Model Extraction Studies Examined For Monoclonal Antibody In Prefilled Syringe (PFS)
By Aryo A. Nikopour
It’s been more than 30 years since monoclonal antibodies were first licensed for clinical use.1
But product developers are still inventing novel ways to improve their safety and efficacy.
FDA approved Orthoclone OKT3 (muromonab-CD3) in 1986 for preventing kidney transplant rejection. As of March 2017, FDA has approved approximately 60 therapeutic monoclonal antibodies (MAbs), and many more are under evaluation in various phases of clinical trials.2
Supporting one of these MAbs, Nitto Avecia Pharma Services developed model extraction studies to evaluate the suitability of a glass prefilled syringe (PFS) for its intended use. The studies were designed to systematically examine the entire PFS assembly when exposed to a formulation buffer.
Non-GMP study uses 6 different methodologies
Nitto Avecia Pharma Services is a cGMP contract development and manufacturing organization.
However, in this case, it conducted a non-GMP study using six different methodologies for examining the placebo-filled syringes (see Table 1).
One of the most challenging analytes in this project is also one of the most benign, according to Aryo A. Nikopour, Senior Vice President of Scientific and Technical Services at Nitto Avecia Pharma Services.
Silicone oil is a nontoxic substance widely used as a plunger lubricant in the barrel of prefilled syringes. With small molecule injectables, silicone oil is harmless.
Another nontoxic analyte Nitto Avecia Pharma Services examined was tungsten (W).
Why were these seemingly harmless analytes included in the study?
Because both silicone oil and tungsten can interact with proteins, leading to aggregation, Mr. Nikopour says. Small molecule therapies are not affected. But the quality of a monoclonal antibody or any protein drug product could be affected by the presence of either analyte, he says.
Silicone-induced protein aggregation happens when a protein adsorbs onto the hydrophobic silicone oil/water interface. This may or may not be reversible. Over time, protein can lose its conformation (denaturation), which is mostly irreversible. Denatured species can revert to the bulk and form aggregates with similar molecules in solution.3
As part of the studies, Nitto Avecia Pharma Services came up with some innovative ways to modify a published method for extracting silicone oil from the syringe.3
Company examines 4 different syringes
But it did not stop with one type of syringe. Instead, it looked at four different syringe types with different buffers. This was to support the client’s intention to use prefilled syringes for multiple products.
Nitto Avecia Pharma Services found different levels of tungsten and silicone oil in the syringes (see Table 2).
Clearly, there was a wide variety of findings, especially when considering free silicone oil — discovered at levels that ranged from less than the quantitation limit to more than 73 µg/mL. This variability demonstrates the importance of having sufficient material to examine multiple syringe types when doing extractables and leachables studies for protein therapeutics.
Aryo A. Nikopour is Senior Vice President of Scientific and Technical Services at Nitto Avecia Pharma Services.
References:
1. Liu JKH. The history of monoclonal antibody development – Progress, remaining challenges and future innovations. Ann Med Surg (Lond). 2014 Dec; 3(4): 113–116.
2. Singh S, et al. Monoclonal Antibodies: A Review. Curr Clin Pharmacol. 2018;13(2):85-99.
3. Concise Encyclopedia of High-Performance Silicones (2014), 381-394.