By Susan M. Dounce, West Pharmaceutical Services, Inc.

 Fig. 1. (a) Total number of injectable new molecular entity (NME) approvals by FDA by year and molecule category. (b) FDA injectable NME approvals by category as a percentage of all injectable NME approvals. The trend lines are to guide the eye. Source: fda.gov. Note: 2017 values are year-to-date as of August 2, 2017.[/caption]

More than 30 years after the first FDA approval of a therapeutic monoclonal antibody (mAb) in 1986, these recombinant protein drugs are beginning to deliver on their potential to revolutionize medicine. Therapeutic antibodies are a manifestation of remarkable advancements in biotechnology and, due largely to their specificity in binding to target molecules, they are having substantially positive impacts on treatment outcomes. Drugs targeting auto-immune diseases such as adalimumab (tradename, Humira®) for rheumatoid arthritis, are improving the quality of life for chronic disease sufferers. [Schiff 2014] Oncology drugs such as trastuzumab (tradename, Herceptin®) are significantly improving long-term progression-free survival rates in cancer patients. [Swain 2015]

With the clinical success of this class of drug molecules, the number of FDA-approved monoclonal antibodies (and closely associated recombinant proteins such as antibody-drug conjugates and Fc-fusion proteins) is growing fast. Antibodies represent the majority of new biologic drug approvals and biologics represent the majority of new injectable drug approvals. Figures 1a and 1b show the injectable New Molecular Entity (NME) approvals since 2011 (where 2017 data represents year-to-date as of August, 2017). Biologic and specifically antibody approvals are increasing, both in absolute number and as a percentage of all injectable drugs.

Since the bioavailability of proteins delivered by oral dosage or inhalation is poor at present, mAbs and derivatives thereof are delivered by injection. This is in contrast to innovative small molecule drugs, which can be more readily delivered in oral dosage forms. Hence, mAbs are typically packaged and stored in liquid or lyophilized format in glass vials, prefilled syringes or cartridges for later injection.

Now that these targeted treatments have been proven for a number of disease states, additional focus can shift toward outcome optimization as it pertains to safety, efficacy and patient experience. There is growing appreciation for, and concomitant scrutiny over, the stability of therapeutic proteins during storage/delivery and how stability issues may impact the safety and or efficacy of the drug product. Stability is the number one objective for mAb formulators and can even impact which molecular candidates advance at the discovery stage. A molecular entity with better stability may preferentially advance over a molecular candidate with higher affinity to the target but lower stability. [Sievers 2017] In such a case, affinity may be optimized in later discovery/development cycles. Despite efforts to achieve the best stability at the discovery and formulation stages of drug development, there are numerous challenges that can be introduced by the packaging/delivery systems.

Proteins are designed by nature to be interactive with and responsive to their environment, and thereby highly subject to chemical and conformational changes. They can have numerous reactive functional groups that may be prone to oxidation, deamidation and other chemical modifications. The same protein can simultaneously carry regions of hydrophobicity, as well as regions of positive and negative electrostatic charge. As a result, proteins can interact with nearly any surface or interface that they encounter whether solid, liquid or gas, and no matter the material (metal, glass, polymer, air, silicone etc.). The interaction can leave the protein wholly unaffected or lead to reversible or irreversible adsorption, chemical or conformational changes, and/or aggregation.

Surfactants are a key element in controlling and maintaining protein stability—especially in the presence of silicone oil. Polysorbate 20 or polysorbate 80 are often used in low concentration by mAb formulators to mitigate protein adsorption at interfaces. Because surfactants are so important to maintaining protein stability, FDA considers them to be critical excipients. [Singh 2017] Furthermore, while they may provide an easy solution to stability challenges, polysorbates are complex raw materials that may contain significant variability in their purity/composition, cause new leachables to appear, and can degrade into free fatty acids that themselves can impact formulation stability. [Singh 2017] Rather than fully relying on surfactants to stabilize a formulation, it may be desirable to minimize the interfacial interactions that can impact stability.

In a vial, prefilled syringe or cartridge, aside from the container walls and elastomer surface, a therapeutic protein may be exposed to thousands of micro-interfaces that can be introduced by air or silicone oil. For example, agitation during shipping and handling can entrap air bubbles which can introduce thousands of new liquid-gas interfaces into the formulation. Furthermore, in a prefilled syringe or cartridge, silicone oil droplets can represent an additional population of micro-interfaces with which a therapeutic protein may potentially interact. Regardless of their nature, thousands of micro-interfaces in a formulation can represent a risk to protein stability, and from this perspective, silicone oil has been the subject of great scrutiny for more than a decade.

Industry opinions on the topic of silicone oil in prefilled syringes vary widely from drug company to drug company (even from person to person within a company) and can range from, “Silicone oil? None for me, thanks,” (indicating a strategy to completely eliminate the risk) to, “I’ve never met a protein that I couldn’t formulate around,” (indicating a strategy to contain the risk). While some proteins are highly silicone-oil sensitive (meaning that aggregates readily form when silicone oil is introduced; abatacept [tradename, Orencia] is one such example), many proteins are not. Nevertheless, ideally, rather than excluding viable molecular entities at the early discovery stage due to silicone oil sensitivity, or relying on surfactants to mitigate the risk, it seems desirable to altogether eliminate this micro-interface-creating lubricant from the packaging systems.

Completely silicone-oil-free syringe and cartridge options for parenteral drugs have historically been a technological challenge. Given the industry-wide investments in bricks-and-mortar fill/finish equipment, primary containers that radically differ from a traditional prefilled syringe or cartridge format are difficult to adopt. Within the confines of a traditional syringe/cartridge configuration, the challenge of eliminating silicone oil then centers around managing the frictional forces at a piston-barrel interface while maintaining seal integrity during storage. In a traditional syringe, friction is managed to acceptable levels by lubricating both the barrel and the plunger with silicone oil which can migrate into the formulation as “free” silicone oil droplets (thousands of micro-interfaces).

Incremental and often significant improvements towards reducing free silicone can be achieved through baked-on silicone technology or other fixed lubricants on the barrel and/or plunger (Fig. 2). It is important to note that those applications demanding a reduction or elimination of silicone oil from the primary packaging materials (i.e. therapeutic protein drugs) are the same products that simultaneously demand barrier-coated elastomers. Ever since the infamous situation surrounding Eprex and an increase in incidents of red cell aplasia in kidney disease patients, [Bovin 2005] barrier-coated elastomers are the standard for primary packaging of biologics. Therefore, the ideal syringe or cartridge system should combine both the attributes of silicone-oil-free and barrier-coated elastomers. The Daikyo Crystal Zenith® (CZ) syringe is currently the only commercial offering that delivers these two critical attributes together in one package. (Fig. 2)

Today, the vast majority of biologic drugs are packaged in glass primary containers and those that utilize prefilled syringe or cartridge formats are siliconized. There are no commercially available prefillable glass syringe or cartridge systems that are able to function in the absence of a barrel lubricant. Numerous suppliers offer polymer syringe and cartridge systems comprised of either cyclic olefin polymer (COP) or cyclic olefin copolymer (COC), which are also siliconized. While polymer syringes derive value from mitigating risks related to glass breakage, they have traditionally struggled to gain significant market share. In general, the main reason for this is that the value of engineered polymer containers is not perceived to sufficiently exceed glass such that the change can be justified. Combining the break resistance of COP, the complete absence of silicone oil, along with the utilization of barrier coated elastomeric closures, as in the Daikyo CZ syringe, together can change the value proposition around engineered polymer systems.

As shown in Figure 2, the Daikyo CZ syringe utilizes a Flurotec barrier coated plunger in combination with a proprietary cyclic olefin polymer (COP) barrel. Together, these two components represent an effective strategy for managing frictional forces in the absence of silicone oil while simultaneously providing sealing properties. The Flurotec fluoropolymer film acts as a dry lubricant and the COP barrel, in contrast to glass barrels, provides a smooth surface with very tight tolerances and nearly zero draft. In tests with unfilled syringes, hydrodynamic forces (the forces associated with a fluid passing through a needle for example) are essentially eliminated and friction forces can be directly measured. What can be observed from these tests is that the magnitudes of the static and kinetic frictional forces (break loose and extrusion forces) are low and the profiles are highly consistent from sample to sample.

The smooth COP barrel surface and the dry lubrication of the Flurotec film proves to be an effective way to manage the frictional forces in the absence of silicone oil, and the elimination of this fluid lubricant can have a significant, positive impact on the stability of sensitive protein drugs. Orencia is a 92 kDa fc-fusion protein with known silicone oil sensitivity. (The package insert for the lyophilized version of this drug product stipulates that for its reconstitution and delivery, a silicone-oil-free [disposable] syringe must be utilized.) As such, this molecule represents a suitable model for investigating the impact of eliminating silicone oil from a prefilled system. Figure 3 shows the measured turbidity (absorbance at 350 nm) of WFI-reconstituted (water for injection) solutions of 2.5 mg/mL Orencia that were stored in either siliconized glass syringes (grey bars) or Daikyo CZ syringes (blue bars) and agitated by continuous end-over-end rotation for up to 48 days. The pink bar at 48 days shows a control solution that was stored in an unsiliconized glass tube at 4ºC without agitation. The silicone sensitivity of Orencia is demonstrated by the increase in turbidity due to aggregate formation observed with the siliconized glass syringes. But even under extreme agitation conditions, the Orencia solution shows no increase in turbidity versus the control when stored in Daikyo CZ syringes.

 Fig. 3. Turbidity (UV absorbance at 350 nm) of a WFI-reconstituted solution of 2.5 mg/mL Orencia® (abatacept) stored in either siliconized glass syringes (grey bars) or Daikyo Crystal Zenith® syringes (blue bars) after continuous end-over-end rotation (extreme agitation), at room temperature for up to 48 days. The pink bar at 48 days shows a control solution, unagitated, stored at 4ºC in an unsiliconized glass screw-top container.[/caption]

Arguably, it took more than 20 years for mAbs to start changing the paradigm of disease treatment. In such a risk-adverse industry, the development, acceptance and commercial implementation of new parenteral drug packaging materials can move even slower than the evolution of drug technologies. What will accelerate change will ultimately be the realization of a better fundamental understanding about how primary packaging can impact patient safety and drug efficacy. As this understanding grows and evolves, mAb producers continue to focus on eliminating risks wherever possible to ensure the fastest time to market for their drugs. The Daikyo CZ technology offers a strategy for de-risking the discovery and development of therapeutic protein drugs through the elimination of a fluid lubricant, utilization of barrier-coated elastomers, the clean manufacturing process of COP (no tungsten or glue), and the full commercial offering of silicone-oil-free containment from vial to prefilled syringe to cartridge for easy lifecycle management. Early drug candidates that are silicone sensitive would not have to necessarily be de-selected from the discovery process. Daikyo CZ engineered polymer containers also de-risk the safety and financial impacts related to glass breakage at the site of filling or during storage/shipment/handling.

To date, there have been more than 35 global regulatory approvals of parenteral drugs packaged in Daikyo CZ vials, syringes and cartridges in the United States, Europe and Japan with numerous pipeline candidates in development. Demands for higher quality, cleanliness and performance combined with an increasing understanding of how to maximize the probability of clinical and commercial success, may ultimately drive significant change in the paradigm in primary packaging towards silicone-free polymer containers for a broad range of therapeutic protein drugs and beyond.

A. Sievers. Early Discovery biophysical analysis of proteins to enable selection of better therapeutic molecules. Colorado Protein Stability Conference, 2017.

M. Schiff, et al. Head-to-head comparison of subcutaneous abatacept versus adalimumab for rheumatoid arthritis: two-year efficacy and safety findings from AMPLE trial. Ann. Rheum. Dis. 2014; 73: 86–94.

S. Swain et al. Pertuzumab, Trastuzumab, and Docetaxel in HER2-Positive Metastatic Breast Cancer. N Engl J Med 2015; 372: 724–734.

S. Singh. Surfactants in Biotherapeutics: Can’t live with them, Can’t live without them. Colorado Protein Stability Conference, 2017.

K. Bovin et al. The increased incidence of pure red cell aplasia with an Eprex formulation in uncoated rubber stopper syringes. Kidney International. Volume 67, Issue 6, June 2005, Pages 2346–2353

Susan M. Dounce, Ph.D., is subject matter expert, Prefilled Syringes, Crystal Zenith®, and Combination Products at West Pharmaceutical Services, Inc. Prior to joining West, Susan held various technical, commercial and academic roles in the healthcare industry with Dätwyler, W.L. Gore, and as an adjunct professor at Temple University. She also serves as vice chair for the PDA Packaging Science Interest Group. She holds a B.S. in Chemistry from the University of Rochester and a Ph.D. in Physical Chemistry from the University of Pennsylvania.

By Susan M. Dounce, West Pharmaceutical Services, Inc.

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