10
`Use of Plastics for Parenteral
`Packaging
`
`John M. Anes, Robert S. Nase, and Charles H. White
`
`The West Company, Phoenixville , Pennsylvania
`
`I.
`
`INTRODUCTION
`
`The field of parenteral packaging has changed in many ways since the advent
`of parenteral drug delivery technology. In the earlier days of practice, medi(cid:173)
`cations were almost exclusively packaged and dispensed in glass. This was
`the only material of choice because of its availability and physical properties.
`Glass has excellent clarity, thermal resistance, barrier properties, and is
`chemically inert. The use of other materials, s uch as rubber and aluminum,
`grew in popularity with the need for better packaging. Rubber was chosen
`to seal glass containers and aluminum to hold the rubber in place. There are
`several identified weaknesses for glass that have been considered acceptable
`due to its use over time as the material of choice. Glass breaks easily, is
`heavy, and requires a rubber closure as a seal.
`Dramatic developments in polymer technology occurred during the 1950s
`that introduced the use of plastics to replace glass . Plastic resins overcome
`the weaknesses of glass but present a new set of possible problems that must
`be considered and understood. Plastics are relatively unbreakable and ex(cid:173)
`tremely light compared with glass. Their weight is approximately one tenth
`the weight of glass on a volume to volume basis. They are readily fabricated
`into a variety of complex shapes thereby providing ease of handling and pack(cid:173)
`aging. Lastly , the cost for plastic products is generally less than glass.
`The use of plastics for the medical industry has markedly expanded in
`recent years. Table 1 [ 1) summarizes the amount of plastics used in medical
`applications in the United States since 1984. The table is broken down by
`material, process types, and areas of use, and it shows that use of plastics
`for medical applications has grown s ince 1984 at an average rate of 5. 7% per
`year, while the total plastics market has expanded at only 4.5% per year.
`
`387
`
`Hospira, Exh. 2015, p. 1
`
`

`
`Table 1 U.S . Resin Sales by Process by Medical Market (millions of pounds)
`
`Process and (market)
`
`1984
`
`1985
`
`1986
`
`1987
`
`1988
`
`1989
`
`1990
`
`Plastic material
`
`Cellulosics
`
`HDAP
`
`(Medical)
`
`Blow molding (pharmaceuticals /cosmetics)
`
`Polypropylene
`
`Blow molding (medical containers)
`
`Injection molding (medical)
`
`Polystyrene
`
`Injection molding (medical)
`
`PVC
`
`Calendering (hospital and health care)
`
`Extrusion (medical tubing)
`
`Dispersion coating (hospital • health care)
`
`Injection molding (hospital l health care)
`
`Total pounds
`
`Total U.S. market (lbs)
`
`0
`155
`
`40
`
`l15
`
`55
`
`22
`
`43
`8
`
`20
`
`0
`165
`
`42
`
`115
`
`60
`
`23
`
`50
`8
`
`25
`
`0
`182
`
`42
`
`120
`
`64
`
`26
`
`54
`10
`
`28
`
`0
`194
`
`48
`
`148
`77
`
`33
`
`70
`
`15
`
`41
`
`3
`202
`
`55
`
`160
`82
`
`35
`
`71
`
`17
`
`42
`
`4
`
`198
`
`51
`
`154
`
`74
`
`40
`
`73
`
`18
`
`42
`
`511
`
`542
`
`584
`44500 46506 49495
`
`740
`
`696
`54763 57952 58251
`
`727
`
`4
`
`202
`
`55
`
`168
`
`90
`
`44
`
`76
`
`20
`
`40
`
`777
`
`61480
`
`Present usage for medical applications
`
`1.14% 1.16% 1. 28%
`
`1. 27% 1.28% 1.25%
`
`1.26%
`
`w co co
`
`::..
`::s
`"' ~
`
`~
`Q
`
`"' !"
`Q
`::s
`i:l.
`'IE
`::s-
`;;;
`
`Hospira, Exh. 2015, p. 2
`
`

`
`Use of Plastics
`
`389
`
`These figures illustrate the strong demand for plastics in medical applica (cid:173)
`tions. How much of these quantities are used for parenteral packaging Is
`difficult to ascertain since there are a broad variety of products currently
`on the market thRt use plastics. Table 2 shows a list of typical parenteral
`products along with the plastic resins commonly used for each application.
`The means for the selection of a plastic material that comes In contact
`with parenteral drugs are not simple. The properties of each resin must be
`thoroughly understood along with its manufacturing process. Plastics do not
`match the barrier properties of glass for oxygen and moisture transmission.
`With plastics, there must be special attention given to the additives present
`in the formulation due to the possibility of their migration from the resin. In
`most cases a compromise is required in the areas of clarity and temperature
`resistance when comparing plastics to glass. All of these properties will
`change to varying degrees depending on the type of plastic selected. The
`product design, fabrication process, environment for manufacture, and the
`method used for product sterilization will also require careful planning and
`are factors that will affect the properties of the final product. This chapter
`covers an overview of each of these areas, all realted to the development of
`plastic products for pa renteral packaging .
`
`II. FUNDAMENTALS
`
`A. Definition of Plastics
`
`Plastics are polymers, both synthetic and natural, which can be shaped when
`softened and then hardened to produce the desired &tructure. A polymer is
`
`Table 2 Examples of Plastics Used for Parenteral Drug Containers
`
`Sterile plastic device
`
`Plastic material
`
`Containers for blood products
`
`Polyvinyl chloride
`
`Disposable syringe
`
`Irrigating solution container
`
`i. v. Infusion fluid container
`
`Administration set
`
`Polycarbonate
`Polyethylene
`Polypropylene
`
`Polyethylene
`Polyolefins
`Polypropylene
`
`Polyvinyl chloride
`Polyes ter
`Polyolefins
`
`Acrylonitrile butadiene styrene
`Nylon (spike)
`Polyvinyl chloride (tube)
`Polymethylmethacrylate (needle adapter)
`Polypropylene (clamp)
`
`Catheter
`
`Teflon
`Polypropylene
`
`Hospira, Exh. 2015, p. 3
`
`

`
`390
`
`Anes, Nase, and White
`
`simply a large organic molecule built up from the repetitious joining of smaller
`molecules or monomers. Most polymers are linked together by carbon to car(cid:173)
`bon bonds with a variety of complex organic groups attached to the carbon
`molecular chain. The repeating monomers are joined together by a reaction
`process called polymerization that utilizes heat, pressure, and various reac(cid:173)
`tion catalysts. The monomers commonly consist of atoms of carbon, hydrogen,
`oxygen, nitrogen, and halogens (fluorine, chlorine, and bromine) [ 2).
`For example, if one takes ethylene gas and processes it by heat and pres(cid:173)
`sure in a closed vessel utilizing a catalyst to bring about the reaction process,
`a repeating ethylene molecule ls formed called polyethylene . After removal of
`the catalyst residue and drying, the polyethylene powder may be melted into
`a mold, or extruded into a tube or sheet to produce a useful shape or struc(cid:173)
`ture. Several processes may be employed to reshape the polyethylene, as
`discussed in later sections.
`There are a variety of monomers that can be used to produce plastic poly(cid:173)
`mers with different structures. For example, styrene monomer is used to
`produce polystyrene. The resulting polymer has a repeating aromatic ring
`attached to every other carbon in the structure backbone. This produces a
`plastic with markedly different physical characteristics from the previous ex(cid:173)
`ample of polyethylene. The structural relationship between the monomer and
`repeating units of three common polymers is s hown In Table 3.
`
`B. General Classifications for Plastics
`
`Thermoplastics Versus Thermoset Plastics
`
`thermoplastics and thermo(cid:173)
`There are basically two main classes of plastics:
`sets. At some stage of their conversion into finished products, both types
`are fluid enough to be formed or molded. Thermoplastics are polymers that
`soften upon heating to higher temperatures and solidify again upon cooling.
`Thermoplastics may be remelted repeatedly. They are reprocesslble and there(cid:173)
`fore reusable. Thermosets in their fluid condition are s till chemically reactive
`and harden by a further reaction , called crosslinking, between groups on
`nearby chains, forming a three dimensional network [ 3) • Subsequent heating
`that would somewhat soften the structure cannot restore the flowability that
`typifies the uncrosslinked, uncured resin. Therefore, thermoset plastics
`cannot be reprocessed once they are crosslinked. Typical thermosets are
`phenolics, formaldehyde resins, epoxies, and crosslinked polyesters. For
`
`Table 3 Monomers and Repeat Units of Three
`Common Polymers8
`
`Polymer
`
`Monomer
`
`Repeat unit
`
`Polyethylene
`Polyvinyl chloride
`Polystyrene
`
`=CH
`CH
`2
`2
`CH
`=CHCI
`2
`<;:H2=CH
`@
`
`+CCH 2CH
`+
`2
`+CCH2CHCI+ n
`+C~H 2CH+ n
`@
`
`Hospira, Exh. 2015, p. 4
`
`

`
`Use of Plastics
`
`391
`
`parenteral packaging, thermoplastic materials are preferred over the thermo(cid:173)
`set polymers due to their availability, reusability, and processability. There(cid:173)
`fore, the remaining discussion will be confined to thermoplastics .
`
`Classification of Thermoplaslics
`Engineering Versus Commodity Resins. Thermoplastics can be further
`classified into engineering thermoplastics and commodity thermoplastics. Engi(cid:173)
`neering thermoplastics are normally plastics that are able to withstand a load
`or to be formed into some sort of structural product. These plastics ore spe(cid:173)
`cifically formulated to achieve some desired set of properties, as for example,
`stiffness or impact resistance . These materials may be higher priced than
`commodity resins, but provide added value in being designable for various
`applications. One example of an engineering thermoplastic is an i. v. spike
`that is designed to penetrate a rubber i. v. stopper.
`In this case, rigidity and resistance to breakage are engineering proper(cid:173)
`ties tha t are essential to the application. Commodity plastics are normally
`lower-cost resins that are designed for large volume production. The variety
`of formulations and performance features are limited since large volumes of a
`single plastic are important to maintaining low prices. However, many com(cid:173)
`modity thermoplastics have attributes desirable for parenteral packages and
`other applications. Polypropylene is an example of a commodity- type thermo(cid:173)
`plastic that has application in certain types of parenteral vials.
`
`Rigid Versus Flexible Resins. Thermoplastics can be either rigid or nex(cid:173)
`ible, depending on the complexity and degree of crystallinity of their polymer
`structure [ 4] . Polymers that are synthesized from simple monomer units such
`as polyethylene tend to be flexible . Bulky aromatic structures, as well as
`crystalline structures, tend to produce greater rigidity . Some thermoplastics
`such as polyvinyl chloride can be plasticized to achieve a high degree of nexi(cid:173)
`bility utilizing additives such as dioctyl phthlate. Application examples are
`medical tubing, parenteral bags , and other nexible containers where lack
`of rigidity is desired [ 5 I .
`On the other hand, many applications require rigidity and dimensional
`stability. Certain load-bearing applications such as rigid vials, clamps, etc. ,
`require substantial rigidity.
`
`Transparent Versus Opaque Plastics. The degree of transparency, or
`opacity, exhibited by a plastic material is also related to Its molecular struc(cid:173)
`ture. Perhaps the greatest influence on clarity is the degree of crystollinity.
`Highly crystalline materials, such as high-density polyethylene or nylon, tend
`to be opaque because crystallites refract light and, therefore, do not trans(cid:173)
`mit light. Some amorphous plastics, such as general purpose polystyrene or
`polymethylmethacrylate, transmit light and exhibit a high degree of clarity.
`Several plastics, including acrylics, polystyrene, polycarbonate, and
`polymethylpentene have light-transmitting properties close to, or better than,
`glass [ 6). Other plastics, such as polypropylene, have good liquid contact
`clarity. This means that when liquid is in contact with the surface of the
`plastic, it appears clear . A list of common transparent polymers is shown
`in Table 4.
`If plastics are to compete with glass in pharmaceutical packaging applica(cid:173)
`tions, clarity is one of the most important characteristics. Other necessary
`
`Hospira, Exh. 2015, p. 5
`
`

`
`392
`
`Anes, Nase, and White
`
`Table 4 Transparent Polymers
`
`Polymer
`
`Symbol
`
`Acrylonitrile
`methylmeth-
`acrylate styrene
`
`Transparent
`ABS
`
`Acrylic
`Nylon
`(amorphous)
`
`Polycarbonate
`Polyester
`
`Polymethylpentene
`
`Polystyrene
`
`Polysulfone
`
`Rigid polyvinyl
`chloride
`Polypropyleneb
`
`PMMA
`
`PC
`
`PET
`
`TPX
`PS
`
`PVC
`
`pp
`
`Degree of
`transparency
`
`Light transmissions
`(%)
`
`Translucent
`
`72-88
`
`Clear
`
`Clear
`
`Clear
`
`Clear
`
`Clear
`
`Clear
`
`Transparent
`(amber)
`
`Transparent
`
`Translucent
`
`88-92
`
`86-90
`
`87-91
`
`90
`
`90
`
`87-92
`
`75
`
`74-76
`
`<70
`
`aPercentage of light passing t hrough vs. light refracted as measured by
`r efractometer.
`bpoJypropylene has good contact clarity.
`
`properties to be discussed in later sections are heat resistance for steriliza(cid:173)
`tion, impact resistance (resistance to breakage and abuse), and barrier prop(cid:173)
`erties for adequate shelf life. Although there is a long list of plastics that
`can be made opaque, clarity is often more difficult to achieve. Applications
`where clarity is important are parenteral vials and bottles, syringes and i. v.
`bags. Opaque plastics are used in i . v . spikes, clamps, closures, etc. , where
`properties other than clarity are needed.
`
`C . Basic Polymer Structure
`
`The chemical structure of a polymer molecule determines its physical, chemi(cid:173)
`cal, and mechanical properties, as well as its heat stability and resistance to
`aging.
`Elements of structure such as molecular weight, molecular-weight distribu(cid:173)
`tion , degree of crystallinity , and additive content are primary determinants
`of these properties. Polymer properties can be varied during polymerization
`-the basic chemical process carried out to produce the polymer. As described
`in Section II .A, the polymer is formed under the influence of heat , pressure,
`catalysts, or a combination, within vessels called reactors. One special form
`of property variation involves the use of two or three different monomers as
`
`Hospira, Exh. 2015, p. 6
`
`

`
`Use of Plastics
`
`+ CH 2-CH 2-CH 2- CH 2-CH
`
`-CH 2-t(cid:173)
`2
`
`(a)
`
`393
`
`(b)
`
`Figure 1 The structui-es in poi-entheses represent arbitrary sections of poly(cid:173)
`mer:
`(a) linear polyethylene and (b) branched polyethylene.
`
`comonomers, i.e., copolymerizing them to produce copolymers (two comono(cid:173)
`mers) or terpolymers (three comonomers).
`Polymers that are formed into long linear chains will have different per(cid:173)
`formance characteristics than those that are branched or interconnected to
`form a three-dimensional structure. The arrangements of the repeating struc(cid:173)
`tural units in a linear and branched polymer are illustrated in Figure 1.
`Multi- or copolymer systems are those that have more than one type of
`repeating unit, and this often results in more favorable properties, such as
`toughness or flexibility, than are present in the individual homopolymers.
`The resulting properties are also influenced by the "manner" in which the
`repeating units appear in the polymer chain. The specific properties will be
`discussed in a later section . By employing different synthesis techniques,
`copolymers can be made with alternating, random, block, or grafted repeating
`units within the polymer chain. Each type of copolymer structure is illus(cid:173)
`trated in Figure 2.
`Unlike small organic molecules, polymers contain molecules with different
`chain lengths. The chain- length distribution of a polymer can be claculated
`statistically. This is generally referred to as the molecular- weight distribu(cid:173)
`tion (MWD) of the polymer. This information can be used to predict or evalu(cid:173)
`ate polymer processing parameters and performance characteristics. When
`two polymers have identical chemical structures but have different MWD, the
`processing parameters and performance characteristics of the two polymers
`may be considerably different.
`The degree of order in a polymer system is directly related to the degree
`of crystallinity . By definition, a crystalline polymer system is one in which
`a high degree of order prevails. Conversely, an amorphous (noncrystalline)
`
`Hospira, Exh. 2015, p. 7
`
`

`
`Anes, Nase, and White
`
`394
`
`Alternating
`
`-A-B- A-B-A-B-A-B-A-B-A-B-A-B-
`
`Random
`
`-A-B-A-A-B-A- B-B -A- A-A - B -A- B-
`
`Block
`
`-A - A-A- A-B -B-B-B- B-A-A-A-A-A-
`
`Graft
`
`B
`I
`B
`D
`I
`I
`B
`B
`I
`I
`-A- A-A-A-A-A-A-A-A-A-A-A-A-A-
`i
`I
`B
`B
`I
`I
`B
`B
`I
`I
`B
`B
`!
`B
`
`Figure 2 Four types of multicomponent polymer systems where A and B repre(cid:173)
`sent two different repeating units.
`
`system is devoid of order. Generally speaking, most polymers have both
`amorphous and crystalline regions, the degree of each varying with the in(cid:173)
`dividual polymer system . Crystallinity is largely determined by the type and
`size of the repeating unit and how well the polymer chains ere arranged in a
`lattice array .
`Crystallinity is an important parameter in determining many of the plas(cid:173)
`tic's physical and chemical properties. In general, the higher the degree of
`crystallinity a polymer has, the more brittle and rigid it will be. As stated
`earlier, such a polymer will also exhibit less permeability and transparency.
`Since polymers are not generally as inert as glass, they may be subject
`to degradation and oxidation during the useful life of the product. Further(cid:173)
`more, degradation and processing difficulties may be encountered during the
`fabrication of the product. These problems can be reduced or eliminated by
`the use of additives to protect the basic polymer.
`
`Hospira, Exh. 2015, p. 8
`
`

`
`Use of Plastics
`
`D. Additives
`
`395
`
`Given the complexity of polymer structures described in the previous section,
`plastics can be prepared for specific application without the addition of any
`other ingredients. Others may contain additives to impart specific desired
`qualities to the final plastic product. Additives are frequently used to modify
`the physical and chemical properties of the plastics.
`Each polymer type has its own unique characteristics and often has use
`limitations. By the addition of other molecules as additives, it is often pos(cid:173)
`sible to improve a particular polymer's performance characteristics. For ex(cid:173)
`ample, plasticizers such as dioctylphthalate give flexibility to a rigid poly(cid:173)
`vinyl chloride polymer. The additives most commonly found in thermoplastic
`packaging materials are antioxidants, heat stabilizers, lubricants, plasticizers,
`flllers, and colorants. These additives are combined with the polymer during
`its manufacture, or compounded in as a post operation. The concentration of
`additives in polymers varies from as little as 0. 01% to as much as 60%, depend(cid:173)
`ing upon the type of polymer and purpose of the additive. The following gen(cid:173)
`eral discussion will identify the additives sometimes used in parenteral plas(cid:173)
`tic packages.
`During storage of these parenterals, the additives could extract or leach
`into a drug solution in intimate contact with the plastic container. Therefore,
`it is important to evaluate the physical and chemical compatibility of a drug
`formulation in a packaging system under various storage and time conditions
`to insure safety and stability of the drug product. Whenever possible, eval(cid:173)
`uations should be conducted under conditions simulating those to which the
`product probably will be exposed. Evaluations should take into consideration
`not only the physical and chemical compatibility of the drug formulation with
`the primary packaging system, but also should include an investigation of
`the long-term effects (2 to 3 years) on mechanical properties of the primary
`packaging system.
`Additives for specific types of plastic will be discussed in detail where
`appropriate in Section IV.
`
`Antioxidants
`
`Many plastic materials are susceptible to oxidative degradation and require
`antioxidants to slow down the process and to give them a longer shelf life.
`Polymers are often exposed to heat, light, ozone, and mechanical stress
`In the presence of oxygen during the fabrication process and end use pro(cid:173)
`cesses and storage . The resulting oxidative effects will cause the formation
`of free radicals, which contribute, in turn, to the degradation of the polymer
`with a gradual loss of Important physical and mechanical properties of the
`plastic. The presence of effective antioxidants in the plastic formulation will
`significantly reduce the degree of degradation and, therefore, help to extend
`the lifetime of the plastic package.
`Degradation of a plastic material is a sequential process involving initia(cid:173)
`tion, propagation, and termination phases. Free radicals are formed on expo(cid:173)
`sure to heat, radiation, or mechanical shear. Antioxidants intercept the radi(cid:173)
`cals or prevent radical formation during processing or during the shelf life
`of the plastic .
`
`Hospira, Exh. 2015, p. 9
`
`

`
`396
`
`Anes, Nase, and White
`
`There sre two types of sntioxidsnts. Primary sntioxidsnts interrupt oxi(cid:173)
`dative degrsdstlon of plastics by tying up the free radicals. Such primary
`sntioxidsnts ss the hindered phenolics snd the sromstlc amines both hsve s
`reactive NH or OH group snd csn donate hydrogen to the free radicals. Phe(cid:173)
`nolics, such ss butylsted hydroxytoluene (BHT), sre the most widely used
`in plastic parenteral pscksging. BHT hss s broad FDA spprovsl snd is used
`in polyolefins, polyvinyl chloride, snd polystyrene, among others.
`Secondary sntioxidsnts decompose the unstable hydroperoxides formed
`in the plastic degradation process to inert products, thus preventing the pro(cid:173)
`liferation of rsdicsls. They sre used in conjunction with primary antioxidants
`to provide added stability to the plastic materials. The most popular ones
`are thioesters and phosphites.
`Antioxidants in parenteral packages can migrate to the surface and then
`leach out into the contents. Further, the combination of antioxidants with
`other additives may interact with the drug solution to alter its potency.
`Therefore, one must be aware of the antioxidant chemical species used when
`considering a parenteral package formulation,
`
`Heat Stabilizers
`
`During the manufacturing process of certain polymers, and /or the fabrication
`process for the final package component, heat, pressure, and shear energy
`can cause degradation of the polymer structure or cause discoloration of the
`polymer. Addition of a heat stabilizer will reduce these undesirable reactions.
`Heat stabilizers are generally required in the manufacture of polyvinyl chlor(cid:173)
`ide polymers (PVC). Metallic stearates and expoxidized plasticizers are the
`most commonly used heat stabilizers.
`Stabilizers are also used to retard or to prevent the deterioration of plas(cid:173)
`tic materials resulting from exposure to light, heat, and pressure and to im(cid:173)
`prove their aging characteristics. The commonly used families of stabilizers
`include epoxy compounds (expoxidized soybean oil), organotins (octyltln),
`snd mixed metals (barium and cadmium benzoate). Some of the stabilizers
`have some solubility in aqueous media and, consequently, could be extracted
`into a drug solution. Therefore, these stabilizers must be carefully chosen.
`
`Lubricants
`
`The term lubricant is used to describe s wide range of additive materials that
`esse the movement of a melted polymer against itself, or against other mate-
`rial s urfaces , commonly mets!. Lubricants csn be classified into internal or
`external lubricants, depending upon their purpose in the polymer process.
`A principle difference between internal and external lubricants is their com(cid:173)
`patibility with plastic resins. Internal lubricants must be compatible with
`given polymers since their action is to reduce internal cohesive forces allow(cid:173)
`ing the molecules greater mobility . The results are lower melt viscosity, in(cid:173)
`creased flow, and reduced energy requirements for processing. Stated simply,
`internal lubricants enhance the ease with which polymer molecules slip past
`one another. Examples of internal lubricants are fatty-acid amides, fatty-
`acid esters, and polyethylene waxes.
`External lubricants must be relatively incompatible with the polymer as
`they must migrate to the surface during hot processing to reduce friction
`
`Hospira, Exh. 2015, p. 10
`
`

`
`Use of Plastics
`
`397
`
`between the polymer and hot metal surfaces. The addition of a lubricant
`avoids resin sticking to the hot metal surfaces increasing material output and
`avoiding possible degradation. Examples of external lubricants are zinc
`stearates, silicones, and fluorocarbons.
`The quantities of lubricants used vary significantly from one plastic to
`another. Typical concentrations of external lubricants such as metal stearates
`are 0. 05 to 3. 0%, while bisamide synthetic wax is used as an internal lubricant
`in concentrations from 0.5 to 3.0%.
`
`Plasticizers
`
`Plas ticizers are a broad group of chemically and thermally stable materials,
`ranging from liquids to solids. They are used In plastic compounds to impart
`flexibility , resilience, reduced brittleness, and softness to various polymers.
`At the same time, they may facilitate processing.
`Plasticizers may be liquid monomers, viscous polyesters and epoxides, or
`solid rubbery polymers. The most commonly used plasticizers in parenteral
`plastics are dioxtyl phthalate and low-molecular-weight polyesters .
`More than 80% of all plasticizers are used with PVC; the rest go into such
`plastics as celluloslcs, nylon, polyolefins, and styrenlcs. Phthalates are the
`most popular plasticizers. For example, 30 to 40% of phthalate ester is added
`to PVC material to produce a flexible intravenous fluid bag, such as the Via(cid:173)
`flex (Baxter) and Lifecare (Abbott).
`As is true of stabilizers, plasticizers can migrate to the surface of a plas(cid:173)
`tic container and are, therefore, potentially extractable into a drug solution.
`
`Fillers
`
`Addition of fillers to base polymer may result in reduced flexibility and im(cid:173)
`pact resistance, improved heat stability and /or reduced material cost. In the
`parenteral plastic containers made from such plastics as PVC, small amounts
`of submicron fillers are used as brighteners. The addition of these fillers
`may impair the transparency of the plastic container.
`
`Colorants
`
`Certain plastics have an inherent color that is not aesthetically desirable and,
`upon aging, the color becomes more intensified. To rectify this problem,
`parenteral manufacturers may add a colorant or tint to hide the undesirable
`color of the polymer. Both dyes and pigments are available for use in plas(cid:173)
`tics. Experience has shown that dye molecules have a tendency to bleed out
`of the polymer matrix upon aging, but pigments have been shown to be non(cid:173)
`bleeding. Ultramarine blue is one of the most commonly used colorants for
`parenteral plastics.
`From the foregoing discussion, the reader is now aware of basic "plastics"
`vocabulary, making it possible to examine in some detail the important poly(cid:173)
`mers for the parenteral industry. In Section IV, polymer types will be de(cid:173)
`scribed in a systematic manner to facilitate comparison . They will be discussed
`with consideration for the physical, chemical, and mechanical properties of
`the plastic, the additives necessary for processing and stability, and the po(cid:173)
`tential problems that they (polymer and additives) might present to the paren(cid:173)
`teral manufacturer.
`
`Hospira, Exh. 2015, p. 11
`
`

`
`398
`
`Anes, Nase, and While
`
`Ill. FABRICATION PROCESSES
`
`There are many processes used to convert plastic resins from pellets into de(cid:173)
`sired shapes or configurations. As covered in the section on fundamentals,
`this means using heat to excite the molecules of a polymer in preparation for
`a forming process. All plastic processes are similar in the use of three basic
`elements to convert the resin from a pellet to its processed shape.
`
`1. Heat: excites molecular structure to allow free movement of molecules
`to form the free flowing polymer into a desired shape
`2. Pressure:
`3. Time : required to allow for transfer of heat into the plastic followed
`by time for removal of heat (cooling)
`
`These three basic elements will be discussed in detail for each of the processes
`covered in this section. When selecting a process there are several factors
`that must be considered. In most parenteral packaging applications, it is
`necessary to use several types of processes to complete a product for ship(cid:173)
`ment to a customer. This is especially true when the product package is in(cid:173)
`cluded in the overall project, as in fabrication of the outer package for pro(cid:173)
`tection during shipping. Use of flexible and rigid blister packaging ls widely
`used as an outer protective pack .
`It can be clear, provide a large area for
`product labeling, and offers the potential to maintain product sterility.
`Generally the product design or configuration will dictate what process
`must be used to manufacture the item. It is important in the design cycle to
`understand the strengths and weaknesses of the process alternatives. A prod (cid:173)
`uct can be designed to utilize or , perhaps, eliminate a particular type of pro(cid:173)
`cess. This is a critical step in the development stage, because the processes
`used will have a significant effect on the total manufacturing costs. There
`are times when making an intentional design modification will eliminate the
`need for a complete process step or change the efficiency or throughput of a
`manufacturing step.
`With this in mind it is important, in the design cycle, to work closely with
`a group that has a high level of technical experience in the specific process
`areas that may apply to the product under development.
`The following sections cover a review of each of the key plsatic processes
`used in parenteral packaging applications . Each process description will in(cid:173)
`clude a review of the basic steps involved along with the important factors
`affecting efficiency for each. Some examples will also be used to give a better
`understanding.
`
`A. Extrusion of Plastics
`
`The process of extrusion involves the melting of a plastic and forcing it through
`a die under pressure to form a desired shape. There are several different
`types of extrusion, depending on the die arrangement used to form the plastic.
`The three most widely used for parenteral packaging are flat-sheet extrusion,
`profile-tubing, and blown-film extrusion.
`In each process, plastic resin is fed into a Jong barrel which converts
`the plastic into a homogeneous melt through the use of heat, pressure, and
`time. This equipment is known as the extruder, and is shown in Figure 3.
`
`Hospira, Exh. 2015, p. 12
`
`

`
`Use of Plastics
`
`399
`
`Figure 3 Various components of a single- screw extruder, showing three zones
`of the extruder barrel.
`
`The extruder is powered by a drive motor used to turn a screw inside of
`a heated barrel. The screw is a large auger, made of a hard grade of steel
`and is closely toleranced to fit with a precise clearance through the length of
`the barrel . There are three zones; the feed, the transition, and the meter-
`ing (Fig. 3) [ 7). As the screw turns, material is fed by the hopper into the
`feed section of the screw. The material is melted as it feeds forward by heat
`applied on the barrel. As the material passes Into the transition zone (cen-
`ter section), the pressure increases significantly due to a reduction in the
`screw flight width. This pressure increase is essential to create effective
`mixing of the resin and also creates a self generation of heat , called shear
`heating. After passing the transition zone the material goes through the meter(cid:173)
`ing zone (last section) where it is essentially conveyed forward with no change
`in pressure. The purpose for the metering zone is to allow time for a through
`mixing of the resin melt and to stabilize the pressure before entry into a form(cid:173)
`ing die . A picture of a simple extrusion screw, illustrating the basic parts
`is shown in Figure 4.
`The throughput or capacity necessary for a particular application will
`determine the required extruder size. Throughput is expressed in pounds of
`resin per hour which relates directly with the diameter of the screw.
`
`Feed Section
`!6 turns)
`
`Transition
`(7 tlJ'nS)
`
`Metering
`Section
`(7 turns)
`
`Heb Angle --l
`
`I
`I
`I r-- Lead
`
`Figure q Illustration of a simple extruder screw, showing the b