IN COOPERATION WITH
`
`Insiilulc of_
`Packaging
`Professionals
`
`PACKAGING
`DRUGS
`
`AND
`
`PHARMACEUTICALS
`
`Wilmer A. Jenkins
`Formerly Director
`Packaging Products Division
`Polymer Products Department
`E.
`I. du Pont de Nemours & Company, Inc.
`
`Kenton R. Osborn
`
`Formerly Technology Manager
`Packaging Products Division
`Polymer Products Department
`E. I. du Pont de Nemours & Company, Inc.
`
`I I
`TECHNOMIC
`
`PUBLISHING CO.. INC.
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`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC — Exhibit 1025 — Page i
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`

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`Packaging Drugs and Pharmaceuticals
`aTECHN0MlC‘f:ubl2cm.ion
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`Printed in the United States of America
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`Main entry under title:
`Packaging Drugs and Pharmaceuticals
`
`A Technomic Publishing Company book
`Bibliography: p.
`Includes index p. 347
`
`Library of Congress Catalog Card No. 93-60377
`ISBN N0. 1-5667?)-014-3
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`
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`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLc — Exhibit 1025 — Page ii
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`Published in the Western Hemisphere by
`Technomic Publishing Company, Inc.
`851 New Holland Avenue. Box 3535
`Lancaster. Pennsylvania 17604 U.S.A.
`
`Distributed in the Rest of the World by
`Technomic Publishing AC
`Missionsstrasse 44
`CH-4055 Basel, Switzerland
`
`Copyright ©1993 by Technornic Publishing Company. Inc.
`All rights reserved
`
`No part of this publication may be reproduced. stored in a
`retrieval system, or transmitted, in any form or by any means,
`electronic. mechanical. photocopying, recording. or otherwise,
`without the prior written permission of the publisher.
`
`

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`The Determinants in Selecting or Designing a Package
`
`259
`
`The Relative Importance of Product
`Protection in Package Selection
`
`In theory, product protection is the most significant determi-
`nant. The drug manufacturer's primary concern is that the drug
`product gives the consumer all of its benefits when it is used.
`Adding to this motivation are federal regulations and concerns
`about lawsuits stemming from product failures. In practice how-
`ever, the vast majority of drugs do not have demanding protection
`requirements [such as an absolute barrier] as seen in Table 8.1.
`Also, there is usually a variety of alternative package possibilities
`for the level of protection required. Therefore, in practice, meeting
`product protection needs is generally not highly restrictive in de-
`termining package choice. This is reflected in the growing use of
`plastic packaging for all dosage forms but especially for oral
`solids, where 70-80% are in plastic bottles [12]. The exceptions to
`this generality are noteworthy, however, in that much attention
`has been given to them in packaging studies reported in the litera-
`ture.
`
`Compatibility
`
`For product protection, USP recommendations are specific
`about package type since they depend only on the properties of
`the drug. By contrast, specific compatibility recommendations
`cannot usually be made since interaction of a drug with a package
`depends on the chemistry of botl1 the drug and the package. But
`there are exceptions; for some injectahle fluids, USP recommends
`“g1ass only” or “Type I glass only,” etc. Among the 33 drugs that
`did not fall into one of the 35 general categories in Table 8.1, there
`are a few cases where specific restrictions related to compatibility
`are given: glass or PE, nonmetallic, plastic container and collaps-
`ible lined or coated tube.
`
`Thus the packager has the responsibility to be certain that “the
`container does not interact physically or chemically with the arti-
`cle placed in it so as to alter the strength, quality, or purity of the
`article beyond the official requirements” [13]. While there are a few
`compatibility problems with glass (a prominent case being with
`nitroglycerine preparations) and with metal containers for corro-
`sive drugs, the concern has been primarily with plastic packages.
`Beginning in the early 1970s many compatibility studies of
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Phannaoeuticals LLC — Exhibit 1025 — Page 259
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`260
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`PACKAGES USED FOR PHARMACEUTICALS
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`drug/packaging systems were conducted. For sterile dosage forms,
`an excellent summary was published in 1984 by Wang and Chien.
`They summarize in one table the results of sorption studies on 115
`different drugs [14]. A significant change [discoloration or 10% or
`greater absorption of the drug] occurred in 36% of the systems
`studied. While compatibility problems are considerably less
`common for other dosage forms. they have been encountered, and
`quantitative analysis of the problem is not always easy.
`The term compatibility encompasses three different conse-
`quences of chemical interaction between the package and any of
`the components of a drug product formulation. The first results in
`actual reduction in drug availability or potency through sorp-
`tion—the removal of the drug by the package. The second results
`in contamination as the formulation extracts substances from the
`
`package. The third causes breakdown of the package by deteriora-
`tion of its strength, stiffness or barrier properties as the formula-
`tion chemically attacks the package.
`
`Sorption
`
`When formulation components are removed by a package two
`different processes are involved: adsorption onto the surface and
`absorption into the package wall by diffusion. A component may
`also desorb from the outer surface of the package and pass into the
`atmosphere if it is volatile enough. Strong adsorption or absorp-
`tion requires a strong chemical interaction between the com-
`ponent and the packaging material. In addition, for a high level of
`absorption the packaging material must be permeable to the com-
`ponent. Glass has a chemically active surface but is an absolute
`barrier so that while adsorption can be strong, no absorption oc-
`curs. For plastics, on the other hand, both adsorption and ab-
`sorption are possible. In the literature, when adsorption and ab-
`sorption occur together,
`there is
`rarely a distinction made
`between the two and therefore the term sorption will be used to
`indicate both are taking place.
`The usual method for measuring sorption is to soak a known
`quantity of the packaging material, usually a thin film or section
`of the container wall, in a solution of the drug product or in the
`formulation if it is a liquid. Either the amount of a component lost
`from the solution or the weight gain by the packaging material is
`measured. Of course, sorption studies of actual product/package
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`Petition for Inter Partes Review of US 8,338,470
`Amneal Phannaeeuticals LLC — Exhibit 1025 — Page 260
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`

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`The Determinants in Selecting or Designing a Package
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`25]
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`systems have also been made. When a multicomponent formula is
`involved, separation of the interaction of the different components
`is much more complicated. In one example of a sophisticated
`technique used for this purpose, phenylephrine, a decongestant,
`was labeled with radioactive carbon and placed in PE nasal spray
`bottles. Concentration changes of the active drug alone were fol-
`lowed using internal liquid scintillation spectrometry which dis-
`tinguished the phenylephrine interaction from those of the other
`components in the formulation [15].
`There have been many studies of sorption kinetics leading to a
`number of different mechanisms and equations aimed at predict-
`ing rate of sorption and its dependence on key variables such as
`drug composition, plastic type, and temperature. However, as
`Wang and Chien conclude: “Given the conflicting results in the
`literature, it is difficult to predict sorption activity. It seems more
`appropriate, at this stage of knowledge,
`to study such activity,
`rather than try to predict it” [16].
`
`Leaching
`
`Leaching is primarily a problem with IV fluids and large
`volume parenterals. Widely studied examples are the leaching of
`plasticizers from PVC IV bags, extraction of additives from rubber
`closures and corrosion of glass surfaces. Most leaching problems
`occur with plastics because of the presence of additives such as
`fillers, activators and plasticizers. Leaching can cause discolora-
`tion, precipitation. change in pH, and contamination that can
`lead to increased toxicity or instability of the drug.
`The USP describes several tests for leaching [17]. For glass, a
`powdered sample in purified water is autoclaved at 121°C and the
`water is then tested for the amount of alkali present. This test is
`used to confirm that a container intended for injectable fluids is
`made of the appropriate type of glass. For plastics, purified water
`at 70°C is used as the extracting medium for containers. The water
`is then examined for volatile, nonvolatile and heavy metal resi-
`dues as well as acidity and alkalinity. In addition biological tests
`are performed in two stages: in vitro tests on cultures of mamma-
`lian Ilbroblasl cells and in viva tests on small animals. Materials
`
`to meet the requirements of the in vitro tests must
`that fail
`undergo in vivo testing. For the in vitro tests, plastic samples are
`extracted with saline solution at either 50°, 70°, or 121°C de-
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Phannaceuticals LLc — Exhibit 1025 — Page 261
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`

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`262
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`PACKAGES USED FOR PHARMACEUTICALS
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`pending on the heat resistance of the plastic. The extraction
`medium is expanded to include polyethylene glycol, vegetable
`oil, drug product vehicle and water for the in vivo tests. Evidence
`of biological activity, as judged by visual observation, after con-
`tact of the extract with the cell culture or of adverse reaction after
`
`injection of the extract into animals, means failure. For plastic
`containers for ophthalmic fluids, the incidence of eye irritation in
`rabbits caused by extracts denotes failure [18].
`In extraction tests, it is desirable to identify all the materials
`leached out. The detection of acidity, alkalinity and metal salts is
`straightforward but identification of organic molecules is much
`more difficult. Sophisticated techniques reported in the literature
`include UV spectrometry, mass spectrography, nuclear magnetic
`resonance, atomic absorption spectrometry, gas chromatography
`and thin layer chromatography. In one interesting example, a high
`performance liquid chromatograph was used to detect in levothy-
`roxine sodium tablets [used to treat hypothyroidism] the presence
`of materials from the package. In this case, diethyl phthalate was
`found and its source was the PVC container used for the desiccant
`
`[19].
`A number of different mechanisms and equations have been
`
`derived from leaching data, yet there appears to be little de-
`pendence on these equations for predicting results for systems not
`yet studied. Evaluations of specific systems of interest is the
`course most often followed.
`
`Modification of the Container
`
`The physical or chemical alteration of packaging materials by
`drug products is called modification. Permeation, sorption and
`
`leaching all can alter properties of plastics and may also lead to
`degradation. Some solvent systems have been found to be respon-
`sible for considerable changes in the mechanical properties of
`plastics. Oils, for example, soften PE and fluorinated hydrocar-
`bons attack PE and PVC. Changes in PE caused by some surface
`active agents have been noted. In some cases, the drug formu-
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`lation may extract the plasticizer, antioxidant or stabilizer and
`change the flexibility of the package. PVC is an excellent barrier
`for petroleum-based solvents but the plasticizer in PVC‘. is ex-
`tracted by solvents, leaving the plastic hard and stiff.
`Stress cracking of the container occurs when fluid causes the
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`etition for Inter Partes Review of us 8,338,470
`Amneal Phannaoeuticals LLC - Exhibit 1025 — Page 262
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`

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`The Determinants in Selecting or Designing a Package
`
`253
`
`container to slowly develop cracks, usually in areas of unrelieved
`stress induced during fabrication. This problem is particularly
`acute for polyethylenes and increases in severity with increasing
`density. Polystyrene is attacked by many chemicals which cause it
`to craze and crack and therefore is generally used only for dry
`products. Polypropylene does not stress crack under any circum-
`stances and generally shows excellent resistance to chemicals.
`Good resistance to chemicals is characteristic also of PET and
`
`nylons.
`Container modification is evaluated by measuring changes in
`physical properties and observing physical changes after expo-
`sure to the intended contents. For stress cracking, a notched plas-
`tic bar is suspended under load in a test liquid. The time required
`for the notch to propagate and the bar to break is measured.
`
`The Relative Importance of
`Compatibility in Package
`Selection
`
`Sorption can change product potency; leaching can cause phar-
`maceutical products to discolor, precipitate, change pH, and
`become contaminated; and container modification can lead to
`container breakdown and product leakage. Although any of these
`compatibility problems can be serious, alternative, problem-free
`systems can usually be found. General guidelines (such as those
`outlined above for various plastics] have been developed and rea-
`sonably adequate theoretical analyses are available to help avoid
`problems. However, this is not a black-and-white situation. Some
`loss in drug potency is acceptable. Minor incompatibility is
`sometimes tolerated if its harmlessness can be assured and there
`are sufficient offsetting advantages of the package system. One ex-
`ample is the PVC bag for IV fluids where the disadvantageous
`leaching of nontoxic plasticizer is offset by the advantages of shat-
`terproofness and collapsibility of the bag versus the glass bottle
`alternative.
`
`In summary, compatibility problems, though extensively stud-
`ied in the exceptional cases, are not often encountered for the vast
`majority of packaged drugs. Such problems are especially rare for
`solids, the principal dosage form. Additives in plastics are rarely
`toxic. Nevertheless, compatibility testing must be part of the
`screening process for package alternatives.
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Phannaceuticals LLC - Exhibit 1025 — Page 263