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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1027 – Page i
`
`

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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1027 – Page ii
`
`

`

`PREFACE AND ACKNOWLEDGEMENT
`
`The aim of this book is to provide for persons working with sterile
`pharmaceutical products a detailed account of the compatibility and sta(cid:173)
`bility of sterile formulations and packaging components. The intention i~
`to present what is known in concise form, and to indicate how to avoid or
`resolve problems.
`For hospital pharmacists, it is hoped that this book will serve as a valuable
`handy reference to assist them in identifying and solving the problems of
`sterile packaging. The tremendous increase in popularity of intravenous
`admixture programs makes it imperative that greater attention be paid to
`recognizing such problems. For manufacturing chemists involved in de(cid:173)
`veloping sterile pharmaceutical products, it is hoped that their awareness
`of the current knowledge of relevant physicochemical principles will enable
`them to design products that will have only minimal problems of compat(cid:173)
`ibility and stability, both for the shelf life of the product and during its
`preparation and administration in hospital.
`The book is arranged by type of interaction between formulation and
`packaging component, ie., sorption;oleaching, and permeation, thus per(cid:173)
`mitting an efficient presentation and analysis of common factors. Some
`important concepts are presented more than once, to ensure that they are
`not overlooked.
`Ortho Pharmaceutical Corporation provided extensive assistance in the
`preparation of this book. We thank the Ortho librarians for their efficient
`help, the operators in the Ortho Word Processing Center, Mrs. Katie
`McAllister and Miss Karen Daniels for their patience and skill, and Miss
`Carol Neuwiesinger for her skillful drawing of the figures. Dr. Glenn Van
`Buskirk's thorough review of the manuscript lessened markedly the number
`of errors that may appear in the book.
`Dr. Joseph Robinson and Dr. Michael Enzinger, as well as other members
`of the Research Committee of the Parenteral Drug Association, provided
`valuable comments and criticisms of the manuscript. Mr. Robert L. Bu(cid:173)
`chanan of Tompkins Rubber Co. and Mr. Joseph Wong of Endo Labora(cid:173)
`tories Inc. provided helpful assistance in the initial literature search. Dr.
`David Frost, consultant editor, improved the readability of the text con(cid:173)
`siderably.
`
`Yu-chang John Wang
`Yie W. Chien
`
`Petition for Inter Partes Review of US 8,242, 158
`Amneal Pharmaceuticals LLC- Exhibit 1027- Page iii
`
`

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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1027 – Page iv
`
`

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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1027 – Page v
`
`

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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1027 – Page vi
`
`

`

`I. INTRODUCTION
`
`1
`
`Sterile pharmaceutical packaging is defined as a primary packaging
`system that holds and is in direct contact with a sterile pharmaceutical
`formulation throughout the shelf life of the product. It consists of a con(cid:173)
`tainer, possibly with a closure, and is considered an integral part of the
`pharmaceutical product. Examples of sterile pharmaceutical packaging
`are vials, ampules, plastic bags, plastic bottles, etc. This report encompasses
`primary packaging systems for such sterile pharmaceutical products as
`small- and large-volume parenterals, sterile irrigating solutions, and oph(cid:173)
`thalmic products, but not those for sterile diagnostic products and medical
`devices.
`The primary packaging system should provide adequate protection
`against any ingress of foreign matter or egress of its contents, and it should
`possess acceptable physicochemical compatibility and long-term stability
`with the drug formulation within it until the drug formulation has been
`administered. Maintenance of a 2· to 3-year shelf-life is desirable. It is worth
`remembering that no container or closure is completely inert.
`To make an intelligent selection of a primary packaging system that is
`compatible, both physically and chemically, with a sterile drug formulation,
`one should know about all potential instability/incompatibility problems
`of a packaging system with a particular drug formulation. This knowledge
`should derive from careful evaluation of: (1) the composition of the pack(cid:173)
`aging system; (2) the treatment to which it will be subjected; and (3) the
`composition of the drug formulation.
`Physicochemical interactions between sterile pharmaceutical products
`and their packaging components have been reported in the literature. We
`discuss these interactions, offering a quantitative analysis of them. Inter(cid:173)
`actions are discussed in three categories: sorption, leaching, and permeation.
`In each category, discussion of the mathematical equations that are per(cid:173)
`tinent to an interaction is followed by evaluation and discussion of those
`critical parameters, such as temperature, that have been shown to influence
`the interaction. Finally, details of the interactions related to various
`packaging materials are presented as a bandy guide for those involved in
`selecting a suitable primary packaging system for a formulation to achieve
`maximum compatibility and stability.
`Numerous reviews have discussed interactions beLween pharmaceutical
`products and packaging components (Autian, I963a,b; Polack, 1967; Busse
`and Hughes, 1969; Coates, 1973; Armstrong, 1974; Varsano and Gilbert,
`1969). Autian (1963a,b) treated the subject in great depth and provided
`some guidance for quantitative analysis. Since the early '60s, however, a
`
`Petition for Inter Partes Review of US 8,242, 158
`Amneal Pharmaceuticals LLC- Exhibit 1027- Page 1
`
`

`

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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1027 – Page 2
`
`

`

`PRIMARY PACKAGING SYSTEMS
`
`3
`
`II. PRIMARY PACKAGING SYSTEMS
`
`'fhe primary packaging system for a sterile pharmaceutical product
`consists of a container and a closure system:
`
`A. Containers
`
`Depending on composition of the materials used, containers may be
`classified as either glass or plastic. Their physicochemical and mechanical
`properties, as well as the processes involved in their manufacture, may be
`described as follows:
`
`1. Glass c-0ntainers
`
`Glass has traditionally been considered t he container material of choice
`for most sterile pharmaceutical products. However, it should n ot be as(cid:173)
`sumed tha~ glass is a totally inert material or that it is the ideal primary
`packaging component, either technically or commercially. General reviews
`on glass container for sterile products were provided by Adams (1977) and
`Anschel (1977).
`a. Nature and composition of glass
`Glass is a noncrystalline solid and, thus, shows only short-range order
`to 10 A. It is also called a supercooled liquid because, under certain condi(cid:173)
`tions, i i can order itself and crystallize, a process known as "devitrifica(cid:173)
`tion."
`Glass consists of a mixture of oxides. The primary glass-forming (net(cid:173)
`work-forming) oxides are Si02, B203, Ge02, P 20r,, V205> and Al20 3. Among
`these, Si02 is by far the major component for practically all commercial
`glasses. Silicone oxide is known to be the component responsible for the
`three-dimensional network of glass, the silicon dioxide tetrahedron.
`Additionally, fluxes such as Cao, Na20, K20, BaO, or Li20, are needed
`to decrease the softening temperature of glass and, thereby, make it easier
`to process (Holloway, 1973). A stabilizer, such as Al203, Sb20 3, Pb02, or
`ZnO, is also added to make the glass less prone to crystallization or devi(cid:173)
`trification and, thus, more durable. The general functions of glass formers,
`fluxes, and stabilizers are shown in Table I. Except for boric oxide, which
`can enter into the silicon dioxide tetrahedron structure, most of the inor(cid:173)
`ganic oxides, such as those of sodium, potassium, calcium, magnesium,
`aluminum, barium, and iron, are only loosely bound in the network inter(cid:173)
`stices and are, thus, relatively free to migrate. These migratory oxides can
`leach into a drug solution that is in intimate contact with the glass container,
`particularly during the process of thermal sterilization. The dissolved or
`
`Petition for Inter Partes Review of US 8,242, 158
`Amneal Pharmaceuticals LLC- Exhibit 1027- Page 3
`
`

`

`4
`
`J>l lA 'l' E<'H >' l<';\L H E l'OH'I' >JO. 7,
`
`TABLE I
`Common Constituents of Glasses and Their Effect on Properties
`
`Constituent
`
`Function
`
`Physical and Chemical Properties
`
`Si02
`
`Network former
`
`Pb02
`Al20 3
`
`Stabilizer
`Stabilizer
`
`Na20
`
`Network modifier (flux)
`
`K 20
`
`Network modifier (flux)
`
`LbO
`
`Network mcxlifier (flux)
`
`Cao
`
`Network mcxlifier (flux)
`
`Source. Holloway ( 1973\.
`
`Crystalline silica has very high melting point
`and liquid silica has very high viscosity. High
`concentration of silica in a glass confers
`high softening temperature, low thermal
`expansion. good chemical durability.
`Will join network structure of silica glasses and
`reduce viscosity without producing adverse
`changes in thermal expansion and durability.
`Is a component of all heat-resisting and
`" Chemical" glasses.
`Can link SiO. tetrahedrons.
`Can join network in A104 tetrahedron which are
`different in size from Si04 • Strongly
`suppresses devitrifica1ion; increases process
`viscosity.
`Markedly lowers softening temperature. Raises
`thermal expansion and ionic conductivity.
`Reduces durability.
`Similar to Na20. but the larger K~ ion is less
`mobile than the Na+ ion.
`Similar to Na20 . but the smaller u+ ion is more
`mobile than the Na ... ion.
`Inhibits mobility of alkali ions, hence increases
`resistivity and dlXability of alkali glasses.
`Shortens lhe working range.
`
`extract,ed oxides may affect solution pH, catalyze physicochemical reac(cid:173)
`t.ions, or even enter int.o the reactions themselves. Additionally, some
`components of glass a re also prone t o attack by drug solutions; as a result,
`flakes may be dislodged into the solution lAvis, 1975).
`A true glass can be formed from the combination of Si02 and Na20. A
`true glass is, hvwever. soluble in water and is thus called water glass. With
`the addition of a stabilizer. the water solubility of true glass is greatly re(cid:173)
`duced and an insoluble soda-lime glass is formed.
`1) Soda-lime glasses
`Soda-lime glasses account for approximately 90% of all commercial
`glasses. They are fairly resist.ant to chemicals, but cannot withstand sudden
`changes in temperature. Depending on the concent rat ion of Na20 , B 20 3,
`
`Petition for Inter Partes Review of US 8,242, 158
`Amneal Pharmaceuticals LLC- Exhibit 1027- Page 4
`
`

`

`PRIMARY PACKAGING SYSTEMS
`
`5
`
`TABLE II
`Major Chemical Constituents of Container Glasses and Glasses Used for
`Handling Ultrapure Solutions
`
`Typical Concentration (wt % ) a
`LlzO 8203 cao MgO Bao
`SI02 Al203 Zr02 Na20 KzO
`73
`5
`74
`11
`81
`73
`71
`66
`
`3
`13
`10
`
`4
`0.5
`
`2
`
`1
`2
`2
`6
`1
`20
`
`0.5
`0.5
`0.5
`0.5
`0.5
`
`17
`13
`4
`7
`11
`9
`
`1
`5
`
`15
`
`Glass Type
`
`Soda-lima A
`Soda-lime B
`Borosilicate A
`Borosilicate B
`Alkali-resistant
`Chemically
`Strengthened
`High-silica
`Vitreous-silica
`
`96
`100
`
`0.5
`
`3
`
`• In all except high-silica and vitreous-silica glasses, F. Cl. S04 • As. and Sb can be present in the range
`0.05-0.5%.
`
`CaO, and MgO in the glass network, soda-lime glasses are further classified
`into A and B types (Table II).
`The chemical resistance of soda-lime glass containers can be increased
`by de-alkalization of the glass surface, generally b:-; exposing the glass to
`S02 gas to remove Na20 prior to use:
`Na20 + S02. + 1h 02 -~ Na~04
`The sodium sulfate formed remains on the surface of the glass as a fine
`precipitate that is water soluble and can be rinsed off easily. The de-al(cid:173)
`kalization treatment can be accelerated if S02 is used in the presence of
`H20. This treatment reduces the extractable alkali by a factor of 25. By
`means of S02 treatment, a soda-lime B glass (USP Type III or Type NP
`glass) can be upgraded to a USP Type II glass.
`The chemical resistance of de-alkalized glass is comparable to that of
`borosilicate glass in acidic and neutral solutions, but resistance to alkaline
`solutions is increased only slightly by de-alkalization treatment. De-al(cid:173)
`kalized glass containers are widely used for intravenous infusion solu(cid:173)
`tions.
`2) Borosilicate glasses
`Borosilicate glasses are chemically highly resistant and are known
`commercially as Pyrex® and Kimax®. Typical compositions of these glasses
`are shown in Tables III and IV.
`
`Petition for Inter Partes Review of US 8,242, 158
`Amneal Pharmaceuticals LLC- Exhibit 1027- Page 5
`
`

`

`6
`
`PD.'\ TECHl\IH'.'\I. Hf<:J>OHT 1\0. ;,
`
`TABLE Ill
`Typical Composi1ions (in % ) of Chemically Resistant Borosilicate Glasses
`Manufactured by Kimble
`
`Component
`
`KG-33
`
`Code
`KG·34
`
`N51A
`
`A 203
`
`Si02
`8203
`Al203
`Cao
`MgO
`Bao
`Na20
`KiO
`Ti02
`Fe203
`
`Uses:
`
`80.3
`13.0
`2.4
`0. 1
`
`4.2
`
`74.6
`11.3
`5.0
`
`2.7
`6.0
`
`74.4
`9.5
`5.5
`0.9
`0.3
`2.2
`6.6
`0.6
`
`7 1.6
`9.2
`5.3
`0.8
`0.1
`2. 1
`6.4
`0.7
`2.8
`0.3
`
`Scientific
`ware. process
`pipe
`
`Blown
`bottles
`
`Ampuls
`vials
`
`Amber ampuls
`Amber vials
`
`Soorce: Bacon ( 1968).
`
`TABLE IV
`Typical Composition (in % ) of Alkali-Resistant Glasses Manufactures by
`Corning
`
`Component
`
`Si Oz
`B20 3
`Al20 3
`Cao
`MgO
`Li20
`Na20
`K20
`ZrO,
`
`Source: Bacon ( 1968).
`
`Code
`
`7740
`
`80.3
`13.0
`2.4
`0.1
`
`4.2
`
`72SO
`
`71.3
`
`0 1
`0 1
`08
`11.S
`0.1
`15.8
`
`Borosilicate glasi:;ei:;, are a lso known as USP Type I glasses, can be divided
`into A and R subclasses (Table II). Class A. P yrex glass. is more difficult
`to fabrica te and has a lower thermal expansion coefficient. than class B.
`Class B borosilicate glass. as exemplified by the so-called neutral glass, is
`
`~ ..
`
`Petition for Inter Partes Review of US 8,242, 158
`Amneal Pharmaceuticals LLC- Exhibit 1027- Page 6
`
`

`

`PRIMARY PACKAGING SYSTEMS
`
`7
`
`commonly used in the manufacture of chemically resistant ampuls and vials
`for pharmaceuticals.
`3) Am ber glass
`Certain metals can be added to glass to produce such colors as amber,
`which results from an interaction between added ferric oxides and ferrous
`oxides and sulfur. Additional components are used to produce three types
`of amber glass for pharmaceutical use: reddish amber, 4% Mn0 2 and 0.01%
`Cr03; greenish amber, 0.1% to 1% S03; and brownish amber, 2% to 3%
`Ti02.
`Other colors can be produced by incorporating CoO for blue, NiO for gray,
`Cr203 for green, and CuO for bluish-green. These coloring metals in amber
`glass are potential sources of trace ions, particularly of iron.
`b. Classification of glass conta iner by USP
`The United States Pharmacopeia (USP) has classified glass containers,
`according to their degree of chemical resistance, into four types:
`J) Type I is made from a chemically high resistant borosilicate glass,
`composed principally of silicon d ioxide and boric oxides. This glass has
`low leachability and a low thermal coefficient of eKpansion. I n general,
`it is suitable for all parenteral drug products although sulfur dioxide
`treatment is sometimes utilized to increase its chemical resistance still
`more.
`2) Type fl is made from de-alkalized soda-lime glass, composed of rela(cid:173)
`tively high levels of sodium oxide (13-17%) and calcium oxide (5-11 %)
`(Table II). The existence of these two oxides makes Type ll glass con(cid:173)
`tainers chemically less resistant than Type I (which contains 4-7% Na20
`and 1% CaO). A Type II glass container, however, has a lower concen(cid:173)
`tration of migratory oxides than does Type III, and its chemical resis(cid:173)
`tance can be increased by sulfur dioxide treatment, under controlled
`conditions of temperature and humidity to de-alkalize the internal
`surface of the glass containers. However, this de-alkalized surface will
`break down if it is repeatedly exposed to heat sterilization, depyroge(cid:173)
`nation or alkaline detergents. )'hus, Type II glass containers possess
`relatively good chemical resistance for one-time use. A Type II glass
`contajner melts at a lower temperature, can more easily be molded, and
`has a higher coefficient of thermal expansion than does a Type I glass
`container. lt may be suitable for use as a container for a drug solution
`that has been buffered to a pH below 7 or one that is not react ive with
`the glass.
`3) Type III is also made from a soda-lime glass that contains relatively
`high levels of sodium oxide and calcium oxide, as do Type II glass con(cid:173)
`tainers. However, a Type III glass container has a higher concentration
`
`Petition for Inter Partes Review of US 8,242, 158
`Amneal Pharmaceuticals LLC - Exhibit 1027 - Page 7
`
`

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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1027 – Page 8
`
`

`

`f>RlMARY PACKAGING SYSTEMS
`
`9
`
`TABLE V
`Sterile Plastic Devices for Parenteral Drug Administration
`
`Sterile Plastic Device
`
`Plaslic Material
`
`Containers for 01000 product
`
`Polyvinyl chloride
`
`Disposable syringe
`
`Irrigating solution container
`
`I. V. infusion fluid container
`
`Administration set
`
`Polycarbonate
`Polyethylene
`Polypropylene
`
`Polyethylene
`Polyolefins
`Polypropylene
`
`Polyvinyl chloride
`Polyolefins
`
`Nylon (spike)
`Polyvinyl chloride (tube)
`Polymethylmethacrylate (needle adapter)
`Polypropylene (clamp)
`
`Catheter
`
`Teflon
`Polypropylene
`
`Adapted from Turco and King (1979).
`
`monomers have the general chemical structure
`
`CH,=C::::::~
`
`where R 1 and R2 can be H , CH3, phenyl, COOH, COOR, OCOCH3, C=N,
`F, Cl, CONH2 , or pyrrolidone.
`The polymer produced by addition polymerization may be represented
`as:
`
`when n refers to the average number of monomer units in the polymer
`molecule. Depending on the chemical types of R 1 and R2 , a great variet;y
`of polymers can be produced (Tables VJ and VII). Teflon®, also known as
`polytetrafluoroethylene fCF2-CF2+n, is a unique polymer produced
`
`Petition for Inter Partes Review of US 8,242, 158
`Amneal Pharmaceuticals LLC- Exhibit 1027- Page 9
`
`

`

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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1027 – Page 10
`
`

`

`PRIMARY PACI<AGlNG SYSTEMS
`
`11
`
`TABLE VII
`Polymers by from Addition Polymerization of Monomers with both R 1 and
`R2 that are Not Hydrogen Atoms
`
`Monomer Structure Monomer Name
`
`lsobutylene
`
`Methyl styrene
`
`Vinylidene chloride
`
`Vinylidene fluoride
`
`Methacrylic acid
`
`Methyl rnethacrylate
`
`CH3
`I
`CH2=1
`CH,
`
`CH3
`I
`CH,==c
`
`©
`
`CJ
`I
`CH2=Cht
`
`/
`CH2=C \.
`
`CH,
`I
`CH2==C
`J
`C=O
`
`6H
`XH3
`CH2=
`
`b=O
`I
`0 tH,
`
`Polymer Name
`
`Polyisobutylene (PIB)
`
`Potymethylstyrene
`{PMS)
`
`Polyvinylidene chloride
`(PVC2)
`
`Polyvinylidene fluoride
`(PVF2 )
`
`Polymelhylacrylic acid
`(PMAC)
`
`Polymethyl
`methacrylate
`(PMMA)
`
`Polymer Structure
`yH3
`-+CH2-C)n
`I
`CH,
`fH3
`
`-+CH2-C7n ©
`
`91
`-f-CH1- C1,r
`I
`Cl
`
`F
`I
`-+CH.-c+i;
`I
`F
`fH3
`
`-(-CHr-Ctn
`I
`C=O
`I
`OH
`
`f"·
`-fCr,1,-CHt;;.
`I
`C=O
`I
`0
`bHi
`
`2) Polymerization by condensation
`Condensation (or step-reaction) polymerization commonly occu·rs with
`monomers that contain two different types of organic functional groups.
`It may be illustrated by the reaction of two amino acid monomers:
`
`H 0
`I
`II
`
`H 0 H H 0
`I
`II
`I
`I
`II
`HiN--C~C~N--C--C
`I
`I
`I
`R
`R OH
`
`Petition for Inter Partes Review of US 8,242, 158
`Amneal Pharmaceuticals LLC - Exhibit 1027 - Page 11
`
`

`

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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1027 – Page 12
`
`

`

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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1027 – Page 13
`
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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1027 – Page 14
`
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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1027 – Page 15
`
`

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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1027 – Page 16
`
`

`

`PRIMARY PACKAGING SYSTEMS
`
`17
`
`Although the thermosetting resins have been widely used for making
`closure systems and also a few specialized containers (e.g., menthol sticks,
`for almost 50 ye.ars), the use of thermoplastics for packaging pharmaceu(cid:173)
`ticals did not start until the late '40s and early '50s. It is widely recognized
`today that plastics deservedly play a significant role in all facets of phar(cid:173)
`maceutical packaging, provided that their advantages can be properly ex(cid:173)
`ploited and their potential disadvantages, in terms of physicochemical
`interactions with the pharmaceutical formulations, are fully evaluated and
`controlled.
`
`.,,;:· ··
`
`.·.
`
`Petition for Inter Partes Review of US 8,242, 158
`Amneal Pharmaceuticals LLC - Exhibit 1027 - Page 17
`
`