high temperatures. A
`typical procedure for depyrogenation of glassware and equipment
`is maintaining a dry heat temperature of 250° for 45 min. It has
`been reported that 650° for 1 min or 180° for 4 hr likewise will
`destroy pyrogens. The usual autoclaving cycle will not do so.
`Heating with strong alkali or oxidizing solutions will destroy
`pyrogens. It has been claimed that thorough washing with deter—
`gent will render glassware pyrogen-free if subsequently rinsed
`thoroughly with pyrogen—free water. Rubber stoppers cannot
`withstand pyrogen-destructive temperatures, so reliance must be
`placed on an effective sequence of washing, thorough rinsing with
`WFI, prompt sterilization, and protective storage to ensure ade—
`quate pyrogen control. Similarly, plastic containers and devices
`must be protected from pyrogenic contamination during manu—
`facture and storage, since known ways of destroying pyrogens
`affect the plastic adversely. It has been reported that anion-
`exchange resins and positively charged membrane filters will
`remove pyrogens from water. Also, although reverse osmosis
`membranes will eliminate them, the most reliable method for
`their elimination from water is distillation.
`A method that has been used for the removal of pyrogens
`from solutions is adsorption on adsorptive agents. However,
`since the adsorption phenomenon also may cause selective
`removal of chemical substances from the solution, this method
`has limited application. Other in«process methods for their
`destruction or elimination include selective extraction proce-
`dures and careful heating with dilute alkali, dilute acid, or mild
`oxidizing agents. In each instance, the method must be studied
`thoroughly to be sure it will not have an adverse effect on the
`constituents of the product. Although ultrafiltration now
`makes possible pyrogen separation on a molecular—weight basis
`and the process of tangential flow is making large-scale pro—
`cessing more practical, use of this technology is limited, except
`in biotechnological processing.
`SOURCES OF PYROGENS—Through understanding the
`means by which pyrogens may contaminate parenteral products,
`their control becomes more achievable. Therefore, it is important
`to know that water is probably the greatest potential source of
`pyrogenic contamination, since water is essential for the growth of
`microorganisms. When microorganisms metabolize, pyrogens will
`be produced. Therefore, raw water can be expected to be pyrogenic
`and only when it is appropriately treated to render it free from
`pyrogens, such as WFI, should it be used for compounding the
`product or rinsing product contact surfaces such as tubing, mixing
`vessels, and rubber closures. Even when such rinsed equipment
`and supplies are left wet and improperly exposed to the environ-
`ment, there is a high risk that they will become pyrogenic. Al-
`though proper distillation will provide pyrogen—free water, stor—
`age conditions must be such that microorganisms are not
`introduced and subsequent growth is prevented.
`Other potential sources of contamination are containers and
`equipment. Pyrogenic materials adhere strongly to glass and
`other surfaces. Residues of solutions in used equipment often
`become bacterial cultures, with subsequent pyrogenic contam-
`ination. Since drying does not destroy pyrogens, they may
`remain in equipment for long periods. Adequate washing will
`reduce contamination and subsequent dry—heat treatment can
`render contaminated equipment suitable for use. However, all
`such processes must be validated to ensure their effectiveness.
`Solutes may be a source of pyrogens. For example, the
`manufacturing of bulk chemicals may involve the use of pyro-
`genic water for process steps such as crystallization, precipita—
`tion, or washing. Bulk drug substances derived from fermen—
`tation will almost certainly be heavily pyrogenic. Therefore, all
`lots of solutes used to prepare parenteral products should be
`tested to ensure that they will not contribute unacceptable
`quantities of endotoxin to the finished product.
`The manufacturing process must be carried out with great
`care and as rapidly as possible, to minimize the risk of micro—
`bial contamination. Preferably, no more product should be pre-
`pared than can be processed completely within one working
`day, including sterilization.
`
`Ex. 1024 - Page 7 of 7
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`Ex. 1024 - Page 7 of 7
`
`