Sterile Dosage Forms
`
`Their Preparation and Clinical Application
`
`Salvatore Turco, M.S., Pharm. D.
`
`Professor of Pharmacy
`Temple University School of Pharmacy
`Philadelphia, Pennsylvania
`
`Robert E. King, Ph.D.
`
`Professor of Industrial Pharmacy
`Philadelphia College of Pharmacy and Science
`Philadelphia, Pennsylvania
`
`3rd Edition
`
`%(
`
`Lea & Febiger
`
`Philadelphia
`
`1987
`
`MYLAN ET AL. - EXHIBIT 1006
`
`0001
`
`MYLAN ET AL. - EXHIBIT 1006
`
`0001
`
`

`
`
`
`Lea & Febiger
`600 Washington Square
`Philadelphia, PA 19106-4198
`U.S.A.
`(215) 922-1330
`
`_
`
`
`
`7
`5
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`_
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`4 -
`1/7”
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`
`K
`l
`- \_1
`
`The use of portions of the text of The United States Pharmacopeia, Twenty-fil‘St R€ViSi0I1,
`official July 1, 1985, is by permission received from the Board ofTrustees ofThe United States
`Pharmacopeial Convention, Inc. The said Convention is not responsible for any inaccuracy
`ofquotation, or for any false or misleading implication that may arise by reason ofthe separation
`of excerpts from the original context.
`
`First Edition, 1974
`Second Edition, 1979
`
`1,
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`.
`
`1»
`/
`
`1
`
`1
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`..
`'7:
`
`*
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`3/
`
`Library of Congress Cataloging-in-Publication Data
`
`Turco, Salvatore J.
`Sterile dosage forms.
`
`Includes bibliographies and index.
`1. Solutions (Pharmacy)--Sterilization.
`2. Parenteral therapy. 3. Drug trade--Hygienic
`aspects. I. King, Robert E., 1923-
`.
`II. Title.
`[DNLM: 1. Dosage Forms. 2. Drug Compounding.
`3. Sterilization. QV 778 T933s]
`RS201.S6T87
`1987
`615’.63
`ISBN 0-8121-1067-6
`
`86-21470
`
`
`
`Copyright @€9T37
`
`Lea & Febiger. Copyright under the International Copyright Union. All
`
`Rights Resei ed. This book is protected by copyright. No part of it may be reproduced in
`any manner or by any means without written permission of the p11l)lishcr.
`
`PRINTED IN THE UNITED STATES OF AMERICA
`
`Print No. 4
`
`3
`
`2
`
`1
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`0002
`
`

`
`Chapter 4
`
`Large Scale Preparation
`
`Whether sterile products are prepared on an industrial scale or made extempo—
`raneously by the hospital pharmacist,
`the raw materials used, the procedures in-
`volved, the packaging, and the care taken determine whether the final products will
`have the required characteristics previously described. Quality must be built into
`the products from the beginning; it cannot be imparted after the products have been
`made. Although the extemporaneous preparation ()f one or two units ofsterile prod-
`ucts by the hospital pharmacist may appear to be simpler than the preparation of
`tens of thousands of units by a large group of personnel in an industrial setting, in
`essence there is a great similarity in factors that must be considered. The 1nai11
`differences are found only in the steps taken, owing to the large quantity of materials
`used and the number of personnel involved in industrial operations. In the following
`discussion, the preparation of a large number of units of sterile products is described.
`In Chapter 5, the conditions necessary in the extemporaneous preparation of a few
`units are described, and the similarities between the two operations are noted.
`
`Environmental Control
`
`If sterile products are to be free from particulate matter, they must be prepared,
`sterilized, and packaged in an environment free of particulate matter. In the overall
`processing, certain steps have more critical requirements than others. In Figure
`4-1, note that critical steps include the preparation of the filling area, the procedures
`of washing and sterilizing the packaging components, and the preparation of the
`personnel who fill or subdivide the product into its final package.
`The filling area, or room in which the solution is subdivided into its final package,
`is critical, because at this point, the solution is exposed to both the environment
`and the personnel involved. Thus, this area must be maintained as free as possible
`from particulate matter, such as dust, lint, and fibers. The air supplying these areas
`can be passed through high efficiency particulate air (HEPA) filters capable of re-
`moving particles of 0.3 pm or greater with an efficiency of 99.97%. Microbial con-
`taminants present in air are usually found on dust and other particulate matter and
`are also hereby removed. Thus, the filtered air coming into this critical area is free
`of both particulate and microbial contamination. The air is supplied under positive
`pressure, i.e., the air in the critical area, having a higher pressure than air in the
`adjoining areas, flows outward when doors are opened. This prevents particulate
`contamination from sweeping into the critical filling area.
`The critical filling area is constructed from materials that can easily be cleaned
`and disinfected. The walls can be stainless steel or regular wall material covered
`with an epoxy resin paint. Likewise, the work surfaces and floor are smooth and free
`()f cracks and crevices. The entire facility may be irradiated with ultraviolet lamps
`
`36
`
`0003
`
`0003
`
`

`
`Preparation of
`Personnel
`
`Preparation
`of Area
`
`Filtration:
`clarification
`
`Subdivide,
`Seal, and Label
`
`Sterilization:
`AutoclaveI
`
`Critical
`
`Control —-> Distribution —> Storage
`
`—->Manipulotion
`
`:
`‘
`F'lt
`clarrilllzocxrlion and —?——> subdivide
`sterilizotion
`and Seal
`
`Inspect
`
`
`
`
`
`NOlJ.VHVd3HclEFIVOS3E)HV'|
`
`IIIIIIIIII
`
`(Drug stable to heat)
`
`I
`(Drug unstable o heat)
`\i
`.
`l.
`ll
`
`II
`
`Preparation
`of Solution
`
`Critical
`
`Washing containers
`and closure:
`
`Figure 4-1.
`
`Flow sheet for the preparation of sterile products.
`
`0004
`
`

`
`STERILE DOSAGE FORMS
`
`Figure 4-2. A, Vertical laminar air flow in production facility. Air turbulence is minimized
`and environmental control can be achieved. 8, Prefiltered air is forced through a high
`efficiency particulate air (HEPA) filter and flows downward over filling equipment,’ contin-
`ually bathing the area with clean air. (Courtesy of Wyeth Laboratories, Philadelphia, PA.)
`
`to assure the disinfection of all surfaces exposed to the rays and to maintain sterility
`once personnel have entered the room. Personnel must be protected from ultraviolet
`irradiation while they are working in this area.
`
`Laminar Air Control
`
`From his work in the space technology program in the early 19605, Dr. VVillis
`Whitfield developed the concept of laminar air flow while trying t() improve on
`conventional clean rooms.1 He noticed that filtered air forced through wall or ceiling
`ducts creates swirls in the airstream that can trap particles and microorgaiiisms in a
`room. His concept of laminar air flow is a bank of filtered air that moves through a
`work area in a parallel configuration and at suflicient speed to sweep contamination
`with it and create a minimum of turbulence (Fig. 4-2). Laminar flow is defined in
`federal regulations as “air flow ir1 which the entire body of air within a confined
`space moves with uniform velocity along parallel lines with a minimum of eddies.”
`The velocity of the air for effective laminar air flow is usually stated as 90 : 20 feet
`per minute throughout the undisturbed room area.
`The concept of laminar air flow has been applied in the parenteral drug industry
`in a number ofways. Some companies, when building new facilities, have constructed
`laminar air flow rooms for their critical operations. In these rooms, an entire wall
`consists of HEPA filters through which the air is forced. The m()st critical operations
`are placed closest to the laminar air flow wall, and the less critical are placed farther
`away. Laminar air flow units have been placed above filling machines, with the vertical
`laminar air flow washing all particulate material froin the area where the open con-
`tainers receive the solutions. Constructed in the form of hoods,
`laminar air flow
`equipment is used extensively for sterility testing and for aseptic manipulations in
`hospitals; the latter application is discussed in the next chapter.
`By federal standards, clean rooms have been classified into three groups: Class
`100, Class 10,000, and Class 100,000.? This classification is based on the particle
`count. The maximum allowance of particles permissible is 0.5 pm and larger or 5.0
`pm and larger. The limits are expressed as follows:
`Class l00—Particle count not to exceed a total of 100 particles per cul)ic foot
`of a size 0.5 pm and larger.
`Class l0,000—Particle count not to exceed a total of 10,000 particles per cubic
`
`0005
`
`0005
`
`

`
`LARGE SCALE PREPARATION
`
`39
`
`foot of a size 0.5 pm and larger, or 65 particles per cubic foot of a size 5.0
`pm and larger.
`Class l00,000—Particle count not to exceed a total of 100,000 particles per
`cubic foot of a size 05 um and larger, or 700 particles per cubic foot of a
`size 5.0 pm and larger.
`
`All clean room facilities must be monitored to assure that they are receiving proper
`maintenance.“ The rooms are monitored for both viable and other particulates to
`confirm adherence to established standards. The microbial content of the ambient
`air can be determined by settle plates (fallout plates) or mechanical air-sampling
`devices such as the Anderson sampler and the Reynier slit air sampler. Settle plates
`consist of open Petri dishes containing sterile nutrient agar, which are exposed to
`the air for a prescribed length of time. After the plates are incubated at a specified
`temperature and for a specified period of time, a count is made of the number of
`colonies on each plate. The disadvantages of the technique are that only the larger
`particles settle rapidly and that the volume of air tested is not known. These draw-
`backs are avoided when the mechanical air—sampling devices are used. Air is drawn
`through these instruments at a specified rate over a Petri dish containing sterile
`nutrient medium. After incubation, the counts can be expressed as the number of
`colonies per cubic foot of sampled air. Surface swabs subjected to the same procedures
`are used to determine microbial contamination of floors and flat surfaces.
`Nonviable particulates are counted by electronic devices such as the Royco particle
`counter. Standards are established, and deviation from these standards for both viable
`particles and other particulates can be readily detected. Cleaning procedures and
`schedules are of utmost importance in maintaining the low levels of particulate
`contamination required for the satisfactory manufacture of sterile products.
`Likewise, HEPA filters, whether they are located in hoods, walls, or ceiling, must
`be routinely checked for the presence of cracks and the maintenance of proper
`velocity (see “Environmental Control” in Chap. 5). Manufacturers of laminar flow
`equipment, as well as private laboratories, offer maintenance contracts for the con-
`tinued safe operation of the equipment.
`
`Personnel
`
`The greatest source of particulate matter and possible microbial contamination in
`the preparation of sterile products, and the most difficult to monitor, is the personnel
`involved. When working in this critical area, personnel are garbed in jumpsuits,
`including hood and gloves. Their shoes are covered with disposable boots. The
`uniforms are most satisfactory when made from monofilament fabrics, such as Dacron
`or Ty-Vek, which do not shed lint or fibers. By nature, the personnel should be
`conscientious and reliable. The best standard operating procedures fail when they
`are not followed. Motivation of personnel is accomplished by giving them a thorough
`understanding of the importance of their tasks, and such motivation becomes critical
`to the operation. These personnel include not only the persons involved in the filling
`operation but also those given responsibility in other areas, such as maintenance.
`Failure to do their jobs adequately can result in the failure of the production lot, or
`worse, the passing through control of a lot of material that fails in one or more of
`the requirements for sterility, freedom from particulate matter, or freedom from
`pyrogens.
`
`0006
`
`0006
`
`

`
`40
`
`STERILE DOSAGE FORMS
`
`Packaging Components
`
`Materials used for packaging and administering parenterals include components
`made of glass, rubber, stainless steel, and plastic. Regardless of its composition or
`form, the packaging material constitutes a likely source for stability problems, par-
`ticulate matter, and pyrogens.5 Since the initial use of glass for sterile products early
`in this century, much progress has been made in glass technology, and many problems
`rising from its use as a packaging material have been solved.
`
`Glass
`
`The degree of resistance of the product to glass varies with the type of product to
`be packaged in the container. The chemical attack rate of aqueous solutions on glass
`is high but varies with the pH and the constituents of the aqueous solution. On the
`other hand, solutions of a hydrophobic nature, such as oils, organic solvents, or dry
`sterile solids, show little chemical attack 011 the glass. Aqueous solutions containing
`heat-stable drugs frequently are terminally sterilized in the final glass container, and
`the heat of the sterilization process accelerates the chemical attack on the glass. The
`chemical attack by parenteral products on glass is due primarily to released alkali,
`which can cause deleterious effects on the parenteral solution following changes in
`pH, composition, color, and stability.
`Class is made by fusing amorphous silicon dioxide (sand) with metallic oxides at
`high temperatures.“ The characteristics of the resultant glass depend on the nature
`and quantities of the alkaline earth and metal oxides. Glass prepared from silica, in
`combination with a relatively high amount of boron oxide and small amount of the
`alkaline earth oxides, is a borosilicate glass with high chemical stability, low coefficient
`of thermal expansion, and high resistance to heat shock. Glass containing no boron
`oxide and high quantities of the alkaline earth oxide is a “soft” glass having poor
`chemical and heat resistance. The latter glass is more easily worked (i.e., molded),
`and therefore is lower in cost. Amber glass used for products sensitive to light contains
`manganese oxide, which gives the glass its color.
`For parenteral products, the compendia have classified glass based on its resistance
`to water attack and its release of alkali. The U.S.P. classification is as follows: Type
`1—highly resistant borosilicate glass; Type II—treated soda—lime glass; and Type
`III——soda—lime glass. Type II glass is essentially soda—lirne glass that after being
`molded into the desired form is treated with acidic gas under controlled humidity
`and elevated temperatures to neutralize the alkali present on the surface of the glass;
`the alkali forms sodium sulfate, which is subsequently removed in washing the
`containers. The sterilization of glass packaging components is also influenced by the
`type of glass. Class components molded from Type I glass may be sterilized before
`or after filling with solution, whereas Type II glass should be sterilized by dry heat
`prior to filling; Type III glass must be sterilized by dry heat before filling.
`Initially, glass packaging components for new products are made from Type I glass
`to eliminate as many container problems as possible. As experience and stability data
`are collected for a product,
`the manufacturer may find it possible to use a less
`expensive glass, such as Type II or Type III. Products having a pH greater than 7.0,
`or one that may become alkaline before the expiration date, should not be packaged
`in Type II or Type III glass containers. Type II glass containers may be used for
`solutions having pH values less than 7.0. Both Types II and III are suitable for oils
`and sterile powders.
`
`0007
`
`0007
`
`

`
`LARGE SCALE PREPARATION
`
`TABLE 4-1. Composition of Rubber Packaging Components
`
`Component
`Rubber
`Vulcanizing agent
`Accelerator
`Activator
`Fillers
`Plasticizer
`Antioxidants
`
`Composition
`Natural, neoprene, or butyl
`Sulfur
`Guanidines, sulfide compounds
`Zinc oxide, stearic acid
`Carbon black, kaolin, barium sulfate
`Dibutyi phthalate, stearic acid
`Aromatic amines
`
`One source of precipitate observed in solutions packaged in glass results from the
`reaction of components of the solution with the alkali leached from the glass, or the
`leaching of metallic ions, which act as catalysts for other reactions. Solutions con-
`taining phosphates, citrates, or tartrates are subject to flake formation, owing to
`reaction with materials from the glass. Precipitates were observed when commercially
`prepared solutions of dextrose 5% in water are combined with solutions containing
`40 mEq potassium chloride.7 The precipitate was shown by analysis to be silica and
`alumina. It is highly probable that the silica was material leached from the glass
`container.
`
`Another example of the leaching of solids fro1n glass is the total solids requirements
`for Sterile Water for Injection. Whereas Water for Injection has a limit of 10 ppm,
`Sterile Water for Injection is permitted higher limits depending on container size:
`40 ppm for containers up to and including 30-ml size, 30 ppm for containers 30- to
`100—ml size, and 20 ppm for larger sizes. A greater limit is permitted for Sterile
`Water for Injection because of the leaching of material from the glass during steri-
`lization. The requirement decreases as the volume increases, because the ratio of
`the volume to the wetted inner surfaces decreases.
`
`Rubber
`
`To provide closures for multiple-dose vials, intravenous fluid bottles, plugs for
`disposable syringes, and bulbs for ophthalmic pipettes, rubber is the material of
`choice. Its elasticity, ability to reseal after puncture, and adaptability to many shapes
`tend to make it unique. One must remember, however, that the composition of any
`single piece of rubber represents the combination of many ingredients to give it the
`characteristics required. To understand some of the problems arising from the use
`of rubber for packaging components,
`it is necessary to understand the variety of
`materials in the final composition of the package (Table 4—l).
`The rubber compound is the basic ingredient, and this polymer is vulcanized in
`the presence of sulfur with heat. The vulcanization reduces plasticity and improves
`the resistance of the rubber to changes in temperature. To increase the rate of
`vulcanization, compounds such as guanidine derivatives are present as accelerators;
`these in turn are activated with materials such as zinc oxide and stearic acid. The
`tensile strength, hardness, and permeability are influenced by materials such as
`carbon black and barium sulfate; these materials are called fillers. Plasticizing agents
`and antioxidants are added to reduce the effect of oxygen on the rubber compound.
`The rubber and the additives are mixed, then subjected to heat and pressure during
`the molding process for the given rubber packaging components. Thus, the rubber
`piece that serves as a closure for a parenteral vial or a plug in a disposable syringe
`is a complex material.
`
`0008
`
`

`
`42
`
`STERILE DOSAGE FORMS
`
`Several problems originate from the rubber closure. It the closure is incompatible
`with the solution, the solution can become discolored, turbid, and degraded. Surface-
`active agents in the solution can extract chemicals from the closures; the extractives
`in turn can catalyze or react with ingredients in the solution, causing physical or
`chemical instability. There may be loss of the preservative or other added materials
`in the solution, owing to their absorption into the closure. For moisture—sensitive
`sterile solids, the closure may permit the transfer of moisture, causing the degradation
`of the drug. For every product, the compatibility of the rubbr closure with the sterile
`solution, suspension, or powder must be determined and the best closure selected.
`Once a given rubber closure has been selected for a parenteral product, the rubber
`manufacturer has the responsibility to maintain consistently all characteristics of the
`closure. To do this, tests such as ash, specific gravity, ultraviolet, and infrared spec-
`trophotometric analysis of solvent extract are used.“-9
`One of the most frequently encountered problems associated with rubber closures
`is that of coring.1° Coring is the generation of rubber particles cut from the closures
`when needles or medical devices are inserted; the particles are known as “cores”
`(see “Techniques of Parenteral Administration” in Chap. 6). Cores are deposited in
`the solution or remain in the cannula. It is believed that the cores are cut from the
`
`lower surface of the closure when the heel of the needle enters the rubber. Although
`coring is primarily attributed to the design of the needle, the composition of the
`rubber used for the closure also can influence the degree of coring. The tendency
`of a rubber closure to core sometimes represents a compromise in composition to
`obtain a rubber closure with good stability.
`Coring is observed at time of use of the product. Unduly large gauge needles
`increase the chance of coring. Some precautions may be taken to minimize it. A
`minimum gauge needle should be inserted with the bevel side up at an angle less
`than 45 degrees. After penetration of the closure, but before entrance into the
`container, the needle should be in the vertical position. Rubber closures on products
`that require refrigeration or freezing become more prone to coring. Delaying the
`reconstitution of the product until after the closure has warmed to room temperature
`alleviates the coring tendency. Similar care must be exercised when inserting plastic
`spikes into large volume intravenous fluids. The prepared or reconstituted product
`should be examined for cores. The presence of cores indicates that the product should
`be discarded, or in some instances,
`it may be necessary to remove the cores by
`filtration to salvage the product.
`
`Plastic
`
`The plastic used in preparing packaging material is also complex.” The primary
`constituent is the plastic polymer, usually polyethylene or polypropylene. The poly-
`mers differ in their characteristics. Polyethylene exhibits low water absorption, high
`resistance to most solvents, and low resistance to heat. For this reason, polyethylene
`items cannot be sterilized by autoclaving. On the other hand, polypropylene shows
`high resistance to most solvents and can be autoclaved. In addition to the plastic
`polymer, other chemicals are added to modify the physical characteristics of the
`material, e.g., plasticizers to improve flexibility; stabilizers to protect the plastic from
`light and discoloration; accelerators to increase the rate of polymerization ofthe resin;
`antioxidants to retard oxidation; fillers to modify physical properties such as strength;
`colorants; and lubricants in the case of molded pieces. The composition of the plastic
`and of the solution determines the degree of reactivity between the additives of the
`
`0009
`
`0009
`
`

`
`LARGE SCALE PREPARATION
`
`43
`
`plastic and the components of the solution. Substances can be leached from the
`plastic into the solution, and ingredients from the solution can be absorbed by the
`plastic. The plastic may be permeable to moisture, permitting loss of volume and
`modification of concentration of the solution. The degree to which these problems
`occur depends on whether the plastic device or container, such as a disposable plastic
`syringe,
`is for short-term, one-time use, or whether the device is to be used as a
`package in which a solution is to be stored over a long period of time.
`
`Preparation of Packaging Components
`Before being used to package sterile products, glass and rubber components are
`washed and sterilized. Improper handling of packaging materials in the preparation
`stage is one of the greatest sources of contamination by particulate matter. Glass
`containers received in cardboard and chipboard boxes contain dust generated by
`these packaging materials. This dust and other particulates are difficult to eliminate,
`and frequently, the empty glass containers are vacuumed prior to washing. Another
`approach to reducing troublesome particulates has been the use of “shrink wrapping. ”
`Groups of empty glass containers are wrapped tightly together with plastic film before
`shipment, thus eliminating the contact of the glass with the cardboard cartons. The
`glass containers are passed through a number of cycles in automatic washing equip-
`ment. The cycles vary depending on the type of equipment, but usually consist of
`rinsing the container alternately with cold water and then with steam. The expansion
`and contraction of the glass break down films and allow steam to penetrate and clean
`the surface. This “shock treatment” promotes the removal of all particulate material.
`The washing consists of the following steps: (1) outside, rinse with filtered water; (2)
`inside, rinse with steam; (3) outside, rinse with filtered water; (4) inside, rinse with
`steam; (5) outside, rinse with filtered water; (6) inside, rinse with steam; (7) inside,
`rinse with steam. Rough treatment of glassware in the washing equipment or during
`handling can generate glass particulate matter, which subsequently contaminates the
`filled containers. After washing,
`the glass containers are placed in stainless steel
`boxes and are rendered pyrogen-free and sterile by means of dry heat. The handling
`area for the wet containers is maintained under vertical laminar air How to prevent
`the particulates in the environment from contaminatingthe clean wet containers
`(Fig. 4-3). After heating, the containers are moved to a sterile area and allowed to
`cool
`
`Washing procedures for glass containers have been made more effective for re-
`moving particulate matter by including a fluoride treatment in the wash cycle. The
`containers are washed with either dilute hydrofluoric acid or ammonium bifluoride
`solutions. The glasses are allowed to remain in contact with the fluoride solution for
`approximately 30 seconds before the solution is rinsed away. This treatment removes
`a thin surface, layer of the glass with its adherent particulate matter. When this
`procedure is used, the safety of personnel must be a consideration.
`As a method of sterilization, dry heat is not as efficient as moist heat, and therefore
`higher temperatures and longer exposure times are required. Dry heat sterilization
`is effective for oxidizing, or “burning up," and sterilizing chemicals and oils, provided
`temperatures below their decomposition temperatures are used. Many variables must
`be considered in using dry heat sterilization, including size of the oven, size of the
`load, arrangement of the load, and nature of the material being sterilized. Ovens
`usually have circulating forced-air heat. Glass containers are usually heated at 180°
`
`0010
`
`0010
`
`

`
`44
`
`STERILE DOSAGE FORMS
`
`Figure 4-3. Cozzoli vial washer equipped with filters (arrow) for the water used for the
`two final rinses. The washed vials pass from the machine into a laminar air flow area.
`(Courtesy of Pail Trinity Micro Corporation. Cortland, NY.)
`
`C or higher for 4 hours. This period would be in addition to the time necessary for
`the contents to reach 180° C and would Vary considerably with the factors mentioned
`previously.
`In preparing rubber components such as closures and plugs, the objective is to
`eliminate surface dirt, rubber particles, and water-soluble extractives, and to render
`the closures sterile. The danger is that,
`if they are handled roughly, particles will
`be generated by the rubbing surfaces of the rubber pieces; this can be a source of
`particulate matter found later in the filled container. Methods of preparation vary in
`the industry, but usually they consist of gently agitating the closures in a mild
`detergent, thoroughly rinsing the detergent away, autoclaving the closures immersed
`in Water for Injection several times, autoclaving the wet closures in a suitable sealed
`package, and drying at low heat. Autoclaving involves the use of moist heat under
`pressure. Autoclaving the closures in Water for Injection allows for the extraction of
`the water-soluble constituents before the closure is placed on a filled container and
`autoelaved. If this step were not performed, any water-soluble extractives present
`would pass into the parenteral solution.
`Plastic containers are usually washed with filtered air to remove particulate ina-
`terial, then are suitably wrapped and sterilized with ethylene oxide. One of the great
`advantages ofethylene oxide sterilization of plastics is that the gas, owing to its ability
`to diffuse and penetrate, sterilizes the plastic materials after they have been assem-
`
`0011
`
`0011
`
`

`
`LARGE SCALE PREPARATION
`
`45
`
`bled and placed in their final packaged form. Chemically, ethylene oxide is a cyclic
`ether, a liquid to 10° C; above this temperature, it is a gas. It is miscible with water
`and common organic solvents. On the skin, it acts as a vesicant, a11d o11 inhalation,
`it has the toxicity of ammonia gas. It forms an explosive mixture with air and therefore
`is usually used in combination with carbon dioxide (10% ethylene oxide and 90%
`carbon dioxide) or fluorinated hydrocarbons (12% ethylene oxide and 88% Iluorinated
`hydrocarbons). For some industrial applications, 100% ethylene oxide is used.
`As in dry heat sterilization, many variables have to be considered when using
`ethylene oxide as a sterilant. The material to be sterilized is wrapped and placed in
`a chamber, which is subsequently heated to 130° F to increase the effectiveness of
`the ethylene oxide. The relative humidity of the chamber and the moisture content
`of the material are important factors in determining the efficacy of the method.
`Under ideal conditions, a relative humidity of 30 to 50% is desirable. Sufficient
`ethylene oxide is introduced into the evacuated chamber to reach a concentration
`of 450 mg per liter. An exposure time of 4 hours or longer is used, depending on
`the material, type of packaging, and size of the chamber. After the sterilization cycle
`is completed, the material is placed in quarantine for five days to two weeks to allow
`the residual ethylene oxide to vaporize. The time required for the residual amount
`of ethylene oxide to dissipate depends on the nature of the material, the method of
`packaging, and the conditions under which the material was sterilized.“
`Another concern iii the use of ethylene oxide is the presence of reaction products;
`ethylene oxide can react with water to form ethylene glycol, with chloride ion to
`form 2-chloroethanol, and with sulfhydryl groups to form 2-mercaptoethanol. VVhen
`present in sufficient concentration on the sterilized item, these reaction products
`can cause untoward and toxic reactions. As a sterilization process, ethylene oxide
`must be adapted t() the material and conditions involved. Recommendations can be
`considered only in general terms.
`
`Preparation of Product
`Equipment used for the preparation of sterile products should be clean, sterile,
`and free of pyrogens. If the size of the mixing containers precludes the elimination
`of pyrogens with dry heat, they should be thoroughly rinsed with Water f()r Injection
`prior to use. The purest chemical grades of the added substances should be selected.
`Following its formulation in a clean but not necessarily sterile area, the solution is
`ready to be taken into the sterile filling areas. In some manufacturing facilities, the
`mixing tanks are taken into the filling areas; in other facilities, the solution is pumped
`through the lines installed through the walls. Since the solution is not sterile at this
`point,
`it should be packaged and sterilized within 24 hours. If this is not possible,
`the bulk solution must be sterilized and stored as a sterile solution.
`
`Clarification and Sterilization
`
`Subsequent handling depends on whether the drug in solution is heat stable or
`heat labile. Heat—stable solutions are clarified (passed through a suitable filtration
`medium to remove particulate matter), subdivided into the final containers, sealed,
`and subjected to terminal sterilization by autoclaving (Figs. 4-4 and 4-5). Heat-
`labile solutions are passed through a suitable filtration medium for both clarification
`and sterilization, and then subdivided into the final sterile containers and sealed (see
`Fig. 4-1).
`
`0012
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`
`STERILE DOSAGE FORMS
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`Figure 4-4. Schematic drawing of parts of an autoclave. (Courtesy of American Sterilizer
`Company, Erie, PA.)
`
`In general, filtration media can be divided into two broad groups, depth filters
`and screen filters. Depth filters have been made from asbestos, fritted glass, and
`unglazed porcelain. They trap particles in tortuous channels, thereby clarifying the
`solution. All the media are available in a large number of pore sizes, the finest being
`suitable for removing microorganisms with subsequent sterilization of the solution.
`These media represent an older group of filters. As a group, they hav