The glass ceiling: The advantages of polymers over glass in biologic drug delivery

Graham Reynolds, Global Biologics, looks at the advantages of polymer containers over glass in biologic drug delivery

For drug manufacturers one of the early considerations for any container system is likely to be the interaction between the drug and the container closure system. Many companies evaluate both a glass and plastic option at an early stage of the development process to ensure that they have an appropriate solution that may help to optimise time to market and ultimate effectiveness and quality of the product. As part of compatibility testing, interaction with any materials that might be present in the system are examined.

Traditionally, glass has been used to store and deliver a range of injectable drugs. However, the rising popularity of biologic therapies—used for a number of conditions such as cancer, autoimmune diseases, cardiovascular issues and diabetes—has changed glass’ position as the default system in drug containment. Glass is not always compatible with biologics and other complex or high-viscosity drug products, and that incompatibility can result in costly recalls and, worse, compromise patient safety. As a result, greater consideration has been given to alternative containment systems, such as plastic, in recent years. In some cases, incompatibility with glass (or related processing materials such as silicone oil lubricants for prefillable syringes) can inhibit progress through the drug development and commercialisation process.

Plastic’s pace of adoption has been different in various markets due to local regulatory and cultural forces. In Japan, for example, presentation of products in a plastic format is common due to an emphasis on visual product quality and disposability. In the United States and Europe, this trend has been slower, but examination of plastic materials as part of stability studies is rapidly expanding as part of product lifecycle management and risk mitigation, especially with the launch of new biologics.

The utilisation of the wrong container and container closure system can put patients in jeopardy. In general terms, glass will not disappear; however, while glass certainly has its place in drug containment and delivery, plastic alternatives, such as cyclic olefin polymers have a number of very tangible advantages.

Preventing risks associated with breakages

Large molecule drugs require a level of stability that must be considered at every step of the

manufacturing and packaging process. In cases of a combination product (eg when a drug container is incorporated into a mechanical delivery device, such as an auto-injector) there needs to be a consideration of the tolerances of the various elements and the impact on functionality. Plastic offers significantly higher dimensional precision compared to glass and has benefits when considering these types of combination systems. In addition, glass can be more prone to breakage, resulting in potentially dangerous particulates in the drug or loss of sterility. Breakage can also occur during secondary operations, including labeling, auto-injector assembly and even during usage. Polymer components, on the other hand, are more resistant to breakage during shipping, handling, manufacturing and throughout the overall supply chain, drastically reducing patient risk.

Delivering biologics comfortably and effectively via glass containers can be difficult due to the large dose volumes typically required. For example, the traditional volume limit for a conventional glass syringe and auto-injector is 1mL, but the high concentrations necessary of a novel biologic often exceed that limitation. In addition, a higher dose volume may enable less-frequent dosing and the improvement of patient adherence and outcomes. Plastic components, however, can incorporate design flexibility, allowing for complex shapes, configurations, custom sizes and unique solutions not possible with glass.

Another cause for breakage of glass containers is related to the low temperatures at which biologics must be stored to avoid compromising the drugs. Conversely, plastic containers offer a more robust containment system at low temperatures and cells can be stored for months at a time and still exhibit rapid recovery two hours after thawing.

Elimination dangerous chemical reactions

Glass is not an inert material. Its chemistry can and does interact with certain medications in ways that can alter a drug’s safety, stability, purity and effectiveness. Certain additives applied to the inner walls of glass syringes, may also interact with medications. Plastic components comprised of cyclic olefin polymers can reduce or eliminate the risks associated with glass-based chemical interaction.

When a drug’s chemistry interacts with the chemistry of a glass vial, a process called delamination may occur, causing the glass to corrode and flake. Glass vials are particularly susceptible to delamination in areas that have been flamed during manufacturing, such as the vial’s base or shoulder. This interaction is especially prevalent with high pH medications, including many biologics, biopharmaceuticals and other new and advanced therapies. Unlike glass, polymers used for plastic components will not delaminate.

The increasing use of proteins as therapeutics has also created a concern related to the potency and safety of drugs contained in glass pre-filled syringes. Silicone oils, which are used as lubricants to aid the movement of the plunger, can degrade proteins. Protein aggregation can induce an immune response that could neutralise the effect of the drug. Plastic pre-filled syringes, when used in conjunction with plungers fully coated with fluoropolymer barrier films, don’t require silicone oils, thus removing the potential interaction.

Fixing a needle into a glass syringe can also result in potentially dangerous chemical reactions. The process involves 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 also posed risk for leachables, particulates or protein aggregation. Organic solvent from a partially dried epoxy used to attach a needle to the syringe barrel can leach into a product and cause an increase in protein oxidation followed by aggregation. With plastic syringes with insert molded needles, no such process is necessary.

Reducing recalls

From a patient safety standpoint alone, the advantages plastic containers can have over glass make a compelling argument. Over the last several years, biologics recalls have increased due to quality issues, including fundamental weaknesses in primary glass containers. Earlier in the decade, drug recalls related to glass particles were rising to very concerning levels:  In 2008 and 2009 there were a total of nine FDA recalls related to glass issues; between 2010 and 2012, that number jumped to a total of 47 recalls.

From investigations, to loss of market share, to replacement costs and impact on reputation in the marketplace, a recall affects a pharmaceutical manufacturer’s bottom line significantly. The more important consequence, though, is when a patient’s health and wellbeing is compromised. Utilising plastic containment systems can eliminate the potential for many of the issues leading to drug recalls.

Considerations for drug manufacturers

It is critical for drug companies to perform extensive risk assessments to determine how glass may impact each therapy before containment. Such assessments should be 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 to enable the selection of the most suitable container closure system.

Manufacturers should also consider the final method of drug delivery at an early stage in the development process. For instance, the determination of dose volume can drive selection of container closure and delivery systems. In addition, if the drug container has to be integrated into a delivery system as part of a combination product, early understanding is essential to ensure that the necessary work is done to support regulatory submissions.

Many drug manufacturers are choosing to evaluate both a glass and plastic option at an early stage of the development process to ensure that they have an appropriate solution that may help to optimize time to market. As part of compatibility testing, interaction with any materials that might be present in the system, such as silicone oil, adhesives and elastomer components should be considered.

Conclusion

As more attention is paid to the interaction between biologic therapies and primary drug containers, finding solutions to these challenges has taken on an increased urgency in order to protect patients, enhance therapeutic outcomes and to prevent costly recalls. While glass is suitable for many drug products, the advantages plastics have in certain areas cannot be ignored. By closely collaborating early in the drug development process, pharmaceutical manufacturing companies and their packaging and delivery system partners can identify the specific needs around containment and delivery of both the drug product and the patients who will be using it. The result is an opportunity to effectively develop and optimise the manufacturing process accordingly to ensure a container closure system that facilitates quality, effectiveness and patient safety.