Technical Report No. 5
`
`Sterile Pharmaceutical
`Packaging:
`Compatibility and Stability
`
`Y. John Wang, Ph.D.
`O rtho Pharmaceutical Corporation
`
`Yie W. Chien, Ph. D.
`College of Pharmacy, Rutgers University
`
`PARENTERAL DRUG ASSOCIATION,
`INC.
`
`Avenue of the Arts Building, Suite 1407, Broad & Chestnut Streets,
`Philadelphia, Pennsylvania 19107
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1027 – Page i
`
`

`
`FOREWORD
`
`THIS 18 T H E F IFTH JN A SERIES OF T EC'H NICAL R EPORT s.1- 4 This
`T echnical Report was prepared by Dr. Y. John Wang and Dr. Yie W. Chien
`under the auspices of the PDA Research Committee. It provides a com(cid:173)
`prehensive review of sterile pharmaceutical packaging systems with regard
`to product- package interactions, stability and compatibility.
`In the selection of pharmaceutical packaging systems one must be aware
`of the potential physicochemical interactions with the product. These in(cid:173)
`teractions are discussed in detail from both a practical application and a
`theoretical point. of view.
`
`R. M. Enzinger, Ph.D.
`Chairman
`Research Committee
`
`1 ""Validation of Steam Sterilization Cycles."" Parenteral Drug Association Inc., Technical
`Moncwraph No. I.
`~ ··Validation of Aseptic Filling for Solution Drug Products,"" Parenteral Drug Association
`Inc .. Te<"hni<"al Monograph No. 2.
`" ··Validation of drv Heat Processes llsed for Sterilization & Depyrogenation." Parenteral
`Drug Association Inc .. Technical Report No. a.
`•··Design Concepts for the Validation of a Water for Injection System:· Parenteral Drug
`Asso<·iation Inc .. T echnical Report No . .J.
`
`Petition for Inter Partes Review of US 8,338,470
`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-
`bility of sterile formulations and packaging components. The intention is
`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 he paid to
`recognizing such problems. For manufacturing chemists involved in de-
`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-
`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., sorptiomleaching, and permeation, thus per-
`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-
`chanan of Tompkins Rubber Co. and Mr. Joseph Wong of Endo Labora-
`tories Inc. provided helpful assistance in the initial literature search. Dr.
`David Frost, consultant editor, improved the readability of the text con-
`siderably.
`
`Yu-chang John Wang
`Yie W. Chien
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLc — Exhibit 1027 — Page iii
`
`

`
`TABLE OF CONTENTS
`
`I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`II. Primary Packaging Systems . . . . . . . . . . . . . . . . . . . . . . . . . .
`A. Containers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`1. Glass containers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`a. Nature and composition of glass . . . . . . . . . . . . . . . . .
`1) Soda-lime glasses . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2) Borosilicate glasses
`. . . . . . . . . . . . . . . . . . . . . . . . .
`:s) Amber glass
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`b. Classification of glass containers by USP . . . . . . . . .
`I l 'f ype l
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`:2l Type II
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`:3) Type III . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`4) Type NP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2. Plastic containers . .
`. . . . . . . . . . . . . . . . . . . . . . . . . .
`a. Polymerizat ion
`. . . . . . . . . ... . . . . . . . . . . . . . . . . . . . .
`1) Polymerization by addition
`. . . . . . . . . . . . . . . . . .
`2) Polymerization by condensation . . . . . . . . . . . . . .
`b. Additives (Adjuvantsl
`. . . . . . . . . . . . . . . . . . . . . . . . .
`1) Lubricants
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2> Stabilizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`;~) Plasticizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`.I) Antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`fi) Antistatic agents . . . . . . . . . . . . . . . . . . . . . . . . . . .
`6) Slip agents
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`7) Dyes and pigments
`. . . . . . . . . . . . . . . . . . . . . . . . .
`c. Potent ial problems with plastic containers . . . . . . . .
`13. Closure Systems
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`1. General
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2. Composition of rubber closures
`. . . . . . . . . . . . . . . . . . . .
`a. Primary ingredients . . . . . . . . . . . . . . . . . . . . . . . . . . .
`b. Adjuvants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`:3. Natural rubber . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`4. Synthetic elastomers . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`a. Polyisoprene rubber . . . . . . . . . . . . . . . . . . . . . . . . . . .
`h. Butyl rubber
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`c. Halogenated butyl rubber . . . . . . . . . . . . . . . . . . . . . .
`d. Chloroprene rubber
`. . . . . . . . . . . . . . . . . . . . . . . . . . .
`e. S ilicone rubber
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`f. Nitrile butadiene rubber
`. . . . . . . . . . . . . . . . . . . . . . .
`
`1
`3
`3
`3
`3
`4
`5
`7
`7
`7
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`7
`8
`8
`8
`8
`11
`13
`13
`14
`14
`14
`15
`15
`15
`15
`18
`18
`18
`18
`18
`19
`19
`19
`19
`20
`20
`20
`20
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`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1027 – Page iv
`
`

`
`III. Potential Physicochemical Interactions . . . . . . . . . . . . . . .
`A. Sorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2. Mathematical Models . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`a. Freundlich equation . . . . . . . . . . . . . . . . . . . . . . . . . . .
`b. Simple linear equation . . . . . . . . . . . . . . . . . . . . . . . . .
`c. Langmuir equation . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`d. Diffusion equation-general . . . . . . . . . . . . . . . . . . . .
`e. Diffusion equation-constant drug concentration . .
`f. Diffusion equation- varying drug concentration . . .
`g. Diffusion equation-half-saturation time . . . . . . . . .
`h. First-order equation . . . . . . . . . . . . . . . . . . . . . . . . . . .
`1. Reversible first-order equation . . . . . . . . . . . . . . . . . .
`j. Bi-exponential equation . . . . . . . . . . . . . . . . . . . . . . . .
`3. Factors Influencing Sorption . . . . . . . . . . . . . . . . . . . . . .
`a. Effect of concentration . . . . . . . . . . . . . . . . . . . . . . . . .
`b. Partition coefficient . . . . . . . . . . . . . . . . . . . . . . . . . . .
`c. pH of the solution . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`d. Effect of excipients . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`e. Effect of temperature . . . . . . . . . . . . . . . . . . . . . . . . . .
`f. Structure of the polymeric sorbent . . . . . . . . . . . . . . .
`g. Structure of the sorbate . . . . . . . . . . . . . . . . . . . . . . . .
`4. Drug-Plastic Interactions . . . . . . . . . . . . . . . . . . . . . . . . .
`a. General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`b. Insulin
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`c. Nitroglycerin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`d. Diazepam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`5. Drug-Rubber Closure Interactions
`. . . . . . . . . . . . . . . . .
`6. Sorption of Antimicrobial Agents by Plastics . . . . . . . . .
`a. General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`b. Benzalkonium chloride . . . . . . . . . . . . . . . . . . . . . . . . .
`c. Phenylmercuric compounds
`. . . . . . . . . . . . . . . . . . . .
`7. Sorption of Antimicrobial Agents by Rubber Closures .
`a. General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`b. Benzyl alcohol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`c. Phenol
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`d. Chlorobutanol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`e. Parabens
`f. Mercuric compounds
`. . . . . . . . . . . . . . . . . . . . . . . . . .
`8. Adsorption onto Glass Surfaces . . . . . . . . . . . . . . . . . . . .
`a. General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`21
`22
`22
`23
`25
`25
`26
`27
`29
`31
`33
`34
`35
`37
`38
`38
`40
`40
`43
`44
`46
`47
`49
`49
`59
`60
`62
`63
`63
`63
`71
`73
`74
`7 4
`77
`79
`79
`80
`80
`80
`80
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1027 – Page v
`
`

`
`81
`b. Biological compounds . . . . . . . . . . . . . . . . . . . . . . . . . .
`85
`c. Nonbiological compounds . . . . . . . . . . . . . . . . . . . . . .
`87
`B. Leaching . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`87
`1. General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`87
`2. Mathematical Models . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`87
`a. Square-root-of-time equation . . . . . . . . . . . . . . . . . . .
`h. First-order equation . . . . . . . . . . . . . . . . . . . . . . . . . . .
`89
`c. Log-log equation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`89
`91
`d. Linear equation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`91
`e. Desorption equation . . . . . . . . . . . . . . . . . . . . . . . . . . .
`93
`:~. Factors Influencing Leaching . . . . . . . . . . . . . . . . . . . . . .
`93
`a. Temperature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`94
`b. pH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`94
`c. Excipients
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`4. Leaching from Rubber Closures . . . . . . . . . . . . . . . . . . . .
`95
`5. Leaching from Plastic Containers . . . . . . . . . . . . . . . . . .
`99
`6. Corrosion of Glass Surface . . . . . . . . . . . . . . . . . . . . . . . . 102
`a. Etching process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
`b. Leaching process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
`C. Permeation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
`1. General ............ , . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
`2. Mathematical Models
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
`a. Diffusion equation
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
`b. Compartmental equations . . . . . . . . . . . . . . . . . . . . . .
`111
`3. Factors Influencing Permeation . . . . . . . . . . . . . . . . . . . . 113
`a. Concentration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
`b. Partition coefficient . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
`c. pH of the solution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
`d. Formulation components . . . . . . . . . . . . . . . . . . . . . . .
`116
`e. External environment
`. . . . . . . . . . . . . . . . . . . . . . . . . 117
`f. Diffusion in polymers . . . . . . . . . . . . . . . . . . . . . . . . . . 117
`g. Temperature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
`4. Permeation through Plastic Materials
`. . . . . . . . . . . . . .
`119
`5. Permeation through Elastomers
`. . . . . . . . . . . . . . . . . . . 122
`IV. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1027 – Page vi
`
`

`
`
`
`I.
`
`INTRODUCTION
`
`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-
`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-
`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: (I) the composition of the pack-
`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-
`actions are discussed in three categories: sorption, leaching, and permeation.
`In each category, discussion of the mathematical equations that are per-
`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 handy 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 between pharmaceutical
`products and packaging components (Autian, l963a,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 8,338,470
`Amneal Pharmaceuticals LLC — Exhibit 1027 — Page 1
`
`

`
`2
`
`PDA TECHNICAL IH·:PORT NO. 5
`
`better understanding of these interactions has resulted from developments
`in other fields, such as permeation through plastic films, pharmacokinetic
`modeling, absorption through biological membranes, and sustained-re(cid:173)
`leased dosage forms. This report provides a comprehensive review of those
`publications that discuss the concepts and mechanisms of these physico(cid:173)
`chemical interactions and the utilization of these concepts in the devel(cid:173)
`opment of sterile pharmaceutical products.
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1027 – Page 2
`
`

`
`
`
`PRIMARY PACKAGING SYSTEMS
`
`3
`
`II. PRIMARY PACKAGING SYSTEMS
`
`The 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 containers
`
`Glass has traditionally been considered the container material of choice
`for most sterile pharmaceutical products. However, it should not be as-
`sumed that 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-
`tions, it can order itself and crystallize, a process known as “devitrifica-
`tion."
`
`Glass consists of a mixture of oxides. The primary glass-forming (net-
`work-forming) oxides are SiO2, B203, Ge02, P205, V205, and A1203. Among
`these, SiO2 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, Na2O, K20, BaO, or Li2O, are needed
`to decrease the softening temperature of glass and, thereby, make it easier
`to process ( Holloway. 1973). A stabilizer, such as A1203, Sb2O3, Pb02, or
`ZnO, is also added to make the glass less prone to crystallization or devi-
`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-
`ganic oxides, such as those of sodium, potassium, calcium, magnesium,
`aluminum, barium, and iron, are only loosely bound in the network inter-
`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 8,338,470
`Amneal Pharmaceuticals LLC — Exhibit 1027 — Page 3
`
`

`
`-‘l
`
`l’lL\
`
`'l'E('H.\'l(‘.-\l. RI-T|’(lR'l' NU.
`
`.3
`
`Common Constituents of Glasses and Their Effect on Properties
`
`TABLE I
`
`Constituent
`SiOg
`
`Function
`Network tormer
`
`B203
`
`Network lormer
`
`Pb0;
`Al2O3
`
`Stabilizer
`Stabilizer
`
`Na2O
`
`Network modifier (tluxl
`
`K20
`
`Li,0
`
`Ca0
`
`Network modilier (tluxl
`
`Network modilier (tluxl
`
`Network modifier (lluxl
`
`Source. Holloway E1973)
`
`Physical and Chemical Properties
`Crystalline silica has very high melting point
`and liquid silica has very high viscosity. High
`concentration of silica in a glass confers
`high soltening temperature. low thermal
`expansion. good chemical durability.
`Will join network structure ol 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 loin network in Alo. tetrahedron which are
`clillerent in size from Si04. Strongly
`suppresses devitriiication: increases process
`viscosity.
`Markedly lowers softening temperature. Raises
`thermal expansion and ionic conductivity.
`Reduces durability.
`Similar to N220. but the larger K‘ ion is less
`mobile than the Na’ ion.
`Similar to Nago, but the smaller Lil’ ion is more
`mobile than the Na‘ ion.
`inhibits mobility of alkali ions. hence increases
`resistivity and durability ol alkali glasses.
`Shortens the working range.
`
`extracted oxides may affect solution pH, catalyze physicochemical reac-
`tions. or even enter into the reactions themselves. Additionally. some
`components of glass are also prone to attack by drug solutions; as a result,
`flakes may be dislodged into the solution (Avis, 1975).
`A true glass can be formed from the combination of SiO-_; and Na-__;O. A
`true glass is. however. soluble in water and is thus called water glass. With
`the addition of a stabilizer. the water solubility oftrue glass is greatly re-
`duced and an insoluble soda-limc glass is formed.
`1) Soda-lime glasses
`Soda-lime glasses account for approximately 90% of all commercial
`glasses. They are fairly resistant to chemicals. but cannot withstand sudden
`changes in temperature. Depending on the concentration of NagO. B303,
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLc — Exhibit 1027 — Page 4
`
`

`
`PRIMARY PACKAGING SYSTEMS
`
`5
`
`Major Chemical Constituents of Container Glasses and Glasses Used for
`Handling Ultrapure Solutions
`
`TABLE II
`
`Glass Type
`
`Soda-Iima A
`Soda-lime B
`Borosilicate A
`Borosilicate B
`Alkali-resistant
`Chemically
`Strengthened
`High-silica
`vitreous-silica
`
`Typical concentration (wt %) "
`SID; M203 zro, Na-20 K20 U20 B203 C30 M90 Bao
`
`73
`74
`81
`73
`71
`66
`
`1
`2
`2
`6
`1
`20
`
`.
`
`—
`—
`—-
`—
`15
`—
`
`0.5 —
`96
`100 —
`—-
`
`17
`13
`4
`7
`11
`9
`
`—
`~—
`
`—
`4
`5
`0.5 — —
`0.5 —
`11
`0.5 —
`3
`0.5
`-—-
`13 — —
`—
`0.5 —
`10
`1
`—
`2
`0.5
`1
`— — —
`—
`—
`5
`— — — —
`
`3 — — —
`—— —
`— — —
`
`* In all except high-silica and vitreous-silica glasses. F. CI. 50.. 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 by exposing the glass to
`S02 gas to remove Na2O prior to use:
`
`N820 + S0-gl+ ‘/2 O2 " Na2S04
`
`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-
`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—
`kalized glass containers are widely used for intravenous infusion solu-
`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 8,338,470
`Amneal Pharmaceuticals LLC — Exhibit 1027 — Page 5
`
`

`
`6
`
`l’l)A 'l'l'I('H‘.\'l(‘.-Kl. RF.l’0R'l‘ N0, 5
`
`TABLE III
`
`Typical Compositions (in %) of Chemically Resistant Borosilicate Glasses
`Manufactured by Kimble
`
`Component
`
`KG-33
`
`KG-34
`
`N51A
`
`A 203
`
`Code
`
`SiO2
`8203
`AIQO3
`Ca0
`
`MgO
`BaO
`
`Na2O
`K20
`TD;
`F8203
`
`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
`—
`—
`
`71.6
`9.2
`5.3
`0.8
`
`0.1
`2.1
`
`6.4
`0.7
`2.8
`0.3
`
`Scientilic
`ware. process
`pipe
`
`Blown
`bottles
`
`Ampuls
`vials
`
`Amber ampuls
`Amber vials
`
`Source: Bacon (1968).
`
`Typical Composition (in %) of Alkali-Resistant Glasses Manulactures by
`Corning
`
`TABLE IV
`
`component
`
`SiOp
`B203
`N903
`CaO
`Mg0
`U20
`Na2O
`K20
`Zr0p
`
`Source. Bacon (1968).
`
`Code
`
`7280
`
`71.3
`—
`’
`0.1
`0.1
`0.8
`11.5
`o.1
`
`7740
`
`80.3
`13.0
`
`0.1
`—
`-
`4.2
`_
`—
`
`Borosilicate glasses. are also lmown as USP Typel glasses, can be divided
`into A and B <.:u|)(-lasses (Table 11). Class A. Pyrex glass, is more difficult
`to fabricate and has a lower thermal expansion coefficient than class B.
`Class B borosilicate glass. as exemplified by the so-called neutral glass, is
`
`fiflmz.
`
`Petition for Inter Partes Review of US 8,338,470
`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) Amber 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% Mn02 and 0.01%
`CrO;;; greenish amber, 0.1% to 1% S03; and brownish amber, 2% to 3%
`'l‘i02.
`Other colors can be produced by incorporating C00 for blue, Ni0 for gray,
`Cr2O3 for green, and CuO for bluish-green. These coloring metals in amber
`glass are potential sources of trace ions, particularly of iron.
`h. Classification of glass container by USP
`The United States Pharmacopeia (USP) has classified glass containers,
`according to their degree of chemical resistance, into four types:
`1) Type I is made from a chemically high resistant borosilicate glass,
`composed principally of silicon dioxide and boric oxides. This glass has
`low leachability and a low thermal coefficient of expansion. In 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 II is made from de-alkalized soda-lime glass, composed of rela-
`tively high levels of sodium oxide 03-17%) and calcium oxide (5-1 1%)
`(Table II). The existence of these two oxides makes Type II glass con-
`tainers chemically less resistant than Type I (which contains 4—7% Na2O
`and 1% CaO). A Type II glass container, however. has a lower concen-
`tration of migratory oxides than does Type III. and its chemical resis-
`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-
`nation or alkaline detergents. (Thus. Type ll glass containers possess
`relatively good chemical resistance for one-time use. A Type II glass
`container 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. It 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 reactive 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-
`tainers. However, a Type III glass container has a higher concentration
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC - Exhibit 1027 - Page 7
`
`

`
`8
`
`I'll:\ Tl·TH\:H':\I. 1n:1·uBT ~II . .-,
`
`of migratnr>· oxid<.>s than does a Type II co11tai1H'r. and it has not been
`subjected to de-alkalizat ion t real nwnt. It is usuall>· suitable onl>· for
`anh>·drnus liquids or for dr>· drug products.
`4) Type NI) is also made from a soda-li me glass and is not suitable for
`parenteral drug produ<'ts.
`
`2. Plastic containers
`
`Plastics fall into two general dasses: t.h ermosets and thermoplast.ici:;.
`Because of their unusual versatil it>·· thermoplastics have found wider ap(cid:173)
`plication than thermoset::;. especially in the medical/pharmaceutical
`field.
`Thermoplastic polymern are gradually finding use as packaging materials
`for sterile preparations. such as parent.erals and ophthalmic solutions. One
`of the principal advantages of plastic containers is that they are not. as
`fragile as glass. ln addition. thf> fl exibil ity of poly\·inyl chloride IV bags is
`an advantage in the int raw nous ;1dministrat ion of large \'olumes of drug
`solution. because no air interchange is required.
`Prior to the recognition oft he potential of plastic materials in health care
`practice. glas::> was the dominant material used in the primary packaging
`of pharmaceutical products. The fragilit:·; and weight of glass, coupled with
`the broad range of propertie::-; offered b>· plastics. have resulted in marked
`increases in the use of pla::>tics for pharmaceutical packaging during the last
`two decades (Giles and Pecina. 19';'5) . Today. for example. plastics are used
`in Sllch ::>terile primary packaging s>·stems as syringe::>. bottles, vials, and
`ampuls (Table \'). F'ifteen >·ears ago. only glass would have been considered
`for these uses.
`a. Polymerization
`Plastic materials are prepared from monomers by polymerization. To
`achieve polymerization, the monomers mu::>t be bifunctional, i.e., the
`monomers must. be capable of fo rming two covalent bonds. There are t wo
`classical wa~·s in which a monomer can achieve bifunctionality: first, a
`monomer may contain an unsaturated C= C bond, e.g., ethylene
`(CH 2= CH 2); second, a monomer may possess two different organic- func(cid:173)
`tional groups that can react with one another. e.g., an amino acid
`(NH2-CHR- COOH).
`Polymerization can proceed by either of two basic processes, determined
`largely by the way in which the monomer has attained bifunct.ionality.
`· 1) Polymerization by addition
`Polymerization by addition (or free radical reaction) is commonly per(cid:173)
`formed with monomers that contain an unsaturated C=C bond. These
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1027 – Page 8
`
`

`
`
`
`PRIMARY PACKAGING SYSTEMS
`
`9
`
`Sterile Plastic Devices for Parenteral Drug Administration
`
`TABLE V
`
`Sterile Plastic Device
`
`Plastic Material
`
`Containers for blood product
`
`Polyvinyl chloride
`
`Disposable syringe
`
`irrigating solution container
`
`i.V. infusion fluid container
`
`Administration set
`
`Polycarbonate
`Polyethylene
`Polypropylene
`
`Polyethylene
`Polyoielins
`Polypropylene
`
`Polyvinyl chloride
`Polyoielins
`
`Nylon (spike)
`Polyvinyl chloride (tube)
`Poiymethylmethacrylate (needle adapter)
`Polypropylene (clamp)
`
`Catheter
`
`Teflon
`Polypropylene
`
`Adapted lrom Turco and King (1979).
`
`monomers have the general chemical structure
`
`__ ZR
`CH,-—C \R;
`
`where R, and R2 can be I-I, Cl-I3, phenyl, COOH, COOR, OCOCH3, CEN,
`F, Cl, CONH2, or pyrrolidone.
`The polymer produced by addition polymerization may be represented
`as:
`
`__(_CH2_C2Rl_)h
`\R,
`
`when n refers to the average number of monomer units in the polymer
`molecule. Depending on the chemical types of R. and R2, a great variety
`of polymers can be produced (Tables VI and VII). Tei'lon®, also known as
`polytetrafluoroethylene {-CF2—CF-g—},,,
`is a unique polymer produced
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Phannaceuticals LLc — Exhibit 1027 — Page 9
`
`

`
`10
`
`!'DA Tf<X'H;\ l l'\L H!-:l'l1HT '<0 .. \
`
`TABLE VI
`Polymers Produced by Addition Polymerization of Vinyl-Type Monomers
`
`Monomer Structure Monomer Name
`
`Polymer Structure
`
`Common Polymer
`Name
`
`Ethylene
`
`Propylene
`
`Vinyl chloride
`
`Styrene
`
`Acrylic acid
`
`Acrylic acid ester
`
`Acrylonitrile
`
`Vinyl fluoride
`
`Vinyl acetate
`
`Acrylamide
`
`Vinyl pyrrolidone
`
`H,C=CH,
`
`CH2-Cll
`I
`CH,
`
`CH,= CH
`I
`Cl
`
`H,C=CH
`
`©
`
`H2C=7H
`
`C= O
`I
`OH
`
`H ,C-CH
`I
`C= O
`I
`OR
`
`H1C= CH
`!
`c =:N
`
`CH,=C H
`
`J.
`
`H2C=CH
`!
`0
`l
`C= O
`I
`CH,
`
`H 2C=CH
`I
`C=O
`I
`N H2
`
`H ,C=CH
`I
`N
`
`CH/ \=o
`2
`I
`l
`CH2-CH2