Pharmaceutical
`Dosage Forms:
`Parenteral Medications
`Volume1
`
`Second Edition, Revised and Expanded
`
`. I
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`!
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`I.
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`Library of Congress Cataloging — in - Publication Data
`
`Pharmaceutical dosage forms , parenteral medications I edited by
`Kenneth E. Avis, Herbert A. Lieberman, and Leon Lachman.
`rev. and expanded.
`
`-— 2nd ed.,
`
`cm.
`p.
`Includes bibliographical references and index.
`ISBN 0-8247-8576-2 (v. 1 : alk. paper)
`1. Parenteral solutions. 2. Pharmaceutical technology.
`Kenneth E.
`II. Lieberman, Herbert A.
`III. Lachman, Leon.
`[DNLM: 1. Infusions, Parenteral.
`WB 354 P536]
`RS201.P37P48 1992
`615'. 19--dc2O
`DNLM /DLC
`for Library of Congress
`
`I. Avis,
`
`2. Technology, Pharmaceutical.
`
`91 —38063
`CIP
`
`This book is printed on acid-free paper.
`
`Copyright © 1992 by MARCEL DEKKER, INC. All Rights Reserved
`
`Neither this book not any part may be reproduced or transmitted in any form
`or by any means, electronic or mechanical, including photocopying, micro-
`filming, and recording, or by any information storage and retrieval system,
`without permission in writing from the publisher.
`
`MARCEL DEKKER, INC.
`270 Madison Avenue, New York, New York 10016
`
`Current printing (last digit):
`I0 9 8 7 6 5 4 3 2 1
`
`PRINTED IN THE UNITED STATES OF AMERICA
`
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`_ __
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`158
`
`Motola and Agharkur
`
`Formulation of protein drugs into products using this type of preformuJa-
`tion data base is well documented [72] in the literature.
`It is also a subject
`of a separate chapter of this book.
`
`VI. PREFORMULATION SCREENING OF PARENTERAL
`PACKAGING COMPONENTS
`
`One of the more difficult and often time-consuming requirements during paren-
`teral product development is the selection of compatible packaging components,
`generally comprised of glass, elastomeric closures, and plastics. Although
`the dividing line between where preformulation stops and where formulation
`and package development studies begin may be defined differently among in~
`dustrial organizations, preformulation work done toward package selection is
`often critical to the early smooth development and progression of a parenteral
`product.
`In many cases extension of expiration dates of parenteral products
`are limited to a physical incompatibility involving elastomeric closure and/or
`glass interaction with the formulation.
`For example, the investigation for a compatible elastomeric closure and
`multiple-dose vial can be approached by screening studies initiated at a later
`stage of preformulatlon or, if need be, initially for those requiring the use of
`multiple-dose vials throughout the development program.
`
`A. Closure Selection Process
`
`Basic considerations for the selection of a compatible closure formulation are
`based on numerous factors. Those of high importance at the preformulation
`stage are physical and chemical compatibility of the closure with the formula-
`tion as well as the rate of water vapor permeability, oxygen permeability (if
`oxidation is a problem), sorption of active and preservative. level and type
`of extractives, pH change, color change, and particulate matter formulation.
`These criteria as well as others have been reviewed [83] and presented as
`guidelines [84] for closure selection. The reactivity of the formulation and
`presence of certain excipients, such as preservatives, buffers, antioaddants,
`and chelating agents may influence the general type of elastomer required.
`Several general properties of elastomeric closures useful for initial closure
`screening studies are:
`
`1. Oxygen permeation through butyl rubber is almost 20 times less than
`natural rubber [83], and is therefore of choice in circumstances where
`oxidation is likely to cause color formation, color change, or chemical
`loss.
`
`2.
`
`Swelling characteristics of neoprene in oil at 160°C is 7 to 10 times
`less than for natural rubber or butyl [85], therefore making neoprene
`a prime choice for oil products.
`3. Butyl closures have been shown not to absorb the preservatives ben-
`zyl alcohol and methylparaben from solution, whereas natural rubber
`and neoprene absorbed approximately 10% after 12 weeks of storage
`at 60°C [86] . Significant loss of preservative in a multiple-dose vial
`could result in serious microbial contamination following multiple en-
`tries.
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`Preformulation Research
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`159
`
`4. Elastomeric closures contain metallic salts which may be incompatible
`with certain excipients in a formulation. The presence or absence of
`closure— derived incompatible ions should be determined by an extrac-
`tion procedure [87] using distilled water or the formulation vehicle.
`Should certain metallic ions be present that appear to be incompatible
`with the product, such as zinc for a phosphate-buffered product,
`procedures can be designed to remove the surface excess zinc and
`other group II ions by an appropriate washing and autoclaving pro-
`cedure using edetate disodium [88].
`5. other tests relating to performance and identity characteristics as
`well as a list of potential elastomeric closures in use for various prod-
`uct applications is available [89].
`
`B. Closure Screening Experiment
`Assuming that the investigator has developed general information as described
`above and has previous experience with a similar drug product, a series of
`closures can be identified for screening with appropriate input by the closure
`manufacturer. For example, if five closure formulations are identified for
`trlal with a solution of drug in water at the appropriate pH, the following
`types of tests can be run:
`
`1. Place 400 ml of formulation into each of five 1-liter type-l glass bot-
`tles or flasks.
`Into each flask place a sufficient number of whole
`closures to provide a total exposed surface area of approximately 200
`cm2. The closures should have been previously washed. An ex-
`ample procedure is to wash the closures in a detergent solution such
`as benzalkonium chloride followed by adequate rinsing and autoclav-
`ing for 30 min at 121°C with an appropriate vacuum drying cycle.
`This will ensure an equal pretreatment for all closures. A blank us-
`ing the formulation alone is prepared similarly. The flasks are appro-
`priatelv sealed with either Teflon-lined screw caps or ground- glas
`stoppers.
`2. The containers are placed at room temperature and 35°C on a shaker
`set at a low rpm rate so that the solution movement is obtained with
`minimum discernible closure movement to avoid abrasion. Samples
`are examined at 1- and 2-week intervals for the following:
`
`pH change from initial reading.
`a
`b. Visual comparison of color: Each flask should stand for at least
`5 min to allow for settling. A 10 ml sample is withdrawn from
`the top portion of the sample and placed into an appropriately
`sized test tube. These tubes are then placed onto a white back-
`ground and viewed from the top of the test tube down onto the
`paper. A color ranking is then recorded for each closure formu-
`lation versus the water, such as: no change from initial, slight
`color, pronounced color. and so on.
`If appropriate, APHA color
`can be determined as described previously.
`c. Solution clarity: Visual solution clarity is determined from the
`supernatant liquid of each flask using descriptions such as: clear
`
`‘
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`Motola and Agharkar
`
`with no precipitate, clear with precipitate, cloudy without pre-
`cipitate, cloudy with precipitate, very cloudy. Samples are ranked
`in accordance to degree of clarity.
`d. Particulate matter: A determination is made by shaking each flask
`and quickly withdrawing a 50 ml aliquot by pipet and transferring
`onto a prewashed, preweighed 0.45 um membrane. The precipi-
`tate is washed with 10 ml of fresh distilled water and dried to
`constant weight. Each membrane is weighed and viewed under
`a stereoscopic microscope at a 10x magnification. A rank order
`of sample cleanliness and weight of precipitate is determined.
`e. Physical dimensions: Physical dimensions of the closures are
`checked versus untreated samples to detect swelling, color change,
`and so on, and hardness.
`1. Chemical assay: The chemical assay for active and preservative
`is determined by the appropriate procedure.
`
`Test parameters are checked at weekly intervals for at least 2 weeks, at which
`time each closure is ranked and selection of the best two performing candidates
`is made.
`If all closures are judged unsatisfactory, additional selections must
`be made. Experiments using two or more closure manufacturers at the same
`time may increase changes of success since factors involved in closure product
`compatibility are still unpredictable. Alternatively, a more rigorous extraction
`procedure [87] can be employed where closures contained in extraction flasks
`covered by beakers are autoclaved for 2 hr at 121°C. Following this procedure,
`tests are run on the extract after cooling to room temperature.
`The goal of the screening process should be to identify at least two clo-
`sures that can be recommended to the formulator for long-term product evalu-
`ation.
`
`C. Class Selection
`
`When possible, glass ampuls should be used during preformulation studies.
`The work necessary to identify suitable vial and closure systems usually takes
`much more time than available at this stage. Studies done in ampuls can usu-
`ally be directly carried over to the formulation stage for use in toxicological
`and early clinical trials. Ampuls provide the best seal to either exclude oxy-
`gen or retain an inert atmosphere if required, and their reactivity with formu-
`lations is relatively low compared to glass vials and elastomeric closures , par-
`ticularly over a wide pH range.
`Type I glass, as defined in USP XXII, refers to borosilicate glass, which
`is generally used for preparations intended for parenteral administration.
`Type II glass. soda-lime glass that is treated with an agent such as ammonium
`bisulfite to remove surface alkalinity, is usually used for packaging acidic
`and neutral preparations. To be classified as such, type I and type II glass
`must pass a test related to alkalinity of an aqueous extract.
`Although such a test defines type I glass, there are subtle differences in
`the manufacture of type I glass which may affect compatibility [90, 91] . Some
`type I glass is made without added barium ions. and is highly preferred for
`use with drug solutions containing sulfate ions since leaching of barium from
`the glass matrix can often result in microprecipitates in the form of very in-
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`4 and A9h°7"k0T‘ Preformulation Research
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`161
`
`In such a case. barium-free glass is desirable and should be
`
`"
`
`without pre -
`soluble B11804.
`“P195 939 1‘*mke' recommended.
`Large volume containers as well as small vials and ampuls must be scrupu-
`lldflg each flask lously washed using a production-type washing procedure before carrying out
`15 transferring preformulation studies, especially if examination of particulate matter is to be
`The precipi-
`made and results are to be predictive of product manufactured during the
`Id dried to
`development program.
`lewed under
`X rank order
`etermined.
`assures are
`
`D.
`
`Inspection for Particulate Matter
`
`The inspection of small and large volume parenteral containers for particulate
`E» 00101‘ G1‘-31189 matter can be done by several methods, all of which provide important informa-
`tion .
`
`preservative
`
`veeks, at which
`-ming candidates
`elections must
`a at the same
`
`flosure product
`)l‘0lJ.5 extraction
`traction flasks
`,1 this procedure
`
`east two _c1o-
`produot evalu-
`
`ion studies.
`a usually takes
`apuls can usu-
`toxicological
`' exclude oxy-
`~ity with formu-
`closures , par-
`
`2 glass, which
`nistration.
`h as ammonium
`
`ging acidic
`type 11 glass
`
`differences in
`90.91]. Same
`referred for
`fbarlum from
`
`n of very in-
`
`1 .
`
`2,
`
`3.
`
`General visual inspection of each unit can be made uing a fluorescent
`light source against a light and dark background with or without the
`aid of a magnifying lens. Such inspection is useful in determining the
`presence of visual particulate matter in each unit tested.
`A particle counting device can be used to determine the number of
`particles generated within specific particle size ranges. Quantitative
`data are obtainable and can be used to rank accurately numbers of
`particles among samples [91].
`Samples can be filtered onto retentive membranes and examined using
`a stereoscopic microscope, or by an electron probe, should particu-
`late analysis be desired. This method provides x-ray diffraction data
`and can be used to determine the qualitative composition of a crystal,
`particularly if it is inorganic in nature [87].
`Particles can be examined directly in the vial or ampul by use of a
`specially constructed inverted microscope. This instrument is able
`to focus through the glass wall of the container where the particulate
`matter has settled. Although this method provides only visual anal-
`ya, it can serve to identify specific particles in the container and
`therefore aid the analyst in their recovery by the membrane filtration
`technique.
`
`E. Screening of i.v. Administration Sets
`
`Prior to administration , many injectable products are diluted with a suitable
`LVP, e. g.. 5% dextrose solution (D 5W) or normal saline contained in a glass
`or plastic container.
`Such a diluted admixture is then infused into the patient
`These i.v.
`over a period of time. e.g. . 1 hr, via an i.v. administration set.
`sets are made of plastics, e.g. , polyvinylchloride (PVC), polyethylene (PE),
`or polyolefin (PO) . Many drugs, when exposed to these types of plastics,
`react with the surface. resulting in loss of drug due to adsorption or absorp-
`tion.
`In general, compounds that are poorly soluble in water and are lipo-
`philic exhibit absorptive loss while peptides show adsorptive loss when in
`Preformulation studies should evaluate this type of
`contact with plastics.
`This evalua-
`interaction with the components needed for i.v. administration.
`tion will lead to the selection of an appropriate LVP container and i.v. ad-
`ministration set to ensure complete delivery of the drug to the patient.
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`162
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`Motola and Agharkar
`
`A typical experimental approach consists of preparing admixtures of de-
`sired concentration of drug in a suitable i.v. fluid, e.g. , D5W, in both glass
`and plastic LVP containers. The admixture is then stored at ambient tempera-
`ture using appropriate control for effect of light, if the compound is known
`to be sensitive to light. Samples are withdrawn as a function of time and
`evaluated for potency. pH, color and particulate matter. LVP fluid and con-
`tainer in which essentially no change from initial is observed is then recom-
`mended for the clinic.
`In order to select a suitable i.v. administration set. a simulated i.v. in-
`fusion experiment should be conducted.
`In this experiment. admixture in
`an LVP fluid in a container of choice (glass or plastic) is prepared as de-
`scribed earlier. The infusion set is then inserted into the LVP container.
`
`The container is inverted and placed on a hanger. The admixture is allowed
`to drip through the i.v. set at a suitable rate. e.g. , 1 to 2 ml/min. Samples
`are collected as a function of time during the simulated infusion period. These
`samples are analyzed for the concentration of drug and pH monitored. The
`i.v. set that shows the least (preferably no) loss of drug should be recom-
`mended to the clinic.
`
`Occasionally, all of the tested i.v. sets show a significant loss of drug
`(>5% loss) during simulated infusion.
`In such a case, further investigation
`is needed to assess the cause of this loss and to recommend a viable solution.
`One example of such loss to i.v. sets has been reported [86] and is brief-
`ly described as follows. Perilla ketone is an investigational cytotoxic agent.
`Its aqueous solubility is 0.3 mg/ml.
`
`0
`
`as
`
`A 5 mg/ml formulation was prepared in a hydroalcoholic vehicle composed
`of 10% ethanol, 40% propylene glycol, and 50% water. This was further diluted
`(1: 50) with DSW. This admixture was used to conduct a simulated i.v. infu-
`sion test using three types of i.v. infusion sets.
`In this experiment PVC-
`based l.v. sets showed approximately 60% loss due to absorption; whereas,
`po1yolefin- and polyethylene-based i.v. sets showed a loss of approximately
`25% under the same conditions. Furthermore, analysis of the effluent samples
`as a function of time indicated that most of the loss occurred in the first few
`minutes of contact, indicating that the sorptive loss took place as soon as
`the drug was exposed to the plastic surface.
`In order to eliminate this absorptive loss, the authors [92] proposed to
`evaluate the preparation of the admixture of the drug in a fat emulsion, e.g. .
`lntralipid, suitable for i.v. administration. Partition coefficient (log K) of
`perilla ketone between soybean oil and aqueous phase of Intraiipid was meas-
`urecl and found to be 1. 98, whereas the log K value for the soybean oil:water
`system was 2.62. This similarity in log K values for the two systems sug-
`
`I
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`Motola and Agha!ormulation Research
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`163
`
`SUMMARY
`
`g admixtures of d~ed good affinity of perilla ketone to Intralipid. This affinity should mini(cid:173)
`• DSW, in both glr exposur: o~ drug to t~e pl~s~ic surfa~e . ~urthermore, the authors con(cid:173)
`d at ambient temp~ed that dilution of the mtralip1d emulSion Wlth the formulated perilla ke(cid:173)
`!Ompound is knowfl did not damage the emulsion and no physical changes were observed over
`!tion of time and ) 3 days. Based on this information, an admixture in Intralipid emulsion
`LVP fluid and col prepared and a simulated i. v . infusion test was conducted with PVC-,
`.red is then recom: and PO-based i. v. sets. It was confirmed that there was no absorptive
`3 of the drug to any of the i. v. sets tested.
`simulated i. v. in
`lt • admixture in
`;>repared as de-
`' L VP container.
`lmixture is alloweis chapter presented various parameters that are considered important to
`2 mJ /min. Samplrformulation research of parenteral products. With a good knowledge of
`usion period . Ttysical and organic chemistry and the techniques described, the preformu-
`monitored. The ion investigator can gather significant data to determine key properties of
`3hou1d be recom-1ew compound and guide the formulator toward the next stage of product
`velopment.
`ant loss of drug The following are typical preformulation worksheets that can be used to
`1er investigation .mmarize all data during the progress of experiments.
`a viable solutio1
`i {S6J and is bri~EFORMULATION WORKSHEET
`cytotoxic agent~--------------------------------------------------------------
`Investigator(s):
`
`Start Date:
`
`Compound Name or Designation:
`
`Batch Number:
`
`Molecular Weight:
`
`Molecular Structure
`
`I
`
`'1
`
`'ehicle composed
`ls further dilutE
`:lated i. v. infu(cid:173)
`eriment PVC-
`ion; Whereas,
`approXimately
`effluent sample!
`.n the first few
`! as soon as
`
`;. Color:
`
`a. Description
`
`b . APHA value in solution:
`
`I Proposed to
`emulsion, e.g.,
`:lt (log K) of
`ipid was meas-
`yrbean oil: water 6. Odor:
`/stems sug-
`
`solvent:
`
`wavelength:
`
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`Figure 29 Representative parenteral containers.
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`Formulation of Small Volume Parenterals
`
`227
`
`off of the product temperature several degrees below the eutectic point (- 11°C)
`during the primary drying phase was an indication that the heat applied was
`not excessive.
`
`The application of freeze-drying to processing biological and diagnostic
`products has been growing. with this increased application. new problems
`are beginning to surface, such as the awareness that freeze—dried products
`can undergo structural and/or chemical modifications which might affect their
`physical properties, therapeutic effectiveness, and even their safety in clini-
`cal uses.
`
`lll. CONTAINER EFFECTS ON FORMULATION
`
`Containers for parenteral products serve several purposes; facilitate manufac-
`turing; maintain product protection, including sterility and freedom from pyro-
`gens; allow inspection of the contents; permit shipping and storage; and pro-
`vide convenient clinical use. The container components illustrated in Figures
`29 and 30 must be considered as integral parts of the product because they
`can dramatically affect product stability, potency, toxicity, and safety, and
`therefore must be evaluated carefully with a variety of tests.
`
`A. Glass
`
`The three types of glass recognized by the USP for parenteral use are listed
`in Table 14. Type I is boroailicate and is the least reactive as measured by a
`
`

`
`228
`
`DeLuca and Boylan
`
`•
`
`......-
`
`Figure 30 Representative parenteral closures .
`
`standardized alkalinity test run on powdered (ground) samples. Types II
`and III glass are soda lime, with type II being surface treated with sulfate,
`sulfite, or sulfide to make it less reactive . Type I glass is, theoretically, the
`best all- purpose glass for injectables and should be the only glass that is
`used with alkaline products . However, it is significantly more expensive than
`types II and III. Type II glass is often used for solutions that remain below
`pH 7. 0 during their shelf life, while type III glass can be used for dry pow(cid:173)
`ders that are reconstituted. The particular glass container i ntended for use
`must be an integral part of the product stability program to be described later.
`Unfortunately, specifying the type of glass is not sufficient to ensure the
`consistency needed. Manufacturers have different recipes that bear designa(cid:173)
`tions , such as N-514A, CA-2, KG-33, and KG-35. Table 15 lists the compo(cid:173)
`sitions of various glasses . The glasses vary in additives- such as oxides of
`boron, sodium , potassium, calcium, iron , and magnesium- which alter physi(cid:173)
`cal and chemical properties of the glass . For example, when formulating sul(cid:173)
`fate salts (e.g. , drug substances or antioxidant) , the glass container should
`have minimal amounts of calcium and barium to prevent the formation of insolu(cid:173)
`ble inorganic sulfates [ 43]. To meet t his requirement KG- 33 type I should be
`specified.
`Amber glass containers are often used where the product is suspected of
`being light sensitive. The amber color is imparted by the addition of iron
`and manganese oxides, the cations of which are known to catalyze oxidative
`reactions. Studies have shown that these ions are extracted from glass [72]
`and that the decomposition rate of several drugs, thiomerosal [ 73], amitripty(cid:173)
`lene [74] , and L- ascorbic acid [75] is enhanced in amber glass containers.
`The Parenteral Drug Association has published guidelines on the process(cid:173)
`ing and selection of glass containers [76] . Various surface treatments are
`
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`Formulation of Small Volume Par-enterals
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`Table ‘Ill Parenteral Glass Types and USP XX Test Limits
`
`229
`
`Limits
`
`Type
`
`1
`
`II
`
`III
`
`General
`description“
`
`Type of test
`
`Sizeb
`(ml)
`
`Milliliters
`0.020 N acid
`
`Highly resistant.
`borosilicate glass
`
`Treated soda-lime
`glass
`
`Powdered glass
`
`All
`
`Water attack
`
`100 or less
`Over 100
`
`Soda-lime glass
`
`Powdered glass
`
`All
`
`1. D
`
`0.7
`0.2
`
`8.5
`
`a‘1‘he description applies to containers of this type of glass usually available.
`bsize indicates the overflow capacity of the container.
`Source: USP XXII, p. 1571.
`
`used to improve chemical resistance and decrease alkalinity. For example,
`exposing hot containers to sulfur dioxide reduces sodium content at the sur-
`face and a brief treatment with ammonium bifluoride effectively cleans the
`surface by dissolving a portion of it.
`Containers should be washed in a clean area in which particulate and micro-
`biological contamination is low. Containers are frequently shrink-wrapped
`with plastic to maintain low particle levels after they are manufactured and to
`reduce the amount of cardboard introduced into the parenteral manufacturing
`area. The washing of the glass must effectively clean the surface and remove
`particulates. The procedure consists of a rinse of deionized water, followed
`by a detergent wash and finally a thorough rinse with Water for Injection.
`If
`pyrogen-free water is not used. the glass should be sterilized and depyrogen-
`ated by dry heat immediately after washing.
`
`B. Rubber Closures
`
`The following classification lists most of the polymers utilized as parenteral
`closures:
`
`he
`an
`V
`_
`e
`ter.
`he
`3-
`
`[lg
`,1u_
`be
`
`Di.
`
`_]
`'_y_
`
`1. Unsaturated elastomers
`a. Polybutadiene
`b . Polychloroprene
`c. Pclyisoprene—natura1 or synthetic
`d. Nitrile butadiene rubber
`
`e. Styrene butadiene rubber
`2. Saturated elaatomers
`
`a. Copolymer of polyisobutylene and polyisoprene (butyl)
`b. Ethylene propylene rubber
`c. Ethylene propylene diene rubber
`d. Silicone rubber
`
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`Formulation of Small Volume Parenterals
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`233
`
`In gen-
`3. Durometer: This is a measure of the hardness of rubber.
`eral. a value of 30 to 35 is soft, 35 to 45 average, and above 45 is
`hard. High durometer values usually mean increased resistance to
`puncturing. A high durometer value is needed for syringe plunger-
`heads.
`
`4. Moisture vapor transmission (MVT): MVT is an important considera-
`tion when selecting a closure for hygroscopic powders, lyophilized
`products, and for products in which an inert gas is overlayed. MVT
`is inversely proportional to the thickness of the barrier. Generally,
`increasing the tiller will decrease MVT. Butyl elastomers provide
`good MVT protection, whereas natural rubber is poor.
`5. Puncture resistance: The pressure required to insert the needle
`through the closure is an important physical characteristic.
`Injec-
`tlons which are normally administered with small-diameter needles
`(23-25 gauge) must have lower puncture resistance than those admin-
`istered with needles having a comparatively larger diameter (18-22 ga).
`6. Resealability: Resealability will vary with rubber stocks. Since stop-
`pers must reseal to prevent contamination and leakage, resealability
`is an important characteristic to evaluate.
`7. Tackiness: For ease of handling, stoppers should not stick together
`or clump during processing. This usually occurs when stoppers are
`heated during sterilization.
`
`Product Compatibility
`Normally, if enough tests are run, a closure that is compatible with the paren-
`tars] product can be obtained by this empirical approach. The most common
`compatibility problem which occurs with stoppers is the leaching of ingredients
`from the stopper and the reaction of these ingredients with the product. An-
`other problem is the sorption by the closure of preservatives. as described
`earlier, or other ingredients in solution resulting in subpotency or inadequate
`preservation. Due to the large variety of ingredients in most elastomsric form-
`ulations and chemical reactions they undergo, specific ingredients that might
`leach into thiproduct, and possibly cause discoloration. turbidity, or precipi-
`tation, are 0 en difficult to identify. Qualitative and quantitative determina-
`tions of ingredients from extracts of various stopper formulations, obtained
`under accelerated storage conditions, using various solvents, pH conditions,
`and so on, often provide the fortnulstor with additional insight in selecting
`"‘° %‘i?5?s§‘°§§}?.°fi5’ §‘3£‘}“i‘,2§“;“.‘.?.‘11§.”Z?.“§§;°§'..1.1.g1..1 .1. physical-chemical
`testing of plastic and rubber closures. The biological tests include acute
`isnysltesnic toxicity antd itr1‘ttrac.i1it‘:1eous $'eactlvityt<:sts.h Other 12:5 puttlhlned.
`cu e measuremen o ur
`y, re ucmg ag s,
`eavy me
`, o
`ex
`tractables, and pH.
`Stoppers are normally prepared by washing them in household or commer-
`cial washers using detergents such as tetrasodium pyrophosphate or trisodium
`glaxosghate. min dsomc: cafesl:tpx'eex:1;actit‘); int in autoclave orfugith hot wfater
`y e req
`e pr or o
`ergen
`res
`en
`0 remove para
`11 or sur ace
`wax. Gentle agitation with minimum tumbling should be used to avoid genera-
`tion of particulate matter. Generally, an overflow process is employed to mini-
`mize agitation. Stoppers should be sterilized and dried immediately after wash-
`
`11:.
`‘fia_
`-
`flit
`of Y
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`to
`
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`‘
`lBI1'
`led
`15
`91‘
`I
`ml
`35
`
`gen
`[cal
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`
`mder
`sure
`c_
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`is
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`|g
`
`Petition for Inter Partes Review of US 8,338,470
`
`Amneal Pharmaceuticals LLC — Exhibit 1026 — Page 233
`
`

`
`234
`
`
`
`
`DeLuca and Boylcm
`
`ing. The sterilization cycle (autoclave) should be terminated with a vacuum
`cycle.
`Special treatments of stoppers may include treatment with dilute acid or
`base solutions, solvent extractions, or» extraction in a chelating agent to re-
`move surface metals from the stoppers. An oxiglaze (oxidation) treatment is
`sometimes employed to create a slightly harder and slicker surface. This is
`normally done to facilitate automatic handling during packaging. The oxiglaze
`process is carried out by treating the stoppers with 5% sodium hypochlorite
`in diluted hydrochloric acid. Stoppers are generally coated with a thin film
`of silicone to facilitate handling or insertion into the vials. This is usually
`applied while tumbling the closures in a closed container in the presence of a
`carefully measured quantity of silicone.
`.
`A wide variety of injectable products and containers/closures as well as
`processing conditions can contribute to the presence of aluminum at different
`levels. Examples are salts containing phosphate, or glass vials, rubber clo-
`sures, and autoclaving. which promotes extraction of aluminum from glass
`and rubber ['19- 81] .
`It has only been a recent finding that the accumulation
`of aluminum leads to clinically significant consequences [82]. Continuous
`intravenous therapy, particularly total parenteral nutrition was implicated
`in the inhibition of bone growth [83,84] . Although measures have been taken
`to minimize the problem of aluminum loading. it is unclear what the regulatory
`outcome will be for this issue that affects select, but key patient groups.
`
`IV. STABILITY EVALUATION
`
`A. Compendial and Regulatory Requirements
`
`As internationalization of pharmaceuticals accelerates through corporate mer-
`gers and acquisitions. as well as political events—such as Europe 1991—it
`becomes increasingly necessary for the formulator to become familiar with and
`understand the regulations of the major industrial nations. Additionally, there
`is a concerted harmonization effort among four compendia: Europe, Great
`Britain, Japan, and the United States. Accordingly. this section gives an
`overview of current parenteral product stability regulations in Japan. Europe.
`and the United States.
`
`Japan
`
`The document Requirements for the Registration of Drugs in Japan [85] states
`that "the stability of bulk powders and finished products shall be studied
`under all possible conditions of handling." In addition, decomposition prod-
`ucts should be identified and the toxicity and pharmacology evaluated, if
`necessary.
`Storage tests are divided into three categories:
`accelerated. These are outlined below.
`
`long-term, severe, and
`
`1. Long term testing is designed to answer the question, ‘'13 quality
`maintained in a fixed period of distribution?" Two experimental approaches
`are allowed: namely, Methods A and B.
`In Method A, 3 lots are stored at
`room temperature (or the storage condition on the label, if different) for 3
`years (or longer. if appropriate) and assayed at intervals not exceeding 6
`
`J
`Petition for Inter Partes Review of US 8,338,470
`
`Amneal Pharmaceuticals LLC — Exhlblt 1026 — Page 234
`
`'
`
`-.
`g
`
`m
`
`

`
`9
`Glass Containers
`for Parenterals
`
`R. Paul Abendroth
`
`Kimble Glass, Inc., VIneland, New Jer·sey
`
`Robert N. Clark
`Owens- Brockway, Toledo, Onto
`
`I. INTRODUCTION
`
`This chapter discusses the nature of glass, the pharmacopeial classll'lcatlon
`of glass types, the varieties of glass containers used for parenteral packaging,
`the manufa