Pharmaceutical Development and Technology
`
`ISSN: 1083-7450 (Print) 1097-9867 (Online) Journal homepage: https://www.tandfonline.com/loi/iphd20
`
`Practical fundamentals of glass, rubber, and
`plastic sterile packaging systems
`
`Gregory A. Sacha, Wendy Saffell-Clemmer, Karen Abram & Michael J. Akers
`
`To cite this article: Gregory A. Sacha, Wendy Saffell-Clemmer, Karen Abram & Michael J.
`Akers (2010) Practical fundamentals of glass, rubber, and plastic sterile packaging systems,
`Pharmaceutical Development and Technology, 15:1, 6-34, DOI: 10.3109/10837450903511178
`To link to this article: https://doi.org/10.3109/10837450903511178
`
`Published online: 21 Jan 2010.
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`Pharmaceutical Development and Technology, 2010; 15(1): 6–34
`
`P h a r m ac e u t i c a l P r o d u c t de v e loP m e n t F u n da m e n ta l s
`
`Practical fundamentals of glass, rubber, and plastic
` sterile packaging systems
`
`Gregory A. Sacha , Wendy Saffell-Clemmer, Karen Abram, and Michael J. Akers
`
`Research and Development, Baxter BioPharma Solutions, Bloomington, Indiana, USA
`
`abstract
`Sterile product packaging systems consist of glass, rubber, and plastic materials that are in intimate contact
`with the formulation. These materials can significantly affect the stability of the formulation. The interac-
`tion between the packaging materials and the formulation can also affect the appropriate delivery of the
`product. Therefore, a parenteral formulation actually consists of the packaging system as well as the product
`that it contains. However, the majority of formulation development time only considers the product that is
`contained in the packaging system. Little time is spent studying the interaction of the packaging materials
`with the contents. Interaction between the packaging and the contents only becomes a concern when
`problems are encountered. For this reason, there are few scientific publications that describe the available
`packaging materials, their advantages and disadvantages, and their important product attributes. This article
`was created as a reference for product development and describes some of the packaging materials and
`systems that are available for parenteral products.
`Keywords: Sterile products; packaging; formulation development; glass; rubber; plastic
`
`Introduction and scope
`
`Significant attention and effort are dedicated to the design
`of injectable formulations, development of analytical
`methods and manufacturing processes, and to the study
`of formulation stability. Frequently, much less attention
`is paid to the rational selection and study of sterile pack-
`aging systems. Scientists only direct their focus to the
`package when stability and compatibility problems occur
`that implicate the packaging system. Frankly, packaging
`development takes secondary priority to formulation,
`analytical and process development.
`In searching the literature, there is a paucity of recent
`information regarding packaging development for ster-
`ile products. Therefore, this article was authored from
`the perspective of a fundamental tutorial of parenteral
`packaging that also attempts to incorporate much of the
`available recent literature. Articles are published when
`there are certain problems with packaging systems
`(e.g. extractables and leachables, latex sensitivity, glass
`
`delamination, particle problems, etc.), but there seems
`to be few, if any, extensive review articles focused on
`packaging development, especially for sterile dosage
`forms. Exceptions are book chapters on lyophilization
`containers and closures including specifics on glass and
`rubber.[1–3]
`The Food and Drug Administration (FDA) published
`a guidance document that requires the evaluation
`of four attributes to establish suitability of materials
`and container-closure systems for pharmaceutical
`products.[4,5] These four attributes – protection, com-
`patibility, safety, and performance/drug delivery – are
`featured throughout this article. There is specific focus
`on the chemical and physical properties, manufactur-
`ing, sterilization, product interactions and advantages
`and disadvantages of glass, rubber, and plastic materials
`used in sterile dosage form primary packaging. A brief
`discussion of packaging trends and advances involving
`more convenient drug delivery packaging systems is
`also included.
`
`Address for Correspondence: Dr. Gregory A. Sacha, Research and Development, Baxter BioPharma Solutions, 927 S. Curry Pike, Bloomington, 47404, Indiana,
`USA. Email: gregory_sacha@baxter.com
`
`(Received 16 July 2009; revised 25 November 2009; accepted 25 November 2009)
`
`ISSN 1083-7450 print/ISSN 1097-9867 online © 2010 Informa UK Ltd
`DOI: 10.3109/10837450903511178
`
`http://www.informahealthcare.com/phd
`
`Opiant Exhibit 2320
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685, IPR2019-00688, IPR2019-00694
`Page 2
`
`

`

`Sterile product container systems
`
`There are six basic primary packaging or container
`systems:
`
`1.
`2.
`3.
`4.
`5.
`6.
`
`Ampoules – glass
`Vials – glass and plastic
`Pre-filled syringes – glass and plastic
`Cartridges – glass
`Bottles – glass and plastic
`Bags – plastic
`
`Generally, vials comprise about 50–55% of small volume
`injectable packaging, syringes 25–30%, with ampoules
`and cartridges filling the rest. Bottles and bags are the
`only packaging systems for large volume injectables.
`Usage of all packaging types, except ampoules, is increas-
`ing, especially pre-filled syringes. Each of these packag-
`ing systems for parenteral drug delivery has significant
`advantages and disadvantages. Generally, advantages
`involve user convenience, marketing strategy, handling
`during production and distribution, volume considera-
`tions, and compatibility with the product. The primary
`disadvantage with all these packaging systems is the
`potential reactivity between the drug product compo-
`nents and the packaging components. The reactivity
`is typically manifested through the appearance of par-
`ticulate matter, detection of extractables, evidence of
`protein aggregation, and other physical and chemical
`incompatibilities.
`Selection of the packaging system not only depends
`on compatibility with the product formulation and the
`convenience to the consumer, but also on the integrity
`of the container/closure interface to assure mainte-
`nance of sterility throughout the shelf-life of the prod-
`uct. Container/closure integrity testing has received
`significant attention and usually is an integral part of the
`regulatory submission and subsequent regulatory GMP
`inspections. It is beyond the scope of this manuscript to
`discuss the various container/closure integrity testing
`methods. However, it must be emphasized that formu-
`lation scientists developing the final product including
`the final package must appreciate the need to develop
`appropriate methods to assure proper seal integrity to
`protect the product during its shelf-life from any ingress
`of microbiological contamination. This testing is his-
`torically conducted using microbiological test methods.
`However, the FDA recognizes that microbiological test
`methods have scientific and practical limitations and
`encourages the development of methods that may be
`based on leak rate measurement if they are more useful
`for the particular application.[6,7]
`
`Review of sterile packaging systems
`
` 7
`
`Ampoules (Figure 1)
`For decades, glass sealed ampoules were the most popu-
`lar primary packaging system for small volume inject-
`able products. Ampoules were favorable because they
`offer only one type of material (glass) to worry about for
`potential interactions with the drug product compared to
`other packaging systems that contain both glass or plastic
`and rubber.
`Two disadvantages of glass ampoules are the assur-
`ance of the integrity of the seal when the glass tip is
`closed by flame and the problem of glass particles enter-
`ing the solution when the ampoule is broken to remove
`the drug product. There exist ‘easy-opening ampoules’,
`weakened at the neck by scoring or applying a ceramic
`paint around the neck of the ampoule.[8] The paint weak-
`ens the glass at the point of application and permits the
`user to break off the tip at the neck constriction without
`the use of a file.[9] Nevertheless, glass particles will still
`enter the ampoule and this requires the use of a filter to
`withdraw product from the container. This disadvantage
`makes them a less common packaging option. Glass
`sealed ampoules still exist, but they are not the choice
`for new products in the United States. Elsewhere in the
`world, ampoule products are still widely used and still
`a popular package of choice for new sterile product
`solutions.
`Glass ampoules are Type I tubing glass (Type I and
`tubing glass are discussed in more detail later.) in sizes
`ranging from 1–50 mL. After solution is filled into the
`top opening of the ampoule, the glass is heat sealed by
`one of two techniques – tip sealing or pull sealing. Tip
`sealing has the open flame directed toward the top of the
`ampoule that melts and seals itself while the ampoule
`is rotating on the sealing machine. Pull sealing has the
`open flame directed at the middle portion of the ampoule
`above the neck where the glass is melted while rotating
`and the top portion is physically removed during rota-
`tion. Thus the tip-sealed ampoule has a longer section
`above the neck while the pull-sealed ampoule has a more
`blunt, ‘fatter’ top.
`Modifications of ampoules are available, e.g. wide-
`mouth ampoules with flat or rounded bottoms to facili-
`tate filling with dry materials or suspensions.
`
`Vials
`The most common packaging for liquid and freeze-dried
`injectables is the glass vial (Figure 2). Plastic vials have
`made some ingress as marketed packages for cancer
`drugs, but may require more time before being com-
`monplace in the injectable market. Plastic vials are made
`of cyclic olefin copolymer (COC). The appearance of a
`plastic vial looks identical to a glass vial (Figure 3).
`
`Opiant Exhibit 2320
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685, IPR2019-00688, IPR2019-00694
`Page 3
`
`

`

`8
`
`G. Sacha et al.
`
`Figure 1. Glass sealed ampoules (courtesy of Alcan Global
`Pharmaceutical Packaging, Inc.).
`
`Figure 2. Different types of vials (courtesy of Alcan Global
`Pharmaceutical Packaging, Inc.).
`
`Figure 3. Plastic vials (courtesy of Daikyo/West).
`
`Reasons why plastic vials have not become as com-
`monplace as glass vials include:
`
`1.
`
`Challenges in introducing pre-sterilized containers
`into a classified (ISO 5) aseptic environment. Glass
`vials are sterilized and depyrogenated in dry heat
`tunnels that convey the vials directly into the aseptic
`environment without the need for manual transfer.
`Plastic vials are pre-sterilized (typically irradiation)
`
`at the vial manufacturer and the finished product
`manufacturer needs to determine how to aseptically
`transfer plastic vials into the aseptic environment.
`This is not easily accomplished, especially compared
`to the convenient way glass vials are introduced via
`the dry heat tunnels.
`Challenges in handling and movement of much
`lighter weight containers compared to glass along
`conveyer systems on high-speed filling
`lines,
`with smaller vials (1–5 mL) especially difficult to
`process.
`Concerns about potential interactions with the drug
`product (absorption, adsorption, migration, leacha-
`bles) especially over a 2–3 year shelf life.
`
`2.
`
`3.
`
`Syringes
`Syringes are very popular delivery systems (Figure 4).[10–14]
`They are used either as empty sterile container systems
`where solutions are withdrawn from vials into the empty
`syringe prior to injection or as pre-filled syringes. Pre-
`filled syringes as a form of primary packaging are the
`focus of this section. Glass pre-filled syringes can be
`pre-sterilized by the empty syringe manufacturer or
`can be cleaned and sterilized by the finished product
`manufacturer. Plastic syringes can be purchased or some
`companies have the technology to apply form-fill-finish
`technologies for their own use.[15]
`One company now has the capability to form-fill-
`finish glass syringes from tubing glass.[16] Other options
`regarding syringe size, components, formats, treatment
`of rubber materials, and manufacturing methods are
`summarized in Table 1. Most of the world’s vaccines
`are packaged and delivered in syringes. The growth rate
`for products filled and packaged in pre-filled syringes
`increases about 13% per year.[17] This growth is related to
`the top factors that influence a physician’s choice of a
`drug delivery type, which include ease of use by patients,
`convenience, and comfort.[17]
`Primary reasons for syringe popularity include:
`
`•
`
`•
`
`•
`
`The emergence of biotechnology and the need to
`eliminate overfill (reduced waste) of expensive bio-
`molecules compared to vials and other containers.
`Vaccines, antithrombotics, and various home health
`care products such as growth hormone and treat-
`ments for rheumatoid arthritis and multiple sclerosis
`are more conveniently administered using pre-filled
`syringes.
`Availability of enormous (millions) quantities of pre-
`sterilized ready-to-fill syringes such as BD Hypak®
`SCF and BunderGlas RTF.
`The advent of contract manufacturers specializing in
`syringe processing with lower costs and high speed
`filling equipment.
`
`Opiant Exhibit 2320
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685, IPR2019-00688, IPR2019-00694
`Page 4
`
`

`

`Review of sterile packaging systems
`
` 9
`
`NEEDLE SHIELD
`
`NEEDLE
`
`PLUNGER
`
`PLUNGER ROD
`
`BARREL
`
`FLANGE
`
`Figure 4. Syringe examples (courtesy of Baxter BioPharma Solutions).
`
`Table 1. Pre-filled syringe options.
`Sterilization
`
`Barrel size
`Needle format
`Needle gauge
`Needle length
`Needle shield
`Silicone application
`
`Silicone level
`Type of rubber plunger
`Type of rubber septum (tip)
`Coating of rubber
`Filling machine
`
`Rubber plunger insertion
`
`Pre-sterilized by empty syringe manufacturer and ready-to-fill, Supplied non-sterile, washed and steri-
`lized by product manufacturer
`0.5–100 mL; typically 0.5–10 mL
`Luer tip, use needle of choice, Staked needle affixed to syringe Hub, not used often
`21–32
`½ to ⅝ inch
`Natural or synthetic rubber
`Silicone oil or silicone emulsion, Applied at syringe manufacturer, Applied at finished product
`manufacturer
`Varies, 0.6–1.0 mg per 1 mL syringe
`Synthetic rubber (halobutyl)
`Natural or synthetic rubber, Plastic covers
`Absent or use of fluoropolymer
`Rotary piston peristaltic time-pressure, rolling diaphragm single head up to 10 heads, Up to 600 syringes
`filled per minute
`Insertion tube system, vacuum
`
`•
`
`•
`
`•
`
`•
`•
`
`•
`
`Elimination of dosage errors because, unlike vials,
`syringes contain the exact amount of deliverable dose
`needed.
`Ease of administration, because of elimination of
`several steps required before injection of a drug
`contained in a vial. Sterility assurance is increased,
`because fewer manipulations are required.
`More convenient for health care professionals and
`end users; easier for home use; easier in emergency
`situations.
`Reduction of medication errors and misidentification.
`Better use of controlled and potentially abusive drugs
`such as narcotics.
`Lower injection costs – less preparation, fewer mate-
`rials, easy storage and disposal.
`
`Syringe barrels can either be glass or plastic while syringe
`plunger rods are usually plastic. Plastic polymers for the
`syringe barrel include polypropylene, polyethylene, and
`polycarbonate. However, newer technologies are being
`developed in the area of ‘glass-like’ composite materials.
`Syringes with needles may also have needle protectors
`(Figure 5) to avoid potential dangers of accidental needle
`sticks post-administration. Such protectors either can
`be part of the assembly or can be assembled during the
`finishing process. The use of these protection devices is
`increasing due to the 2000 United States Federal Needle
`Stick Safety and Prevention Act.[18] Needle stick preven-
`tion can be manual (shield activated manually by the user
`although there is still the risk of accidental sticking), active
`(automated needle shielding activated by user), or passive
`(automated needle shielding without action by the user).
`
`Opiant Exhibit 2320
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685, IPR2019-00688, IPR2019-00694
`Page 5
`
`

`

`10
`
` G. Sacha et al.
`
`BD SafetyGlideTM
`Safety Shielding Needle
`
`Figure 5. Syringe with needle guard (courtesy of BD Medical).
`
`Items that must be addressed in selecting and qualify-
`ing components of a syringe include:
`
` ■
` ■
` ■
`
` ■
`
` ■
`
` ■
`
`Container/closure integrity testing;
`Plastic component extractables;
`Sterilizability, especially if needle is part of the pack-
`age to be sterilized;
`Siliconization of barrel and plunger (although
`silicone-free syringes now exist that provide both
`lubricity and inert drug-contact surfaces);
`Compatibility of product with syringe contact parts,
`especially the rubber plunger;
`Appropriate gauge size of needle for product and its
`indication. Syringe needle gauges range from 21G to
`32G. It is important to note some suspensions may
`not flow through the syringe properly if the needle
`gauge is not carefully considered.
`
`Challenges with syringe siliconization
`Like rubber closures, syringes require a ‘slippery inner
`surface’. Rubber requires such a surface for facile move-
`ment of closures along the stainless steel tracks of a rub-
`ber closure hopper or feeding machine to deposit the
`rubber on top of a container at a rate of hundreds per
`minute. Without the slippery surface, rubber closures
`would move haltingly, if at all, and filling at any speed
`
`could not be accomplished. For syringes, the rubber
`plunger must move easily within the syringe barrel with
`the ‘glide force’ being the same throughout the barrel
`(from distal to proximal end).
`There are several concerns related to siliconization of
`syringes – functionality, potential for protein aggregation
`and increased potential for particulate matter. Syringe
`functionality involves forces to initiate movement of the
`plunger rod within the syringe barrel and to maintain
`movement of the plunger rod throughout the barrel to
`the end of the syringe. Siliconization reduces the force
`required for movement of the plunger rod. However,
`excess silicone can result in the visible appearance of
`silicone droplets in the product and can increase the
`potential for interaction of proteins with the hydrophobic
`droplets. Therefore, great effort is made by syringe man-
`ufacturers to minimize the amount of silicone applied
`within the inner surface area of the syringe. Sometimes
`not all the inner surface of the barrel is coated with sili-
`cone. This can lead to an effect called ‘chattering’ where
`the syringe barrel will ‘stick’ and require greater force
`to make it move again. This may not be a problem with
`manual injections where the health care professional or
`the patient giving self-injections will simply apply more
`pressure to overcome the lack of siliconization. However,
`if auto-injectors are used, the spring or compressed gas
`force can be insufficient and lead to incomplete delivery
`of the medication.
`The FDA added a requirement for functionality test-
`ing as part of long-term stability testing of drug products
`contained in syringes and cartridges because of the
`possibility of inadequate/incomplete siliconization of
`syringes resulting in potential inadequate/incomplete
`drug delivery.[19] Articles are being published about tech-
`nologies that apply optical techniques such as confocal
`Raman spectroscopy, Schlieren optics, and thin film
`interference reflectometry to visualize and characterize
`(in situ morphology, thickness, and distribution) of sili-
`cone oil in pre-filled syringes.[20] The articles demonstrate
`that these techniques show uneven distribution of sili-
`cone oil within syringe glass barrels as potential sources
`of chattering and stalling of the syringe plunger during
`injection using auto-injectors.
`Syringe siliconization raises the potential for protein
`aggregation. This is a primary driver for plastic syringes
`perhaps becoming more popular for use with biophar-
`maceutical products since the plastic surface does not
`require silicone for facile movement of the rubber plunger
`and plunger rod through the plastic barrel. Manufacturers
`of plastic syringes have developed alternatives to silicone
`to provide lubricity within the plastic composition of the
`syringe to achieve acceptable functional performance.
`Studies have been published that implicate silicone as
`the cause of turbidity and particle formation in insulin
`products[21] and other protein products.[22] Until plastic
`
`Opiant Exhibit 2320
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685, IPR2019-00688, IPR2019-00694
`Page 6
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`

`

`syringes without the presence of silicone become more
`common, continuous improvements in the consistent
`application and distribution of silicone in syringe barrels
`must be pursued.
`Siliconization also increases the potential for increased
`particulate matter, either real or the fact that electronic
`particle counters detect a silicone droplet as particles.
`Thus, products in syringes could experience higher lev-
`els of particles as measured by light obscuration com-
`pared to the same product in a vial. Typically, the levels
`of particulate matter for syringes still fall way below the
`required limits for subvisible particles as defined by the
`United States Pharmacopoeia (USP) General Chapter
`788. However, if the USP ever decides to require measure-
`ment of particles less than the current lowest level of 10
`µm, then particle levels might be much higher for syringe
`products due to the presence of silicone droplets in the
`range of < 10 µm.
`
`Cartridges
`Cartridges are similar to syringes with respect to having
`a product filled into a glass tube closed on either side
`by a rubber plunger and a rubber disk seal. Cartridges
`are inserted into delivery pens as shown schematically in
`Figure 6. Cartridge/pen delivery systems are used prima-
`rily for multiple dose proteins such as insulin and growth
`hormone, and, historically have been used for dental
`anesthesia and epinephrine emergency uses. Advantages
`include dose accuracy and patient convenience. A poten-
`tial disadvantage includes slightly increased costs.
`Cartridges were used for years in the dental field, but
`did not grow significantly until insulin was manufactured
`in a cartridge and delivered in a specialized pen. Pens
`are the predominant insulin delivery system in most of
`the world, except the United States, where syringes and
`insulin vials still dominate.[23] Some pens use replaceable
`insulin cartridges and some pens use non-replaceable
`cartridges that are disposed of after use. All pens use
`replaceable needles. Most pens use special pen needles
`that can be extremely short and thin. For example, the
`
`5
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`7
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`8 9
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`11 12
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`14
`13
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`1
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`2
`
`3
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`4
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`6
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`Review of sterile packaging systems
`
`11
`
`Becton Dickinson pen uses needles that are 29G to 31G;
`Novo Nordisk pen needles, called NovoFine®, are 30G
`to 31G. Cartridges in delivery pens offer repeatability in
`dosing accuracy compared with syringes. Also, because
`dosing with a pen involves dialing a mechanical device
`and not looking at the side of a syringe, insulin users with
`reduced visual acuity can be assured of accurate dosing
`with a pen.
`
`Bottles
`Bottles typically refer to containers larger than 100 mL,
`thus, large volume injectable solutions or emulsions are
`contained in bottles (or bags) rather than vials. Bottles are
`manufactured by the blow-molded process. Bottles can
`be glass or plastic, both are commonly used in hospital
`pharmacy practice.
`
`Bags
`Bags used for IV fluids include pre-filled or empty con-
`tainers that range in size from 25 mL to greater than 1 L.
`Sizes that are 1 L or greater are often used in hospital
`settings for delivery of total parenteral nutrition. Bags of
`all sizes are used for ease of delivery and ease of trans-
`port. However, maintaining identification of the bags
`can be a problem. Printing on plastic bags is a challenge
`because of the flexibility of the bag material and labels
`adhered to the bags can become difficult to read. This
`was mostly resolved by the introduction of bar coding
`that allows traceability of bags from filling to patient use.
`Compatibility issues between the bag polymer and the
`drug solution have plagued the industry over the years.
`Polyvinyl chloride (PVC) was the polymer material of
`choice for many years because of the important collaps-
`ibility characteristic of PVC. However, PVC was notorious
`for leaching a plasticizer used to add flexibility (di(2-
`ethylhexyl) phthalate [DEHP]). Since the Environmental
`Protection Agency classified DEHP as a probable human
`carcinogen,[24–26] governments and industry have labored
`to provide a similar type of bag material that is non-PVC,
`typically mixtures of polyalkenes (polyethylene and
`polypropylene).
`Plastic bags are manufactured by form-fill-finish proc-
`esses where strips of plastic polymer are sealed on three
`sides, solution is filled into the ‘pouch’, then the bag is
`sealed with the fourth side that contains the spike and
`needle outlets.
`
`Packaging components
`
`GlassA
`
`Where cartridge fits in a pen
`
`Cartridge
`
`Figure 6. Cartridge combination with a delivery pen device (courtesy
`of Merck Serono).
`
`Basic chemistry and composition
`Glass is primarily composed of the element silicon.
`Silicon is a chemical element, one of the 109 known
`substances that constitute the universe’s matter. Second
`
`Opiant Exhibit 2320
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685, IPR2019-00688, IPR2019-00694
`Page 7
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`12
`
` G. Sacha et al.
`
`only to carbon in its presence on earth, one-quarter of
`the earth’s crust is silicon. Carbon is the only element
`capable of producing more compounds than silicon.
`Silicon does not exist alone in nature. It always exists
`as silica or silicates. Silica is silicon dioxide (SiO2), com-
`monly found in sand and quartz. A silicate is a com-
`pound made of silicon, oxygen, and at least one metal,
`sometimes with hydrogen. The most widely recognized
`synthetic form is sodium silicate, or water glass, a com-
`bination of silica with sodium and hydrogen.
`The Assyrian King Ashurbanipal (669–626 BC)
`described glass as “Take 60 parts sand, 180 parts ashes of
`sea plants, five parts chalk – and you have glass”.[27] Glass
`is an inorganic product of melting, which when cooled
`without crystallization, assumes a solid state. Glass is
`structurally similar to a liquid but has a viscosity so great
`at normal ambient temperatures that it is considered a
`solid. Materials lacking the molecular lattice structure
`of a solid state are amorphous. An amorphous form of a
`material possesses the same atomic makeup as the crys-
`talline version, but without a highly ordered geometry.
`Glass is employed as the container material of choice
`for most small volume injectables. It is composed prin-
`cipally of silicon dioxide, with varying amounts of other
`oxides such as sodium, potassium, calcium, magnesium,
`aluminum, boron, and iron. The basic structural net-
`work of glass is formed by the silicon oxide tetrahedron.
`Boric oxide will enter into this structure, but most of the
`other oxides do not. The latter are only loosely bound,
`present in the network interstices, and are relatively free
`to migrate. These migratory oxides may be leached into
`a solution in contact with the glass, particularly during
`the increased reactivity of thermal sterilization. The
`leaching process is a diffusion controlled ion-exchange
`
`process involving exchange of hydrogen ions for the
`alkali ions present in the glass. The result is an increase
`in solution pH. This is especially problematic for pack-
`aged water products (e.g. Sterile Water for Injection) or
`dilute drug products that have little to no buffer capac-
`ity. Additionally, some glass compounds will be attacked
`by solutions and, in time, dislodge glass flakes into the
`solution. This can be minimized by the proper selection
`of the glass composition and appropriate control of the
`container manufacturing process (discussed later).
`Molecular structures of glass are shown in Figure 7.
`Types of glass used in parenteral packaging are mixtures
`of crystalline oxides and carbonates. Glass is melted by
`heating into a viscous liquid that becomes increasingly
`resistant to flow as it cools. Glass is considered a solid
`below ∼ 500°C. It is composed of the network former –
`SiO2 tetrahedron plus network modifiers (e.g. disodium
`oxide or boron oxide) that lower the melting point.
`Stabilizers such as calcium oxide, aluminum oxide and
`more disodium oxide are added to improve durability.
`Some glass contains colorants such as iron or titanium
`oxides.
`
`Basic types
`The USP has aided in this selection by providing a clas-
`sification of glass:
`
` ■
` ■
`
` ■
` ■
`
`Type I, a borosilicate glass.
`Type II, a soda-lime with a chemical surface
`treatment.
`Type III, a soda-lime glass.
`NP, a soda-lime glass not suitable for containers for
`parenterals.
`
`Glassy
`sio2
`
`Crystalline
`sio2
`
`Multi-Component
`Glass
`
`(a)
`
`(b)
`
`Silicon
`Oxygen
`Modifier cation M1
`Modifier cation M2
`Intermediate cation M3
`
`(c)
`
`Figure 7. Silica structures of glass (courtesy of Schott Glass).
`
`Opiant Exhibit 2320
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685, IPR2019-00688, IPR2019-00694
`Page 8
`
`

`

`There is a wide range of compositions that meet the
`requirements for USP Type I glass containers. In gen-
`eral, Type I glass containers are composed principally
`of silicon dioxide (∼ 81%) and boric oxide (∼ 13%), with
`low levels of the non-network-forming oxides (such as
`sodium and aluminum oxides) (Figure 8). It is a chemi-
`cally resistant glass (low leachability) also having a low
`thermal coefficient of expansion (33 × 10−7 cm/cm-°C or
`49–54 × 10−7 cm/cm-°C). The former is called “Type I 33
`expansion glass” and the latter is called “Type X (typically
`51) expansion glass”.
`Glass types II and III (both are soda lime glass with Type
`II being chemically treated to reduce alkali leachables)
`are composed of relatively high proportions of sodium
`oxide (∼ 14%) and calcium oxide (∼ 8%) (Figure 9).
`This makes the glass chemically less resistant. Both types
`melt at a lower temperature, are easier to mold into
`various shapes, and have a higher thermal coefficient
`of expansion than Type I (e.g. 90 × 10−7 cm/cm-°C for
`Type III). While there is no one standard formulation for
`glass among manufacturers of these USP type categories,
`Type II glass usually has a lower concentration of the
`migratory oxides than Type III. In addition, Type II glass
`is treated under controlled temperature and humidity
`conditions with sulfur dioxide or other dealkalizers to
`neutralize the interior surface of the container. This
`surface treatment substantially increases the chemical
`resistance of the glass. However, repeated exposure to
`sterilization and alkaline detergents will break down this
`dealkalized surface and expose the underlying soda-lime
`compound.
`The glass types are determined from the results of
`two USP tests: The Powdered Glass Test and the Water
`Attack Test. The Water Attack Test is used only for Type II
`glass and is performed on the whole container, because
`
`Al2O3
`2%
`
`B2O3
`13%
`
`NaO
`4%
`
`Review of sterile packaging systems
`
` 13
`
`of the dealkalized surface; the former is performed on
`powdered glass, which exposes internal surfaces of the
`glass compound. The results are based upon the amount
`of alkali titrated by 0.02 N sulfuric acid after an autoclav-
`ing cycle with the glass sample in contact with high-
`purity distilled water. Thus, the Powdered Glass Test
`challenges the leaching potential of the interior struc-
`ture of the glass while the Water Attack Test challenges
`only the intact surface of the container. Compendial
`references include USP <661>, European Pharmacopeia
`(PhEur) 3.2.1, and Japanese Pharmacopeia (JP) <57>. It
`is important to note that although the glass powder test
`challenges the leaching potential of the glass structure,
`it does not provide any infor