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`NPS EX. 2054
`CFAD V. NPS
`IPR2015—00990
`
`Page 1
`
`NPS EX. 2054
`CFAD v. NPS
`IPR2015-00990
`
`

`
`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 Joseph P Remington Estate
`
`Copyright 1948, 1951, by The Philadelphia College of Pharmacy and Science
`
`Copyright © 1956, 1960, 1965, 1970, 1975, 1980, 1985, 1990, by The Philadelphia College of
`Pharmacy and Science
`
`All Rights Reserved
`
`Library of Congress Catalog Card No. 60-53334
`ISBN 0—912734-04-3
`
`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 responsible 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 discrepancy 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.
`-
`
`Printed in the United States of America by the Mack Printing Company, Easton, ‘Pennsylvania
`
`Page 2
`
`Page 2
`
`

`
`glass or a coating of pure tin. Such systems are very careful-
`ly designed and constructed and often constitute the most
`costly installation within the plant.
`When the water cannot be used at 80°, heat exchangers
`must be installed to reduce the temperature at the point of
`use. Bacterial retentive filters should not be installed in
`such systems because of the risk of bacterial buildup on the
`filters and the consequential release of pyrogenic sub-
`stances.
`
`Purity—The USP monographs provide standards of pu-
`rity for WFI and SWFI. A few of these standards require
`comment.
`
`SWFI must meet the requirements of the USP Sterility
`Test, but WFI need not since it is to be used in a product
`which will be sterilized. Both must meet the requirements
`of the USP Pyrogen Test (page 492).
`The limits for total solids varies in the two monographs.
`The larger the surface area of the glass container per unit
`volume of water, the greater the amount of glass constituents
`that may be leached into the water, particularly during the
`elevated temperature of steam sterilization.
`The WFI monograph stipulates a maximum of 10 ppm of
`total solids. This is generally considered to be much too
`high to assure a quality of water that permits the stable
`formulation of many drugs. A relatively few metallic ions
`present often can render a formulation unstable. There-
`- fore, it is common practice to set a limit of 0.1 ppm or less of
`ionic contaminants expressed as sodium chloride.
`Ionic contaminant level is not the same as total solids; the
`former is a measure of only the ionic content, while the latter
`is a measure of the undissociated constituents as well. The
`ionic content of water can be measured very easily by means
`of a conductivity meter which frequently is used as an indi-
`cator of the purity. The results are expressed in one of three
`terms:
`as sodium chloride ions, as resistance in ohms or
`megohms or as conductance in micromhos. Ohms and mhos
`have a reciprocal relationship to each other, but they are
`related to ppm sodium chloride by an experimentally deter-
`mined curve. To give one point of comparison, 0.1 ppm
`sodium chloride is equal to approximately 1.01 megohms
`and 0.99 micromhos.
`It should be mentioned that conduc-
`tivity measurements give no direct indication of pyrogen
`content since pyrogens are undissociated organic com-
`pounds.
`WFI may not contain an added substance. SWFI may
`contain a bacteriostatic agent when in containers of 30-mL
`capacity or less. This restriction is designed to prevent the
`administration of a large quantity of a bacteriostatic agent
`that probably would be toxic in the accumulated amount of a
`large volume of solution, even though the concentration was
`low.
`
`Types of Vehicles
`
`Aqueous Véhicles—Certain aqueous vehicles are recog-
`nized 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 So-
`dium Chloride Injection, Ringer’s Injection, Dextrose Injec-
`tion, 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 effect the solubility of certain drugs
`and to reduce hydrolysis. The most important solvents in
`this group are ethyl alcohol, polyethylene glycol of the liquid
`series and propylene glycol. Ethyl alcohol is used particu-
`
`PARENTERAL PREPARATIONS
`
`1549
`
`larly in the preparation of solutions of cardiac glycosides and
`the glycols in solutions of barbiturates, certain alkaloids and
`certain alnltikiiotics. Such preparations usually are given in-
`tramusc ar y.
`These solvents, as well as nonaqueous vehicles, have been
`reviewed by Spiegel and Noseworthyf’ .
`Nonaqueous Velucles—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 unsaturation and free fatty acid content. The oils most
`commonly used are com oiljcottonseed oil, peanut oil and
`sesame oil. It should be noted that the official monographs
`for some of thede oils provide for greater latitude than the
`specifications required for the use of the oil as a vehicle for a
`parenteral.
`Fixed oils are used particularly as vehicles for certain
`hormone preparations. These and other nonaqueous vehi-
`cles, such as ethyl oleate, isopropyl myristate, and benzyl
`benzoate, may be used provided they are safe in the volume
`administered anld do not interfere with the therapeutic effi-
`cacy of the preparation or with its response to prescribed
`assays and testsl The label also must state the name of the
`vehicle so that the usermay beware in case of known sensi-
`tivity or other relactions to it.
`
`Solutes
`
`The requirements for purity of the medicinal compound
`used in an injection often make it necessary to undertake
`special purification of the usual chemical grade available.
`In a few instancds, a special parenteral grade of a compound
`is available, for example, ascorbic acid freed from all traces
`of copper contariiination. As a general rule, the best chemi-
`cal gfiade obtain'able should be used.
`It should be obvious
`that if a few ppm of ionic contaminants in WFI may cause
`stability problerhs, a similar level of contamination in the
`solute itself may likewise, cause stability problems. Metal-
`li‘c catalysis of c emical reactions is one which is encoun-
`tered frequentlyl
`Other factors to be considered with respect to the quality
`of solutes inclu 'e the level of microbial and pyrogenic con-
`tamination, solu ility characteristics as determined by the
`chemical or physical form of the compound and freedom
`from gross dirt.
`Added Substances—The USP includes in this category
`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.
`,
`Enhance the chemical stability of a solution, as do antioxidants, inert
`gases, chelating ageiits and buffers.
`Preserve a pi-eparlation against the growth of microorganisms. The
`term “preservative” sometimes is applied only to those substances which
`prevent the growth of microorganisms in a preparation. However, such
`limited use is inappriopriate, 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, complex-
`ation, oxidation and other invisible reactions may decom-
`pose or otherwise inactivate the therapeutic agent. There-
`fore, added substances must be selected with due consider-
`ation and investigation of their effect on the total formula-
`tion.
`
`Page 3
`
`Page 3
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`

`
`1550
`
`CHAPTER 84
`
`Antimicrobial Agents-—The USP states that antimicro-
`bial agents in bacteriostatic or fungistatic concentrations
`must be added to preparations contained in multiple-dose
`containers. They must be present in adequate concentra-
`tion at the time of use to prevent the multiplication of
`microorganisms inadvertently introduced into the prepara-
`tion while withdrawing a portion of the contents with a
`hypodermic needle and syringe. Among the compounds
`most frequently employed, with the concentration limit pre-
`scribed by the USP, are:
`
`Phenylmercuric nitrate and thimerosal 0.01%.
`Benzethonium chloride and benzalkonium chloride 0.01%.
`Phenol or cresol 0.5%.
`Chlorobutanol 0.5%.
`
`The above limit is rarely used for phenylmercuric nitrate,
`most frequently being 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 effec-
`tive. However, it has been reported that hexylresorcinol
`0.5% and phenylmercuric benzoate 0.1% are moderately bac-
`tericidal.
`
`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 formu-
`la. 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 formu-
`la on the biological activity or availability of the compound;
`for example, the binding and inactivation of esters of p-
`hydroxybenzoic acid by macromolecules such as Polysorbate
`80 or the reduction of phenylmercuric nitrate by sulfide
`residues in rubber closures. A physical reaction encoun-
`tered is that bacteriostatic agents sometimes are removed
`from solution by rubber closures.
`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 buffer capacity as feasible in order not to
`disturb significantly the body buffer systems when injected.
`In addition, the buffer range and effect on the activity of the
`product must be evaluated carefully. The acid salts most
`frequently employed as buffers are citrates, acetates and
`phosphates.
`Antioxidants are required frequently to_preserve prod-
`ucts 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
`bisulfite, sodium formaldehyde sulfoxylate and thiourea
`also are used sometimes. The sodium salt of ethylenedi-
`aminetetraacetic acid has been found to enhance the activity
`of antioxidants in some cases, apparently by chelating me-
`tallic ions that would otherwise catalyze the oxidation reac-
`tion.
`
`Pyrogens
`
`Pyrogens may be anticipated contaminants in crude
`drugs, such as antibiotics produced by fermentation, or they
`may be present as unexpected and unwanted contaminants
`in a finished product as a result of inadvertent contamina-
`tion during processing. The former must be eliminated
`during the purification steps of the drug. The latter can be
`eliminated best by preventing their introduction or develop-
`ment during the process.
`In general, the presence of pyro-
`gens in a finished product is indicative of preparation under
`inadequately controlled clean conditions.
`Pyrogens cause a febrile reaction in human beings. Other
`
`symptoms include cl ills, pains in the back and legs and
`malaise. While pyrogens are rarely fatal, they produce sig-
`nificant discomfort for the patient. On the other hand,
`pyrogens ‘have been 'shown to induce a general nonspecific
`resistance to microoiganisms and, on this basis, have been
`used therapeutically. Recent findings indicate that bacteri-
`al pyrogens, when '
`troduced into the body, stimulate the
`production of an eiidogenous (leukocytic) pyrogen that
`causes the familiar physiological responses.
`Pyrogens are pro lucts of the growth of microorganisms.
`The most potent pyrogenic substances are produced by
`Gram-negative bacteria (endotoxins), but Gram-positive
`bacteria and fungi also produce pyrogenic substances of less-
`er potency. Chemicailly endotoxins have been shown to be a
`phospholipid attacheld to a polysaccharide carrier.
`Pyrogens can be destroyed by heating at high tempera-
`tures. The recommended procedure for depyrogenation of
`glassware ‘and equipment is heating at a temperature of 250°
`for 45 min’. It has belen reported that 650° for 1 min or 180°
`for 4 hr likewise will destroy pyrogens. The usual autoclav-
`ing cycle will not do so. Heating with strong alkali or oxidiz-
`ing solutions will destroy pyrogens. It has been claimed that
`thorough washing with detergent will render glassware pyro-
`gen-free if protectedlduring manufacture and storage from
`heavy pyrpgenic contamination. Likewise, plastic contain-
`ers and devices must be protected from pyrogenic contami-
`nation during manufacture and storage since known ways to
`destroy pyrogens will affect the plastic adversely.
`It has
`been reported that anion-exchange resins will adsorb pyro-
`gens from water and reverse osmosis will eliminate them.
`However, ‘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. Howev-
`er, since the adsorption phenomenon also may cause selec-
`tive removal of chemical substances from the solution and
`the filtrate may be co:ntaminated with the agent, this meth-
`od has limited application. Other in-process methods for
`their destruction or elimination include selective extraction
`procedures 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. New develop-
`ments in ultrafiltration now ‘make possible pyrogen separa-
`tion on a molecular weight basis and the process of tangen-
`tial flow increasingly is making large-scale processing a reali-
`ty.
`'
`Sources of Pyrogens—Pyrogens may enter a prepara-
`tion by any means th t will introduce living or dead microor-
`ganisms. Perhaps the greatest potential source of such con-
`tamination is the water usedin processing. Although prop-
`er giisztillation vgill prlclivide pyrogen-free water, storage
`con i ions must
`e siic t at microorganisms are not intro-
`duced and subsequent growth is prevented.
`Another potential source of contamination is equipment.
`Pyrogenic materials a'dhere strongly to glass and other sur-
`faces. Residues of solutions in used equipment often be-
`come bacterial cultures with subsequent pyrogenic contami-
`nation. Even washedl equipment left wet and exposed to the
`atmosphere may contain sufficient nutrients for microor-
`ganism growth.
`Simzze drying does not destroy pyirogensé
`they may remain in equipment for long periods. A equate
`washing greatly will r'educe and subsequent dry-heat treat-
`ment will render contaminated equipment suitable for use.
`The solute may be a source of pyrogens. Solutes may be
`crystallized or precipitated from aqueous liquids containing
`pyrogeiiiic contaminaiiiion.
`In the process,Ipyrogenls; may 1:6
`trappe within the particle layers.
`In suc cases t e so u e
`must be purified by reicrystallization, precipitate washing or
`other means of eliminhting pyrogens.
`
`Page 4
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`fVn_Q-_ff,,.:-.'3
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`Page 4
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`

`
`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
`prepared than can be processed completely within one work-
`ing day, including sterilization.
`
`Containers
`
`Containers are an integral part of the formulation of an
`injection and may be considered a component, for there is no
`container that is totally insoluble or does not in some way
`affect the liquid it contains, particularly if the liquid is
`aqueous. Therefore, the selection of a container for a par-
`ticular injection must be based on a consideration of the
`composition of the container, as well as of the solution, and
`the treatment to which it will be subjected.
`Table I provides a generalized comparison of the three
`compatibility properties—leaching, permeation and adsorp-
`tion—of container materials most likely to be involved in the
`formulation of aqueous parenterals. Further, the integrity
`of the container/closure system depends upon a series of
`characteristics which determine the effectiveness with
`which it achieves its role. These considerations have been
`reviewed by Morton.8
`
`Plastic
`
`Thermoplastic polymers have been established as packag-
`ing materials for sterile preparations such as large-volume
`parenterals, ophthalmic solutions and,
`increasingly, for
`small-volume parenterals. For such use to be acceptable a
`thorough understanding of the characteristics, potential
`problems and advantages for use must be developed. One
`thorough review of these factors relative to pharmaceuticals
`has been prepared by Autian.9 He stated that three princi-
`pal problem areas exist in using these materials; namely,
`
`PARENTERAL PREPARATIONS
`
`1551
`
`1. Permeation q vapors and other molecules in either direction
`through the wall of the plastic container.
`2. Leaching of c nstituents from the plastic into the product.
`3. Sorption (absorption and/or adsorption) of drug molecules or ions
`on the plastic material.
`
`Permeation, the most extensive problem, may be trouble-
`some by permitting volatile constituents or selected drug
`molecules to migrate through the wall of the container to the
`outside and thereby be lost. The reverse of this also may
`occur‘by which 0 ygen or other molecules may permeate to
`the inside of the container and cause oxidative or other
`degradation of siisceptible constituents. Leaching may be a
`problem when ceiirtain constituents of the plastic material
`migrate into the product. This potential problem often may
`be controlled -by careful formulation of the polymer mixture
`with a minimum 'of additives. Sorption seems to be a limit-
`ed problem in t1 e packaging of parenterals and is found
`inost commonly in association with polyamides such as ny-
`on.
`One of the principal advantages of using plastic packaging
`materials is that they are not breakable as is glass; also, there
`is a substantial wright reduction. The flexibility ofthe low-
`density polyethylene polymer, for ophthalmic preparations,
`makes‘ it possible to squeeze the side wall of the container
`and discharge 0 e or more drops without introducing con-
`tamination into t e remainder of the product. The flexible
`bags of polyvinyl chloride or select polyolefins, currently in
`use for large-vol me intravenous fluids, have the added ad-
`vantage that no
`interchange'is required; the flexible wall
`simply collapses as the solution flows out of the bag.
`Most plastic materialsihave the disadvantage that they are
`not as clear as glass and, therefore, inspection ofthe contents
`is impeded. In addition, many of these materials will soften
`or melt under the: conditions of thermal sterilization. How-
`ever, careful selection of the plastic used and control of the
`autoclave cycle has made thermal sterilization of some prod-
`ucts possible, large-volume parenterals in particular. Eth-
`
`Table l—Comparatlve Compatibility Properties of container llllaterials
`Leaching
`Permeation
`
`Extent‘
`
`Potential
`Leachables
`
`Extent‘
`
`Glass
`Borosilicate
`
`Soda-lime
`
`Plastic Polymers
`Polyethylene
`Low density
`
`High density
`
`PVC
`
`Polyolefins
`
`Polypropylene
`
`Alkaline earth and
`heavy metal oxides
`Alkaline earth and
`heavy metal oxides
`
`Plasticizers,
`antioxidants
`Antioxidants
`
`HCI, especially plas-
`ticizers, antioxi-
`dants, other stabi-
`lizers
`Antioxidants
`
`Antioxidants,
`lubricants
`
`Potential
`Agents
`
`N/A
`
`N/A
`
`Gases, water vapor,
`other molecules
`Gases, water vapor,
`other molecules
`Gases, especially
`water vapor and
`other molecules
`
`Gases, water vapor,
`other molecules
`Gases, water vapor
`
`Adsorption
`(selective)
`Extent“
`
`2
`
`Rubber Polymers
`Natural and
`related synthetic
`
`Butyl
`
`Heavy metal salts,
`lubricants, reduc-
`ing agents
`Heavy metal salts,
`lubricants, reduc-
`ing agents
`Gases, water vapor
`Silicone
`Minimal
`“ Approximate scale of 1 to 5 with “1” as the lowest.
`
`Gases, water vapor
`
`Gases, water vapor
`
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