Glass has a long history of use in the pharmaceutical industry. It has been the primary material used in container closure systems (CCS) due to a variety of characteristics that enabled generally safe and efficient drug delivery. As trends toward biologics and cell-based therapies continue, and more sensitive, high-quality products reach the market, the risks associated with glass containers may diminish its position as a primary CCS material. Glass issues — such as breakage, delamination, leachables, and physical and chemical compatibility — can affect the safety and efficacy of a pharmaceutical product. In fact, in the past five years there have been more than 20 recalls associated with glass issues, including contamination from delaminating (flaking) glass vials, breakage and particulates, which have resulted in more than 100 million units of drugs packaged in vials or syringes to be withdrawn from the market.¹

In 2011, American Regent initiated recalls of Calcium Gluconate Injection, USP due to silicone particulate found in the glass vials. In addition, the company recalled Concentrated Sodium Chloride Injection, USP, and Methyldopate HCl Injection due to potential contamination with particulate because some vials exhibited translucent visible particles consistent with glass delamination.^2,3

Additional recalls include, but are not limited to:

• Sandoz: Zarzio – cracks in prefilled syringes (www.mhra.gov.uk/Publications/Safetywarnings/DrugAlerts/CON105730)
• Hexal: 5-fu Hexal – glass particles in vials
• Amgen: Procrit and Epogen – glass flakes in vials
• Novo Nordisk: Glucagen Hypokit – cracked or broken vials (www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2010/2010_184-eng.php)
• Amgen: Enbrel SureClick Autoinjector – syringe barrel deviated from center line of the syringe barrel, resulted in broken or cracked syringes (www.mediguard.org/alerts/alert/797.html)
• Schering-Plough: Temodar for injection – defects in glass vials may compromise integrity of vials
• GSK: Argatroban – cracked vials may result in non-sterility; up to 0.1% of vials may have been cracked (www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2008/argatroban-nth-aah-eng.php)
• Merck: IVANZ – glass vial breakage and potential glass pieces in vials (www.fda.gov/Safety/MedWatch/ SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm152679.htm)
• Baxter: Hylenex – glass flakes in vials

For additional recall information, please visit the FDA website: www.fda.gov/Safety/Recalls/default.htm

These recalls have spurred the pharmaceutical industry to rethink the perceived inert nature of glass and develop a deeper understanding of risks associated with all materials commonly used in CCS. The pharmaceutical industry is seeking innovative alternatives to glass, such as cyclic olefin polymers, to ensure that CCS are suitable for intended use.

Risks Associated with Glass 

Glass constituents, as well as conditions for shaping container systems, can have an impact on overall glass quality and suitability for use with today’s pharmaceuticals and biopharmaceutical products. Glass is not chemically inert. Variability is inherent to the source of raw materials used in glass and can give rise to differences in a container’s chemical make-up and quality. Silica (SiO2) from naturally occurring sand or rock may originate from various regions. To process glass, fluxes such as sodium or potassium can be added to lower melt temperature. Also, stabilizers may be used to improve durability and reduce the potential for glass to break down into its constituent parts. Finally, there are a variety of naturally occurring minor trace elements in glass that can have an effect on the forming process and an immeasurable impact on the quality of drug products. Variation in the glass batch constituents and forming conditions can affect the quality, durability, workability characteristics and aesthetic appearance with an overall impact on short-term and/or long-term drug product quality.⁴

By law, drug containers must not react or add to a drug product in a way that alters the drug’s safety or quality.⁵ Concerns related to glass include:

• Poor chemical durability resulting in weathering, pitted surfaces or delamination
• Use of silicone lubricants and impact to product quality
• Compatibility concerns related to biopharmaceuticals
• Potential for leaching and interaction with drug products
• Drug product shifts in pH due to glass dissolution
• Reduced performance in glass prefilled syringe systems
• Reduced potency from adsorption of drug product onto glass surface
• Breakage, scratches or particles resulting from packing, transport and filling

Particles

Glass particles or fragments can be present as a consequence of handling during manufacture, washing or filling. Glass-to-glass contact, packing materials and damage from shipping can also contribute to the existence of glass particles. These fragments are detectable using modern inspection techniques; however, there are elusive particles known as glass lamellae or flakes. Lamellae are very small, flexible fragments that can be as thin as one micron with lengths that vary from 10 microns to 1 millimeter. These flakes are not easily observed and can best be seen by swirling contents of a container and viewing with light directed at 90 degrees to see interference colors. The flakes’ physical characteristics are unusual and are similar to ribbons that can fold, as opposed to a particle.

Increasingly, the risk of glass delamination should be considered when developing a drug product. In 2010, several pharmaceutical manufacturers issued voluntary recalls of certain lots of drug products because of the presence of glass flakes. This phenomenon occurs over a period of time ranging from a few months to years. The cause of delamination is complex, since breakdown of the internal glass surface can be caused by a combination of factors including pH, type of buffer and the inclusion of other complexing agents that are risk factors for glass. Although delamination is a concern for all packaging formed from glass, to date, the phenomenon has only been observed in vials.

The following processing conditions noted by the FDA⁶ have been associated with a higher incidence of the formation of glass lamellae:

• Glass vials manufactured by a tubing process (and thus manufactured under higher heat). These vials are less resistant than molded glass vials and may shed lamellae more easily. The processing conditions used to manufacture glass vials can be designed to mitigate the potential for later delamination.
• Drug solutions formulated at high pH (alkaline) and with certain buffers. Common buffers associated with lamellae formation include citrate and tartrate.
• Length of time the drug product is exposed to the inner surface of the container. The time duration has a direct correlation to the potential for glass lamellae formation to occur during the product shelf life.
• Drug products with room temperature storage requirements. Drugs stored at room temperature have a greater chance of glass lamellae formation than do products stored at colder temperatures.
• Terminal sterilization has a significant effect on glass stability.

In addition to the above considerations, tight dimensions can be a significant concern with molded vials. These vials also tend to be less clear, which may have an impact on visual inspection; therefore, molded glass vials come with their own set of challenges.

Although there have been no reported incidents directly associated with adverse events caused by glass, the presence of flakes may pose considerable risk to patients. Upon injection, particles can cause embolic, thrombotic and other vascular events in humans. Also, glass flakes may cause the development of foreign body granuloma subcutaneously, as well as local injection site reaction and increased immunogenicity. Based on the rise in recalls due to glass delamination, the FDA has advised drug manufacturers to “re-examine their supplier quality management program with glass vials manufacturers to assure that this phenomenon in not occurring.”⁷

By working together early in the drug development process, pharmaceutical and packaging manufacturers can examine the risks and potential interaction between the drug product’s formulation characteristics, such as pH, buffer type and ionic strength, and the CCS with which it’s in contact. When the risk for glass attack is identified, an alternate high-performance polymer material, such as a cyclic olefin, can be a beneficial solution.

Breakage 

Glass has high intrinsic strength, which can be significantly compromised by contact with another solid material and/or mechanical or thermal strain. There is residual stress in glass that can lead to cracks or microscopic flaws. The annealing process, size and shape of the container will have an impact on the potential for stress and subsequent fracture. High compression strength and low tensile strength is characteristic of glass materials and applied strain can cause minor flaws to propagate. Vial breakage has also been observed in freeze-thaw operations related to thermal contraction of frozen protein formulations and deformation of glass. Thermal expansion during thawing can generate moderate positive strain on glass and breakage has occasionally been observed during thaw.⁸

The strength of glass is an important consideration, particularly for prefilled syringes. Prefilled syringes (as well as auto injectors) have many advantages over vials for the patient and caregiver. The usability of these devices can improve the patient experience, especially for chronic diseases, such as multiple sclerosis, rheumatoid arthritis and osteoporosis. Auto-injector systems traditionally use 1mL long glass prefilled syringes. These systems have been successful, but there is increased risk for breakage when used with viscous drugs that require high injection forces.

Some of the noted recalls were due not only to breakage, but also concerns for cracks and loss of drug product integrity. Throughout the supply chain — from manufacture, prior to filling, at filling lines, during shipping, storage or prior to administration — glass materials are at risk for breakage, which can result in loss of drug product and potential delay in patient therapy. 

Challenges with Biologics

When it comes to compatibility between glass systems and biopharmaceuticals, there are several known physical and chemical challenges to overcome. In 2006 commercial lots of a drug product delivered by an auto-injector that contained a glass prefilled syringe were recalled in several European countries because of problems with slow or incomplete delivery of the drug.⁹ There was a similar occurrence in 2009 in the U.S. when an auto-injector batch was recalled because of high force-to-fire values.¹⁰

Delivery of medicine is critical for accurate dosing and patient compliance. A low glide force is a measure of smooth injections and an indicator of complete drug delivery. When strong adhesive forces between glass surfaces and liquid formulations resist surface wetting, a greater injection force or enhancement of the system is needed to reduce surface tension. A smooth injection achieves an accurate and less painful patient experience. Silicone oil can be used to facilitate smooth injections when used on a glass syringe barrel; however, insufficient or poor coverage on the barrel can be difficult to overcome. Yet another risk for use of glass is instability of proteins in contact with silicone lubricants. Silicone has been implicated in aggregation and particulation of proteins and antibodies. Aggregation of therapeutic protein products induced by silicone can pose a challenge to development and commercialization and has shown synergistic effects with agitation.¹¹

The use of prefilled syringe systems continues to grow as the convenience and safety benefits are shared by healthcare professionals and patients. The material used in prefilled syringe systems must be compatible with the necessary components of the system and pharmaceutical product; there are particular alerts with regards to processing of glass barrels with needles. The process for fixing a needle into a glass syringe can involve the use of adhesives, or the needles can be molded into the glass with the aid of a tungsten or nylon pin. These processes have posed risk for leachables, particulates or, in the case of biologics, protein aggregation. Organic solvent from a partially dried epoxy used to attach a needle to the syringe barrel has leached into a product and caused an increase in protein oxidation followed by aggregation.¹² In a separate case related to seating needles in prefilled syringe systems, particles were isolated from a protein-based solution and were identified as aggregated protein and tungsten. The origin of the tungsten was traced to the tungsten pins used in the supplier’s syringe barrel forming process.¹³ Another unexpected event was related to a black particle (~300 microns) that was visually observed adhering to the interior shoulder of a prefilled glass syringe containing a biological drug product. The particle was found to originate from the polymeric pin used during the syringe manufacturing process. Nylon-MXD6 and Nylon-6 photo-oxidized-related compounds were detected (260 ng/mL) in both the pin extract and syringe solution.¹⁴

Adsorption of protein onto contact surfaces is another significant problem with glass, especially at lower concentrations. Adsorption behavior of a protein is dependent on the characteristics of the formulation, protein and surfaces. Solid surface characteristics such as roughness, composition and surface charge also affect the protein adsorption phenomenon. Rough surfaces provide greater surface area for higher protein binding capacity, while the chemistry of the surface in conjunction with the formulation pH will determine the charge on the surface. Studies on Type 1 glass vials have shown that the compositions and treatments of the glass influence protein adsorption, which was more apparent at the vial bottom compared to the top or middle. Adsorption also increased with formulations having lower pH.¹⁵

Alternatives for the 21st Century

To combat the risks associated with glass, modern polymeric materials can be considered. The manufacture and processing of polymers allows for flexibility in molding and forming throughout a drug product’s lifecycle. Qualification of such materials is dependent on intended use, and risk assessments should be considered early to support development and protection of the drug product throughout its lifecycle. In cases of recalls, switching to a polymer may mitigate risk of reoccurrence. Cyclic olefin polymers (COP), such as the Daikyo Crystal Zenith^® (Daikyo CZ) polymer, are high-performance materials possessing the valuable properties necessary to manufacture, store, protect and deliver drug products without many of the weaknesses inherent to glass. It is especially suitable for biologic applications since many of the COP’s quality attributes specifically meet the challenging needs of this market. The Daikyo CZ COP has been successfully marketed in Japan for pharmaceutical applications. Companies using the Daikyo CZ COP vials in glass filling lines have transitioned successfully by making minor changes. Aspects of cosmetic quality, biopharmaceutical compatibility and a vision of the future state of pharmaceuticals have been strong forces when considering this alternative.

The Daikyo CZ COP is a modification of polyolefins in which the performance characteristics are enhanced based on use of cyclic olefin monomers and unique polymerization methods. The synthesis allows for better control of the molecular structure with fewer side products and less need for performance additives. Precision molding can be optimized for the intended use, and once the materials are qualified, forming can be adapted as needed. This class of polymers has few ingredients and the desired properties of transparency and break resistance.  It also provides a strong moisture barrier and is easy to sterilize. 

Just as studies have shown that not all Type I glass is created equal, the same holds true for olefin polymers. Compared to other plastics, the optical transmission for COP is very high (> 90%).¹⁶ The mechanical and thermal properties are well suited for sub-zero application, exhibiting high strength and impact resistance. Relative to polypropylene, the flexural strength is three to four times greater while tensile strength can be as much as five times greater depending on the grade.¹⁷ Another important requirement for pharmaceutical applications is dimensional stability.  The Daikyo CZ polymer has thermo-mechanical properties shown to have high dimensional tolerances. The material is physically and chemically stable with relatively few constituents having less potential for drug product interaction. 

Glass as primary contact material for pharmaceutical and biopharmaceuticals has hurdles to overcome with respect to suitability. The need for silicone lubricants, breakage, particles and leachables are among the major concerns. To investigate the silicone oil-induced aggregation of proteins during storage and/or shipment, the Daikyo CZ polymer, which is silicone oil-free, and siliconized glass prefillable syringe systems were evaluated for the effect of protein adsorption onto these surfaces. Aggregation was tested via visual inspection of particulate formation and quantification of turbidity changes by optical density measurements. At protein concentrations as high as 25 mg/ml, an effect of silicone oil on protein aggregation was observed, especially under agitation and air shipment of samples. Effect of end-over-end rotation at room temperature on the aggregation of a therapeutic monoclonal antibody in glass and the Daikyo CZ 1 mL long syringes are illustrated in Figure 1.

 

In contrast to staked needle syringes made of glass, the Daikyo CZ syringe system does not utilize a tungsten pin to create an opening for inserting the needle. Consequently, this syringe system is tungsten-free and therefore a suitable alternative for the packaging of sensitive protein therapeutics. An analysis of tungsten was carried out on prefilled syringes made of COP and glass. Figure 2 shows that the amount of extractable tungsten in the Daikyo CZ syringes is at the level of the solvent blank, while the amount of tungsten in syringes made of glass is significant.

Recalls based on breakage, aggregation or performance may require costly preventive actions and process improvement. These risks can be mitigated with a Daikyo CZ 1 mL long insert needle syringe system.  The concern from breakage was put to the test by comparing the force required to break the flange on a prefilled syringe system. In one example, the glass flange broke  under 160N while the Daikyo CZ flange did not break at 540N, which is well above normal back pressure. The point of break occurred at the distal end. 

The High Cost of Recalls

American Regent initiated recalls of Calcium Gluconate Injection, USP due to silicone particulate found in the glass vials. The recall cited the potential for adverse events to patients upon intravenous administration, including disruption of blow flow within small blood vessel in the lung, granuloma formation and localized inflammation.¹⁸

For a pharmaceutical manufacturer facing a recall, the total cost of quality can exponentially increase the price of manufacturing the drug product. Each recall not only affects a manufacturer’s bottom line through investigations, loss of market share, replacement costs and reputation in the marketplace, but most importantly patients who may have already suffered consequences.

At the 2011 PDA/FDA Glass Quality conference, David Jaworski, an FDA consumer safety officer and team leader, Domestic Case Management Branch in OCMPQ, called attention to the potential public health impact. Cracked vials could become contaminated or lose contents prior to injection, containers could interact with product to reduce its efficacy, and glass particulates and delamination could cause cardiovascular damage and provoke immunological reactions. He noted, “Syringes in 2010 were a major portion of the recalls.” He said that common issues with many of the recalls include the observation of visible defects, such as metal particles, damaged containers, silicone, excess silicone in containers, foreign matter and leaking containers. Conference speakers from Amgen and Merck Sharp & Dohme indicated the cost of conducting recalls could be several million dollars.¹⁹

Performing risk assessments based on factors such as the physical, functional and chemical characteristics of the container closure system as well as the interaction with the drug product enables selection of the most suitable CCS. There are cases when glass may be too risky for use with a particular drug product, as demonstrated by the multiple instances of glass recalls.

Demand for quality and integrity of pharmaceutical and biopharmaceutical packaging systems is on the rise. As cell-based therapies, biologics and personalized medicines are realized, qualification of packaging materials should include identification and assessment of risks during development phases. Identification of critical quality attributes for packaging systems and implementation of appropriate control strategies will lead to successful lifecycle management of the pharmaceutical product.

Many current biologic products are produced, frozen, stored and delivered to the clinical site under extreme temperature conditions for which glass is not the best choice. Additionally, glass may not be the best option for prefilled syringes, considering the need for silicone oil and use of tungsten in the manufacture process. Close technical communication with suppliers of product contact components plays an important role in making a successful pharmaceutical / biotherapeutic product and securing a reliable inventory to meet patient needs.  

References

1. “Breakage and Particle Problems in Glass Vials and Syringes Spurring Industry Interest in Plastics,” IPQ In the News, IPQ Publications LLC, August 7, 2011.
2. “American Regent Initiates Voluntary Nationwide Recall of Concentrated Sodium Chloride Injection, USP, 23.4%, 30 mL Single Dose Vial Due to Particulates,” June 15, 2011, www.fda.gov/Safety/Recalls/ucm259312.htm, accessed on July 28, 2011.
3. “American Regent Initiates Nationwide Voluntary Recall of Methyldopate HCL Injection, USP 5 mL Single Dose Vial Due to Glass Particulates,” June 6, 2011, www.fda.gov/Safety/Recalls/ucm258064.htm, accessed on July 28, 2011.
4. K. Cummings, A History of Glass forming. University of Pennsylvania Press, 2002, ISBN 0812236475.
5. Code of Federal Regulations Title 21 Food and Drugs Part 211.94(a) Subpart E Control of Components and Drug Product Containers and Closures.
6. Questions and Answers on Current Good Manufacturing Practices, Good Guidance Practices, Level 2 Guidance – Control of Components and Drug Product Containers and Closures. www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm124780.htm#1
7. FDA “Advisory to Drug Manufacturers: Formation of Glass Lamellae in Certain Injectable Drugs,” www.fda.gov/Drugs/DrugSafety/ucm248490.htm, March 25, 2011, accessed on July 11, 2011.
8. Ge Jiang, et al, “Mechanistic Studies of Glass Vial Breakage for Frozen Formulations. II. Vial Breakage Caused by Amorphous Protein Formulations,” PDA J Pharm Sci Technol December 2007 61:452-460 journal.pda.org/content/61/6/452.abstract?sid=bfd3884d-8d39-4e0c-8202-711edca940a2#corresp-1
9. “Amgen Recalls Neulasta SureClick in Europe, also Poland,” PMR, October 10, 2006, www.pharmapoland.com/42319/Amgen-recalls-Neulasta-SureClick-in-Europe-also-Poland.shtml, accessed December 9, 2011.
10. “Enforcement report for November 11, 2009,” FDA, November 11, 2009, www.fda.gov/Safety/Recalls/EnforcementReports/ucm190285.htm, accessed December 9, 2011.
11. Renuka Thirumangalathu et.al., “Silicone Oil- and Agitation-Induced Aggregation of a Monoclonal Antibody in Aqueous Solution,” J Pharm Sci. 2009 September; 98(9).
12. Ingrid Markovic, “Risk Management Strategies for Safety Qualification of Extractables and Leachables Substances in Therapeutic Biologic Protein Products,” USFDA American Pharmaceutical Review June 2009.
13. Yasser Nashed Samuel, et al, “Identification of an Extraneous Black Particle in a Glass Syringe: Extractables/Leachables Case Study,” PDA J Pharm Sci Technol May/June 2010 64:242-248.
14. Wei Liu, et al, “Root Cause Analysis of Tungsten-Induced Protein Aggregation in Pre-filled Syringes,” PDA J Pharm Sci Technol January/February 2010 64:11-19.
15. Elizabeth Varmette et al., “An Assay for Measurement of Protein Adsorption to Glass Vials,” PDA J Pharm Sci Technol July/August 2010 64:305-315.
16. Reza Esfadiary, et al. “Characterization of Protein Aggregation & Adsorption on Prefillable Syringe Surfaces,” University of Kansas and West Pharmaceutical Services, Inc., 2007. www.westpharma.com/en/support/Pages/TechnicalResources.aspx
17. Ibid.
18. “American Regent Initiates Voluntary Nationwide Recall of Calcium Gluconate Injection, USP, 10%, 100 mL Pharmacy Bulk Package Due to Particulates,” July 18, 2011, www.fda.gov/Safety/Recalls/ucm263531.htm, accessed on July 28, 2011.
19. Bowman Cox, “The Gold Sheet Glass Quality Crisis Prompts Multi-Faceted Array of Risk-Based Improvements,” The Gold Sheet, August 2011, Vol. 45, No. 8. www.elsevierbi.com/publications/the-gold-sheet?issue=Aug-01-2011

Fran DeGrazio is vice president, Marketing and Strategic Business Development at West Pharmaceutical Services, Inc. She can be reached at fran.degrazio@westpharma.com. Diane Paskiet is associate director, Scientific Affairs at West. She can be reached at Diane.Paskiet@westpharma.com.