Case Study: Optimising Biologics Formulation for Pre-Filled Syringe Manufacture at ten23 health
Pre-filled syringes play a key role in modern biologics. This case study explores how ten23 health resolved formulation challenges to ensure safe and stable drug delivery.
In the ever-evolving field of biopharmaceuticals, ensuring the stability and integrity of biologic drug products throughout manufacturing is paramount. Recently, ten23 health was approached by a biopharmaceutical client facing a particular challenge: persistent particle formation during the aseptic filling of their drug product (DP) into pre-filled syringes (PFS). This issue threatened product stability, safety, and ultimately, patient outcomes.
The Challenge
The original formulation presented several complications. Crucially, it lacked essential stabilising excipients, which led to protein instability and oxidative degradation under the stresses of mechanical processing and exposure to vaporised hydrogen peroxide (VHP) in isolator systems. The key issues identified were:
- High levels of visible and subvisible particles in the Drug Product (post-filling).
- Protein aggregation triggered by interactions with air-liquid interfacial stresses and potentially by silicone oil lubricant.
- Oxidative degradation, likely stemming from residual VHP exposure left after sterilisation cycles of the isolator system.
- Compatibility challenges involving rubber stoppers and glass syringe components.
The stakes were high: the client required a robust (re)formulation to reduce particulate matter, safeguard protein integrity, and maintain clinical efficacy, all while ensuring compatibility with PFS components and the aseptic environment.
Our Approach: Science Meets Strategy
Leveraging our internal expertise, we introduced two key excipients to the formulation:
- Polysorbate 80 (PS80): A well-characterised non-ionic surfactant known to reduce protein adsorption onto surfaces, thereby mitigating aggregation caused by interfacial stress. (HC Mahler et al.. 2010) – check references at the bottom of the text.
- Methionine: An antioxidant amino acid protecting the protein (and other components) from oxidation, especially relevant given product exposure to VHP (Adler et al., 2019 & Allmendinger, A., et al. 2018).
Rigorous Testing
The reformulated product underwent a suite of comprehensive tests to confirm its stability and compatibility:
- Accelerated Stability Studies: Subjecting samples to elevated temperatures and VHP conditions to simulate long-term storage and manufacturing stresses.
- Particle Analysis: Utilising light obscuration and flow imaging techniques to precisely quantify and characterize subvisible particle populations, both pre- and post-filling.
- VHP Residual Testing: Monitoring residual peroxide levels post-sterilisation.
- Si-Oil compatibility: to evaluate if the Si-oil lubricant from the syringe may compromise product quality, we worked with our manufacturing team and the PFS supplier to obtain syringes with higher levels (above specification limits) of Si-oil, manufactured those samples representatively, and performed a stability study.
- Process development: utilizing process development lab experiments, we're fine-tuning filling parameters to minimise shear forces and interfacial stresses due to air-liquid interfaces.
- Extractables and Leachables Profiling: A thorough evaluation of potential interactions between the DP and PFS components was performed, including glass barrels, silicone oil, and rubber stoppers, to rule out adverse effects.
Outcomes: A Resounding Success
The results spoke for themselves:
- Particle Reduction: Incorporation of PS80 reduced subvisible particle counts by over 95%, a substantial improvement over the original formulation.
- Oxidative Protection: Methionine effectively prevented product oxidation, with negligible oxidised methionine detected and biological activity retained following VHP exposure.
- Stability: The reformulated product demonstrated excellent stability under recommended storage conditions, as well as accelerated conditions for at least six months.
- Compatibility: No increase in extractables or detrimental interactions with PFS components was observed.
- Manufacturing Efficiency: Process optimisation enhanced batch consistency and dramatically lowered batch failure risks due to particulate contamination.
Conclusion
This case study exemplifies how ten23 health combines scientific rigour with practical manufacturing insights to solve complex formulation challenges. By integrating Polysorbate 80 and Methionine, and coupling these with strategic process improvements, we delivered a formulation that is not only robust and stable but also compatible with PFS components and modern aseptic environments employing VHP sterilisation.
The success achieved here underscores the importance of targeted excipient selection and process collaboration in the production of high-quality biologic. At ten23 health, we remain committed to advancing biopharmaceutical development through bespoke solutions tailored to each client’s unique needs.
References
- Mahler, H.-C., et al. (2010). Protein aggregation: pathways, induction factors and analysis. Journal of Pharmaceutical Sciences, 98(9), 2909–2934. doi.org/10.1002/jps.22098
- Allmendinger, A., et al. (2018). Biopharmaceutical formulation development and fill-finish challenges in pre-filled syringes. Pharmaceutical Development and Technology, 23(2), 181–190. doi.org/10.1080/10837450.2017.1332133
- Adler, M., et al. (2019). Process analytical technologies for particle monitoring in biopharmaceutical manufacturing. Biotechnology Progress, 35(2), e2756. doi.org/10.1002/btpr.2756
Author: Adithya (Adi) Balasubramanian
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