Considering a Coating Technology as an Alternative to Silicone Oil

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Every pharmaceutical packaging solution faces a consistent and common trilogy of challenges: to safeguard the patient’s safety, protect the efficacy of the drug, and ensure smooth operation when integrated into a device. Containers for injectable drug products—such as prefilled syringes (PFS) and auto-injectors delivering high molecular weight, protein-based drugs—face other specific challenges related to the higher chemical sensitivity of these drugs, lower stability in solution, and strong fluid dynamic characteristics (i.e., high viscosity).

Potential interactions

Most parenteral packaging components require some form of surface treatment or lubrication to improve their processability and functionality, and silicones are used in many pharmaceuticals and medical devices. Although still regarded as an industry-standard solution, silicone oil can present some unwelcome interactions with highly sensitive drug formulations. One key consideration is the integrity, safety, and stability of the formulation over the product’s entire life, from filling to the expiration date. Specifically, silicone migration can generate the accumulation of sub-visible particles, which may lead to non-compliance with pharmacopoeias and potentially registration failure as product safety and efficacy are compromised. Unlike small molecules, high molecular weight proteinaceous drugs demonstrate a propensity to aggregate and generate hazardous particles.

In addition, a protein can adsorb at the silicone oil interface and lead over time to protein denaturation. Denatured proteins are more prone to protein–protein interactions, resulting in aggregation and increased immunogenicity.

Furthermore, excipients used in the formulation can have a detrimental effect on different container materials and lubricants. For example, high pH buffers can induce glass delamination, and the interaction of silicone oil and surfactants can lead to silicone oil-related subvisible particle release.

As a consequence, there is a possible loss of therapeutic response and changes in activity that could affect drug efficacy and safety. Moreover, silicone droplet accumulation or migration may result in a higher reject rate during final product release, which in turn will have an impact on productivity and the total cost of ownership. The performance of auto-injectors could be compromised, as the most common excipients used in parenteral formulations could interact with the silicone oil, leading to variations in glide force and an incomplete dose being
delivered. The probability of encountering silicone-related autoinjector failure increases with chemically aggressive formulations.

Although the integrity of the silicone lubricant layer is essential for syringe gliding and auto-injector performance, degradation over time can become a significant barrier to drug efficiency, and silicone particle migration may trigger an immune response in the patient. The evolution of the critical quality attributes for combination products has resulted in an improvement in silicone lubrication control and distribution. As the trend towards more viscous drugs grows, however, pharma and biotech partners are also investigating alternative solutions in the context of use with protein-based drugs.

Alternatives to silicone

Some work has been done to address the use of silicone oil in prefilled syringes. Some manufacturers have developed syringes equipped with baked silicone; however, baked-on technology is generally not compatible with staked needle design, which is the standard for biologics. Silicone-free glass syringe technology has also been recently introduced as a potential solution, although this may require the development of specialty rubber plungers to optimize the gliding force. Other options include minimizing silicone oil’s use, optimizing the coating distribution profile, and transitioning to plastic syringes (although silicone may still be needed).

Figure 1. A conventional silicone oil coating is sprayed inside a container; a crosslinked coating (SG Alba, Stevanto Group) is chemically bonded to the glass. Figures are courtesy of the authors. Click to enlarge.

As illustrated in Figure 1, in a conventional silicone oil syringe, the silicone oil is sprayed inside the container but is not chemically bonded to the glass. In a new coating technology (SG Alba platform, Stevanato Group), a cross-linked silicone chain leads to improved layer structure using covalent bonds, increasing the connection force between the silicone and glass while retaining lubrication performance. A thin, permanent silicone coating is created.

Study results

A study has been developed in SG Lab Analytics laboratories to compare the performance of a conventional sprayed-on silicone coating and the cross-linked silicone coating. Specifically, the focus was to illustrate the main interdependencies between the presence of an aggressive placebo and silicone oil performance, the change in glide force upon storage time as a good indicator of real-time stability, and that a pharmaceutical placebo solution can be used to predict the functionality and stability of filled syringes.

One-mL long syringes (SG EZ-Fill Syringe, 29G ½-in. 5B TW configuration, Stevanato Group) were stored for six months under static conditions at 40 °C/75% relative humidity, according to ICHQ1A(R2) guidelines (1). Syringes coated with standard silicone oil and SG Alba syringes were compared in this study. The filling solution was selected according to the average excipient concentration commonly used by pharma companies; this placebo solution includes an acetate buffer (1.3 mL) was used that is known to induce a change in the silicone layer distribution and affect mechanical performance (2).

Before filling, a baseline measurement of the thickness of the silicone layer of both coating technologies was established. Using technology based on the principles of white light reflectometry and laser interferometry (RapID Layer Explorer, Unchained Labs) for silicone layer thickness and distribution measurement, it was established that SG Alba presented a reduction in thickness of approximately 30% compared to the conventional coating.

The performed tests were aimed to evaluate the gliding performance (break-loose and glide force test with a dynamometer), particle count according to United States Pharmacopeia (USP) <787> (3), particle morphology (with micro-flow imaging), and inner surface morphology (with differential interference contrast [DIC] microscopy).

Gliding performance

Figure 2. Break-loose performance of a prefilled syringe comparing a crosslinked coating (SG Alba, Stevanato Group) to a conventional silicone oil coating before and after aging. Click to enlarge.

The first study component required accelerated stability testing after filling with the placebo to establish the break-loose performance (see Figure 2). Both the silicone oil and SG Alba demonstrated comparable break-loose performance, with SG Alba presenting a slightly higher increase of the force attributable to the composition of the coating. SG Alba also showed acceptable and predictable values over time.

Figure 3. Gliding force in a prefilled syringe comparing a crosslinked coating (SG Alba, Stevanato Group) to a conventional silicone oil coating before and after aging. Click to enlarge.

The second study component measured mean gliding performance, as shown in Figure 3. Glide force is critical; if the syringe takes longer than a maximum of 12 seconds to dispense, the drug dose may not be delivered fully into the patient. Indeed, the optimal delivery time is around six to seven seconds.

The crosslinked coating technology showed constant mean glide values over the duration of the stability study, with lower variability than the standard silicone oil technology at each time point. In addition, accelerated stability stress and the pH of the placebo did not affect the gliding performance during the whole study.

Particle count

Total particle concentration is a key consideration in establishing the safety profile of the technology. Particle count tests were conducted according to USP <787>. Both coatings met the USP <787> requirements at the applied storage and testing conditions; however, the crosslinked coating demonstrates an almost four times reduction in particle release and a minimum variation of the average values over time, as measured for particles greater than or equal to 10 µm and, as shown in Figure 4, greater than or equal to 25 µm.

Figure 4. A crosslinked coating (SG Alba, Stevanato Group) shows a lower number of particles than the conventional silicone oil alternative, with minimal variation over time. Click to enlarge.

Particle and inner surface morphology

Micro-flow imaging analysis was applied to discriminate silicone oil particles released by the inner coating from other particles, both intrinsic (e.g., rubber particles from the container closure system or glass shards) and extrinsic (e.g., fibers and other environment-related particles).

This test showed an approximately 80% reduction in the silicone oil particles released (in the size range of 10 to 25 µm) from the crosslinked coating compared to the standard silicone oil treatment, as shown in Figure 5. Similarly, at a size range of particles from 25 to 100 µm, a lower amount of silicone oil particles were released in the solution from the crosslinked coating than the standard silicone oil treatment.

Figure 5. The chart compares the concentration of silicone oil particles (in blue) released from the crosslinked SG Alba coating (left) and conventional coating (right). Micro-flow imaging analysis was used to distinguish silicone particles from other particles. Click to enlarge.

The final component of the study was an inner surface inspection of both treated syringes using DIC microscopy. The typical morphology of the SG Alba coating does not undergo critical variations, whereas the silicone oil distribution in the standard syringes is visibly affected over time.

Conclusion

Although traditional silicone oil technology has served the market well for several years, the increased prominence of biologic drugs, such as monoclonal antibodies and recombinant proteins, has necessitated the evolution of coating technologies that can adequately ensure the safety of the patient, the efficacy of the drug, and the smooth operation when integrated in a device. To that end, improved coating technologies are critical to ensuring pharma partners and patients can maximize the benefit of the new and emerging therapies in applications such as ophthalmic in 0.5-mL or 1-mL syringes and subcutaneous injections in both 1-mL and 2.25-mL syringes.

References

1. ICH, Q1A (R2) Stability Testing of New Drug Substances and Drug Products, Step 5 version (2003).
2. G.H. Shi et al., PDA J. Pharm. Sci. Tech. 72 (1) 50-61 (2018).
3. USP, USP General Chapter <787>, “Subvisible Particulate Matter in Therapeutic Protein Injections” (US Pharmacopeial Convention, Rockville, MD, 2014).

About the authors

Jessica Baseggio and Chiara Callegari are research laboratory analysts at SG Lab Analytics, Stevanato Group, and Enrico Barichello is SG Alba Platform product manager, Stevanato Group, enrico.barichello@stevanatogroup.com.

Article Details

BioPharm International 
Vol. 34, No. 11
November 2021
Pages: 25–28

Citation

When referring to this article, please cite it as J. Baseggio, C. Callegari, and E. Barichello, “Single-Use Systems Enhance Flexibility,” BioPharm International 34 (11) 25–28 (2021).