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`fully inserted. Completing the insertion creates a slight overpressure in the headspaoe
`resulting in a tendency for stoppers to "pOp up" slightly after insertion. To address this, a "no—
`pop" ring can be molded into the stopper plug and a corresponding ”blowback" ring can be
`formed into the neck of the vial. The intention is to provide additional mechanical interference
`to help retain the stopper in the seated position until the aluminum overseal is positioned and
`crimped. Here also, care is needed to ensure that the design details of each component are
`appropriately sized and positioned. The container system designer is advised to work closely
`with the component manufacturers to ensure compatibility.
`The blowback feature originally was developed for smaller containers, for example, a vial
`with a naminal fill capacity of 2 cm3 having a fill volume of 2 ml. plus overage. In this
`situation, the volume of the stopper plug can be a significant percentage of the total headspace
`voliu'ne which increases the likelihood of pop—out because of pressurizing the headspace.
`Pharmaceutical companies producing lyophilized products also recognized the possibility for
`the blowback feature to improve the control over the position of the partially inserted stoppers
`during transfer of filled vials between the filling suite and the lyo chamber. Thus, vials and
`stoppers for lyophilization also often incorporate blowback rings.
`
`Prefilled Cartridges
`Glass cartridges are tubular glass containers that are open on one end to receive a suitable
`elastomeric plunger stopper. The opposite end has been tooled to form a neck and flange. After
`filling,
`the tooled end is closed with an aluminum cap which is lined with a suitable
`elastomeric septum. Just before use, a double—ended needle is attached. When the needle is
`attached,
`the end of the needle at
`the aluminum seal pierces the septum allowing the
`medication to be administered. Dental anesthetics and insulin therapy are two important
`markets for prefilled cartridge systems. For ease of use, the systems often are combined with
`reusable holders or, increasingly, adjustable multid ose pen devices. Compared with a vial of
`equal capacity, a cartridge—based system will be longer, smaller in diameter and have little or
`no headspaoe gas. ISO has defined materials, dimensions, performance, and test methods for
`the product contact c0mponents of such systems in ISO 11040. Parts 1 and 4 (16,17) of the
`standard are glass cylinders, while parts 2, 3, and 5 address plungers, septa (disks) and
`aluminum caps. Additional requirements for components used in pen-injector systems are
`defined in ISO 13926 (18) parts l through 3.
`The glass forming process for the finish of a pen cartridge is similar to that used to form
`the neck and flange of a tubular vial. Online 100% inspection and off—line quality control
`checks also are similar. Cartridges are produced from tubing and can be formed using either
`one of two basic process concepts. The neck and flange may be formed, as with tubular vials,
`on the end of the tube. After forming the finish, the cartridge is separated from the tube using
`thermal shock and the open end is flame polished. Alternatively, full length tubes may be first
`cut into blanks using thermal shock and flame polished. On a separate forming line, the flange
`and neck are formed on one end of each blank. The smOothness and uniformity of the open
`end can have an important effect on the ability of the finished cartridge to endure the rigors of
`packaging and distribution.
`In addition to its role as a drug product container during shelf life, at the time of use, the
`cartridge also plays a functional role as part of the drug delivery system. To fulfill
`this
`function, the body of the cartridge must be lubricated to reduce and control the static and
`dynamic friction between [he glass cylinder and the elastomeric plunger. Generally,
`the
`lubricant is an emulsion of polydimethylsiloxane that is added to the final WFI rinse prior to
`depyrogenation using dry heat. The depyrogenation process drives off the residual water
`leaVing behind the lubricating silicone layer. The interactiOn between the glass surface, the
`silicone fluid, the drug product and the elastomer plunger is complex. The processes affecting
`this interaction should be characterized thoroughly, validated and monitored to ensure
`consistent functional performance throughout shelf life. This is especially important for pen—
`injector systems where precise dosing is required. Cartridges for injection devices also may
`have additional dimensional requirements related to dose accuracy or to fit and function
`within the device.
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`Prefilled Syringes
`ln s0me ways, prefilled syringes can be considered an extension of the cartridge concept.
`I’refilled syringes also are formed from glass tubing. With a cartridge, one end is open to
`receive a suitable elastomeric plunger stopper. Unlike cartridges, the open end of a prefilled
`syringe is tooled to form a finger flange by which the syringe is held during administration of
`the dose. The opposite end of the syringe may be tooled to the shape of a male luer taper or to
`accept a plastic luer lok adapter or a small channel may be formed at the inner diameter of the
`tip into which a cannula is later inserted and glued. In each case, prior to filling, the syringe tip
`is fitted with a suitable elastomeric luer tip cap or needle shield. Prefillable syringes can be
`supplied as “bulk" (unprocessed) containers intended to be rinsed, siliconized and sterilized
`just prior to filling.
`[.uer
`tip and Luer Lock syringe barrels can tolerate dry heat
`depyrogenation and the tip cap or tip cap and adapter are assembled under aseptic conditions
`in the filling suite. The adhesives typically used on syringes with glued in cannulae cannot
`tolerate dry heat. "Bulk” staked needle syringes are sterilized by autoclaving rather than by
`d
`heat.
`FY As with cartridges, prefilled syringes are produced from tubing and can be formed using
`either one of two basic process concepts. The tip may be formed, as with tubular vials, on the
`end of the tube. After forming the tip, the syringe body is separated from the tube using
`thermal shock and the open end is flared and tooled to form the finger flange. Alternatively,
`full length tubes may be first cut into blanks using thermal shock and flame polished. On a
`separate forming line, the finger flange is formed on one end of each blank and the tip is
`formed on the other end. The flange forming process may occasionally reduce the inner
`diameter at the flange opening. This may affect processing when mechanical plunger setting
`tubes are used.
`Numerous dimensional and functional attributes of the glass barrels and various in—
`process assembly steps for prefilled syringes are 100% inspected using camera—based systems.
`Other process control and quality checks are performed at the appropriate stages of production
`using both time—based and AQI.~based sampling plans.
`In addition to bulk, unprocessed syringe ba rrels, there also is a significant and growing
`market for prefillable syringes that have been rinsed, siliconized, suitably packaged and then
`sterilized by the syringe manufacturer. These ready to fill systems are sterilized by ethylene
`oxide using validated cycles. Sterility testing is routinely performed on each sterilization
`batch.
`
`As with pen cartridges, prefilled syringes serve double duty as the container~closure
`system during shelf storage of the drug product and as an integral part of the drug delivery
`system at the time of use. In prefillable syringes, the lubricant generally is applied as an aerosol
`mist of silicone fluid. The processes affecting this aspect of the syringe system should be well
`understood and controlled to ensure consistent functional performance.
`For prefilled syringes, there is an additional level of complexity in that the tip cap or
`needle shield also serves a dual purpose. During shelf storage, this product contact interface is
`an integral part of the container—closure system. Yet, at the time of use, the tip cap or needle
`shield must be easily removed. And, for a luer tip or luer lok syringe, system performance
`requirements include the ability to form a leak—tight seal with the injection needle or delivery
`system adapter.
`l’refilled syringes also are increasingly being incorporated into automatic
`injection devices. Additional specification requirements and quality control
`tests may be
`required to ensure consistent drug delivery performance of prefilled syringes and auto—
`injectors.
`While the focus of this chapter is on glass containers for parenterals, it is important to
`recognize that from the perspective of drug product compatibility, prefilled cartridges and
`prefilled syringes have added complexity compared with vial—stopper-seal systems. At a
`minimum, these systems include a second elastomer in the septum, tip cap or needle shield in
`addition to the plunger stopper. These systems also include the silicone fluid lubricant on the
`barrel and generally on the plunger stopper as well. Finally, for syringes with preattached
`needles, the stainless steel cannula and adhesive are in direct contact with the drug product
`throughout shelf life. The potential effects of each of these additional product contact materials
`needs to be assessed during qualification of the container—closure system.
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`Specialty Items
`Other special purpose Container systems, such as dual chamber vials, cartridges and syringes,
`threaded vials for
`infusion systems and high—strength capsules for needle—free injection
`systems also are available. An exhaustive review of these systems is beyond the scope of this
`chapter. The interested reader is encouraged to contact glass container manufacturers to learn
`about speciality products and new developments.
`
`SURFACE CHEMISTRY
`
`There are two fundamental mechanisms of chemical attack that can occur when an aqueous
`solution is in contact with the surface of a glass container (19). Through ion exchange, H30"
`ions in the solution can replace NaJ” ions in the glass. Once the sodium ions have been
`removed from the near surface layer, the rate of diffusion of sodium ions from within the bulk
`glass slows the process considerably. [on exchange is the dominant mechanism of attack for
`most acidic and neutral formulations.
`
`By contrast, hydroxyls and other alkaline species attack the silica network itself by
`breaking Si-O bonds. The rate of attack is highly dependent on the glass formulation and the
`solution pH. Surprisingly, several
`investigators (20 23) have shown that, at the same pH,
`different buffer systems can have markedly different rates of attack. It has been speculated that
`chelating agents are more aggressive toward glass because they are able to pull the various
`metal ions out of the surface. The resulting voids are then more susceptible to the other
`mechanisms of attack. Unfortunately, this means that simple formulation guidelines based on
`pH alone are not adequate.
`In addition, the chemical resistance of the container surface also may vary. As mentioned
`earlier, the forming process can alter the composition, morphology and physicochemical
`characteristics of the container surface. During forming, especially when making the bottoms
`of ampoules and tubular vials, the temperature of the inner surface can exceed the boiling
`point of the more volatile ingredients of the formulation, primarily sodium and boron. These
`elements can vaporize from the hotter surface of the bottom and subsequently condense on the
`cooler sidewall as sodium borate. Then, as the finished container passes through the annealing
`oven, the deposits can be partially reintegrated into the underlying silica network. As a result,
`the alkaline deposits may not be completely removed by the pharmaceutical company’s
`rinsing process but remain as less durable regions of the surface that is in contact with the drug
`product. This phenomenon will occw to Some extent in the production of any container from
`glass tubing. For molded borosilica te glass bottles, vapori7ation and condensation of alkaline
`ingredients is generally not significant since the peak temperature of the glass is inherently
`lower. The resulting quantity of alkaline residue can be controlled by production speed,
`heating rate and maxim um glass temperature. Residual alkalinity can be monitored by testing
`the surface resistance of the finished containers.
`
`The alkaline residues can affect the drug product through three separate but related
`mechanisms. Firstly, the locally alkaline region or leached ions may react directly with the
`formulation. Secondly, by ion exchange with Na" ions in the glass, the loss of H30+ ions from
`the solution can increase the pH of unbuffered or weakly buffered solutions. Thirdly,
`in
`extreme cases, the interaction can trigger the formation of an unstable layer of silica gel which
`can slough off as delaminated glassy particles.
`Chemical dealkalization of borosilicate containers, for example, by the introduction of
`ammonium sulfate solution into the containers just before annealing, has been used, especially
`in the United States, as a means to control or minimize these effects. This process has been
`shown to be highly effective in reducing extractable alkali and the related effect on pH. Some
`users have found that the combination of controlled alkalinity in the forming process plus
`Chemical dealkalization yields precise pH control for unbuffered products. However, studies
`by Ennis {24} showed that ammonium sulfate treatment without proper forming process
`controls did not eliminate delamination.
`In fact,
`in those studies, higher quantities and
`concentrations of treatment solution increased the formation of glass flakes.
`Unpublished studies with which the author is familiar showed that delamination
`resulted from an interaction between excessive residual alkali on the vial surface,
`the
`parameters of the rinsing and depyrogenation processes, and the pH and composition of the
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`VOLUME T.’ HJHMUMHOFI' AMI) PACKAGING
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`drug product vehicle. Anecdotally, acidic residues from exceSsive dealkalization also have
`been reported to have caused a reduction in drug product pH and long term damage to
`washers and deypryogenation tunnels.
`Phenomena such as these highlight the importance of evaluating the chemical durability
`of the inner surface of the finished container using, for example, the USP Surface Test, the Ph.
`Eur. test for surface hydrolytic resistance, ISO 4802—] (25) or similar quantitative spectroscopic
`surface extraction test methods such as ISO 4802-2 (26).
`
`MECHANICAL AND THERMAL PROPERTIES
`
`The preceding section addressed the chemical properties of the product contact surface, which
`can be of vital importance to the physical and chemical stability of drug products stored in the
`containers. Physical integrity of the container as a means to maintain product sterility is
`another equally important requirement of containers for parenterals. In this respect,
`the
`mechanical and thermal characteristics of glasses must be considered. Earlier in this chapter,
`glasses were described as amorphous materials exhibiting the stress—strain characteristics of a
`brittle, elastic solid. Describing glass as a “brittle” material is perhaps consistent with the
`general perception that glass is fragile. By contrast, the notion that glass is "elastic” seems
`contradictory. However, as material science terms, brittle and elastic have more precise
`meanings both of which apply to glas5es.
`[n this Context, brittle refers not to the strength of the material but to the failure mode
`when local stress exceeds local strength. Most metals, when overloaded, will deform in a
`permanent way, technically, "plastic deforrna lion," before breaking. Brittle materials, such as
`glasses, are unable to undergo plastic deformation and therefore break abruptly (27).
`Intrinsically, glasses are very strong materials in response to compressive loads. However,
`surface damage significantly reduces the effective strength under tensile stress. A compressive
`load squeezes the margins of a surface flaw or discontinuity together and has little effect. By
`contrast, a tensile load pulls a surface flaw or discontinuity apart and concentrates the stress at
`the bottom of the discontinuity. Thus, the flaw or discontinuity significantly reduces the
`practical strength of the material as elucidated by Griffith (28).
`Similarly, as a material science term, elastic refers to the response of a material to the
`application and removal of a mechanical load that does not exceed the strength of the material.
`Elastic materials deform when loaded then return to the original shape when the load is
`removed. The stiffness of a material can be characterized by its elastic modulus, also known as
`Young’s modulus, which is the ratio between the applied unit load, or stress, and the resulting
`unit deformation, or strain. In this respect, glasses are relatively stiff. Typically, the elastic
`modulus of glass is about the same as aluminum (29}. liang (30,31) attached strain gages to the
`outer surface of glass vials to observe in real
`time the physical deformations of and
`corresponding stresses in the vials during freezing, frozen storage and subsequent rewarming
`and thawing of various buffers and formulated drug products. Although it was not
`the
`objective of the studies, the work demonstrates the elastic deformation of the glass in response
`to the changing physical dimensions of the c0ntents.
`Because of the combination of stiffness, brittle behavior and reduction in strength at
`surface flaws, one does not usually observe directly the elastic deformation that occurs in glass
`containers before catastrophic brittle failure occurs. Indirectly, when failure occurs, the energy
`stored by elastic deformation may be observed in the form of rapid fracture propagation and
`dispersion of the glass fragments.
`Stress in glass containers can result from forces exerted on the container, either externally
`or internally. Stress also can be the indirect result of nonhomogeneous composition or other
`imperfections from the melting process or from thermal effects. Thermally induced stresses
`may be either permanent artifacts from the glass forming process or a transient response to
`temperature gradients within the glass. Moreover, stress in the glass is additive. The total
`stress at a given point is the sum of the stresses at that point regardless of the source.
`Silicate glasses have relatively low thermal conductivity. As a consequence, heating or
`cooling results in a steep temperature gradient between the heated or cooled surface and the
`underlying glass core. This is the reason that the coefficient of thermal expansion of the glass
`composition is important in determining the thermal resistance of a container. When a
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`container is cooled, the outer surface tries to contract. The contraction at the surface is resisted
`by the warmer core resulting in tensile stress at the outer surface. While this phenomenon is
`the principle behind "cutting" glass by thermal shock, it also can lead to unintended cracks
`during container production as well as during pharmaceutical processing.
`For a given temperature difference, the stress level is proportional to the thermal expansion
`coefficient and the modulus of elasticity of the glass composition (32). Thus, all other conditions
`being equal, a 33expansion borosilicate glass container can withstand a temperature difference
`on the order of three times larger than a container of identical size, shape and geometry made
`from a "9Uexpansion" soda—lime glass. It should be noted that, in addition to the properties of the
`glass, the cooling rate, the geOmetry of the container and the presence of surface flaWS caused by
`handling all contribute to thermal resistance.
`
`QUALITY ATI'RIBUTES
`Several aspects of quality control already have been mentioned in the discussions of the
`manufacturing processes. These described the process points where quality control checks are
`performed rather than the quality attributes being examined. A detailed discussion of the full
`range of possible container defects and cosmetic flaws is beyond the scope of this chapter.
`Nevertheless, it is worthwhile to point out that certain types of flaws can occur only in specific
`process steps. As such, some basic knowledge can be helpful when investigating container
`defects and failures. For example, glass flaws known as knots, stones, cord, seeds, blisters and
`airlines all originate in primary glass melting and tubing manufacture. Certain types of surface
`blemishes can occur only during blow—molding or conversion of tubing into ampoules, vials,
`cartridges or syringes. Finally, there are blemishes and defects that are more likely to be the
`result of interactions between containers and fill—finish equipment or processes. On the other
`hand, scratches, scuffs, bruises, and metal marks may occur at any prostess or handling step.
`Even in these cases, though, detailed examination may yield clues pointing to the root cause.
`For example, a scratch running the full length of the body of a tubing vial and fading into the
`heel and shoulder may indicate that the scratch was present on the tube prior to forming the
`container. Similarly, the location and orientation of a scuff or metal mark may eliminate most
`potential points of contact. The interested reader is advised to explore these topics with
`container producers.
`In addition,
`the Parenteral Drug Association (FDA) has published
`lexicons of attributes for tubular vials and molded bottles (33}. Similar lexicons are being
`developed for ampoules, cartridges and prefilled syringes.
`In some situations, the use of more sophisticated analytical tools may be warranted.
`Glass fracture analysis is the science of determining the origin of the breakage and the nature,
`direction and relative magnitude of the force that caused the breakage. Scanning electron
`microscopy with X—ray diffraction analysis or similar methods can be used to determine the
`elemental composition of surface flaws or of foreign materials that may be present.
`
`ACKNOWLEDGMENTS
`The author is indebted to Frank R. Bacon, R. Paul Abendroth and Robert N. Clark, the authors
`of Glass Containers for Parenterals in the First and Second Editions of Pharmaceutical Dosages
`Forms: Parenteral Medications. Years ago,
`their chapters provided a solid foundation of
`knowledge about glass and glassware for pharmaceutical products. More recently,
`in
`preparing this edition, their examples have guided the work.
`The author also gratefully acknowledges the support and guidance of many coworkers
`and former colleagues as well as the editors. In particular, Ron Forster has been a constant source
`of encouragement. Finally, Nick DeBello, Peter Gassmann, Carlo Pantano, Jochen Pfeifer, and
`Randy Thackrey provided numerous suggestions that improved the content and readability.
`
`REFERENCES
`l. Boyd DC, Danielson PS, ThompSOn DA, et al. Glass in Kirk Othmer Encylopedia of Chemical
`Technology. Hoboken: john Wiley 8r Sons, Inc, 2004565.
`2. Pfaender HG. Schott Guide to Class. 2nd ed. London: Chapman & Hall, 1996:17.
`3. Paul A. Chemistry of Classes. 2nd ed. London: Chapman 6: Hall, 199011, 8.
`
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`91:9
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`$399953
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`11.
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`12.
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`13.
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`14.
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`1:).
`16.
`
`17.
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`18.
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`19.
`20.
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`21.
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`22.
`
`26.
`
`27.
`28.
`29.
`30.
`
`Doyle PI, ed. Glass Making Today. Redhill: Portcmlis Press, Ltd, l9?9:9 24, 233 299.
`l'lutchins [11 JR, Harrington RV. Glass. In: Standen A, ed. Kirk Othmer Encyclopedia of Chemical
`Technology, 2nd ed. Vol. 10. New York: lnterscience Publishers, 1966:5327.
`Bacon FR. Glass containers for parenterals. In: Avis KE, Lachman L, Lieberman HA. Pharmaceutical
`Dosage Forms: Parenteral Medications. 1st ed. New York: Marcel Dekker, Inc., 1986, pp. 97, 10].
`Pfaender HG. Schott Guide to Glass. 2nd ed. London: Chapman & Hall, 1996111 12.
`Claswerke S. Schott Technical Glasses. Mainz: H. Schmidt Gmbl-I & Co, 1990.
`USP 32, Chapter 4.660;». Containers glass. The US. l-‘harmacopeia, 2009.
`European Pharmacopoeia. 6th ed., section 3.2.1. Class containers for pharmaceutical use. European
`Pharmacopoeia Commission, 200?.
`ASTM E 438 92. Standard specification for glasses in laboratory apparatus. American Society for
`Testing and Materials, 1992.
`ISO 9187 112006. Injection equipmenl for medical use
`Organization for Standardization, 2006.
`ISO 3362 1:2009. Injection containers and accessories part 1: injection vials made of glass tubing.
`International Organization for Standardization, 2009.
`ISO 8362 42006. Injection containers and accessories part 4: injection vials made of moulded glass.
`Interna tional Organization for Standardization, 2006.
`CPI 2710. Biological finish (sizes 11 33), CPI drawing number 27103. Class Packaging Institute, 1999.
`ISO 11040 1:1992. Pre filled syringes part 1: glass cylinders for dental local anesthetic cartridges.
`International Organization for Standardiyation, 1992.
`ISO 11040 4:2007. Pre filled Syringes
`pa rt 4: glass barrels for injectables. International Organization
`for Standardization, 200?.
`ISO 13926 1:2004. Pen systems part 1: glass cylinders for pen injectors for medical use. International
`Organization for Standardization, 2004.
`Paul A. Chemistry of Classes. 2nd ed. London: Chapman & Hall, 1990:180 204.
`Adams PB. Surface properties of glass containers for parenteral solutions. Bull Parenter Drug Assoc
`1977; 31:213 22.6.
`Bacon FR, Russell RI—I, Baumgartner CW, et al. Composition of material extracted from soda lime
`containers by aqueous contents. Am Ceram Soc Bull 1974; 53:64] 645, 649.
`Borchert 5], Ryan MM, Davidson R1,, et al. Accelerated extractable studies of bomsilicate containers.
`] Parent Sci Tech 1939; 43(2):!3? 69.
`. Bacon FR, Raggon FC. Promotion of attack on glass and silica by citrate and other anions in neutral
`solutions. ] Am Ceram Soc 1959; 42:199 205.
`. Ennis RD, Pritchard R, Na kamura C. et al. Glass vials for small volume parenterals: influence of drug
`and manufacturing processes on glass delamination. Pha m1 Dev Tech 2001; 6(3)=393 405.
`. ISO 4802 1:2010. Glassware hydmlytic resistance of the interior surfaces of glass containers part 1:
`determination by titration method and classification. International Organization for Standardization,
`2010.
`ISO 4802 2:2010. Glassware hydrolytic resistance of the interior surfaces of glass containers part 2:
`determination by flame spectrometry and classification. International Organization for Standardi'za
`tion, 2010.
`Glaswerke S. Schott Technical Glasses. Mainz: 11. Schmidt Gmbll & Co., 1990:17.
`Griffith AA. The phenomena of rupture and flow in solids. Phil. Trans. R. Soc. Land. A 1921; 221:163 198.
`Glaswerke S. Schott Technical Glasses. Mainz: H. Schmidt Gmbl'l 8: (.30., 1990:19.
`Jiang G, Akers M, et al. Mechanistic studies of glass vial breakage for frozen formulations. I. Vial
`breakage caused by crystallizable excipient mannitol. FDA J Pharm Sci Tech 200?; 61(6):44'l 451.
`. ]iang G, Akers M, et al. Mechanistic studies of glass vial breakage for frozen formulations. ll. Vial
`breakage caused by amorphous protein formulations. PDA J Pharm Sci Tech 2007; 61 (6)1452 460.
`32.
`Glaswerke S. Schott Technical Glasses. Mainz: 11. Schmidt Gmbli & (.30., 1990:20.
`33.
`PDA Glass Task Force. Identification and classification of nonconformities in molded and tubular
`glass containers for pharmaceutical manufacturing. Technical report No. S 3 2M. I’DA I Pharm Sci
`Technol 2007; 61(3 suppl TR43):2 20.
`
`part 1: amoules for injectables. International
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`12 I Plastic packaging for parenteral drug delivery
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`Vlnflfl D. Vllivalam and Frances L. DeGrazin
`
`INTRODUCTION
`
`Driven by the development of biotechnology products, newer drug therapies, and
`reformulation of poorly soluble drugs, parenteral delivery is expected to provide strong
`growth in years to come. Routes of administration include subcutaneous, intramuscular,
`intradermal and intravenous injections. Drug products have been almost exclusively dispensed
`in glass containers, primarily because of the clarity, inertness, barrier property and thermal
`resistance of these containers. With the development of plastic polymer technology over the last
`30 years, plastics have become logical alternatives for small—volume parenteral {SVP) and large—
`volume parenteral (LVP) packaging. Although plastic containers have become well-established
`as Containers for LVP products, plastics have been, until recently, used on a limited scale for
`SVPs.
`
`Glass vials are the primary container of choice because of their excellent gas and
`moisture barrier properties. More importantly,
`there is an extensive knoWIedge base on
`processing, filling, regulatory review and commercial availability of glass containers. Glass,
`however, may not be the best solution for all chemical or biological drug candidates. Glass
`contains free alkali oxides and traces of metals. Depending on the characteristics of the drug
`being packaged, it is likely that delamination could occur for high pH products over time,
`thereby affecting the shelf-life of the drug product. Proteins and peptides can be readily
`adsorbed onto the glass surface and can be denatured or become unavailable for treatment.
`With a glass prefillable syringe (PPS), potential leachables such as silicone, tungsten and
`adhesive can affect
`the stability of biopharmaceutical products. Glass may break during
`proceSsing or transportation and when stored at low frozen temperatures. In these and other
`areas, plastic containers have made clear in—roads in the parenteral drug delivery market.
`With the proliferation of new polymers and newer process technologies, most of the less-
`desirable characteristics of plastic containers have been overcome and the use of plastic
`packaging as vials and syringes is increasing. This chapter will discuss the role of plastic in
`pharmaceutical parenteral drug delivery. The discussion will provide insights on the following
`areas:
`
`0 Advances in plastic resins for SVP packaging with an emphasis on cyclic olefins as
`well as other plastics used: The properties of these plastics, applications and challenges
`will also be discussed.
`
`0 Plastic vial systems: This section will discuss in detail the development activities in this
`area including the use of plastic vials in lyophilization and the use of reconstitution
`devices.
`
`' Plastic PFS systems: As more biopharmaceutical drugs and higher viscosity
`formulations are delivered in a PFS,
`there is the need for a break—resistant, high—
`quality, plastic PPS. Challenges with glass include breakage, reactivity of glass and
`leachables, such as silicone, tungsten and adhesive. Discussion will
`include how
`plastic PFS offer options to solve these challenges.
`0 IV bags and disposable bags: Following a brief overview of use of plastics for IV bags
`for LVPs, discussion will focus on new developments in the use of plastics for
`disposable bags in the packaging of bi010gics, including considerations for selection of
`disposable bags.
`0 Quality and regulatory considerations: U.S. Pharmacopeia (USP), European Pharma—
`copoeia (Ph.Eur.} and Japanese Pharmacopoeia (JP) compendial requirements will be
`discussed and referenced for plastic containers.
`
`Regeneron Exhibit 1015.320
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`3 D
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`VOLUME 1' tUHMUtflllOfll AMI) PACKAGING
`
`This chapter provides the reader with adequate information on recent developments,
`availability and use of various plastic Packaging systems for pharmaceutical drug products,
`including suitable references to commercialized drugs products.
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`ADVANCES IN PLASTICS
`
`Plastic resins are the most wid