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The high viscosity of highly concentrated monoclonal antibody formulations not only presents processing and storage difficulties, but also formulation and delivery challenges.
Monoclonal antibodies (mAbs) are typically given as intravenous infusions, but subcutaneous administration is fast becoming the preferred alternative, especially for patients with chronic diseases who require frequent dosing of the mAb over their lifetime. Subcutaneous injection of a drug using a self-administered delivery device such as an autoinjector, pen, or prefilled syringe is not only more convenient for the patient, but it also reduces healthcare costs by minimizing hospital visits.
When developing mAb formulations for subcutaneous administration, volume and viscosity are crucial considerations. Because the subcutaneous space limits the volume that can be delivered, mAb formulations tend to be developed as highly concentrated solutions, often in the range of hundreds of milligrams per mL, which consequently give rise to high viscosities. “Intermolecular interactions are thought to play a role [in viscosity],” says Nicholas Warne, senior director, Formulations, Pfizer. He explains that the proteins within the mAb molecule have the potential to align themselves at specific domains, causing the solution to form transient, networked structures. The literature has reported that a protein solution’s viscosity can be predicted based on the formulation and protein characteristics such as the shape of the protein molecule (1, 2), charge distribution on the protein, which is formulation-dependent (3, 4), and the kinetics of self-association (5–7).
High viscosity not only presents difficulties in processing and storage, but it is known to pose formulation and delivery challenges, as viscous solutions require high injection force to administer the drug and may also require prolonged injection time. The pain and discomfort experienced by the patient can have a negative impact on compliance and adherence to the medication. For drug developers, it is important to bear in mind the potential product loss that could result from the highly viscous solutions sticking to the contact surface of the primary packaging. If drug delivery is through an autoinjector, the challenge will be to ensure that the device can produce the required force to function properly throughout its shelf life, hence necessitating extensive modeling and accelerated aging to simulate the high stress placed on the device.
According to Warne, the acceptable viscosity range for subcutaneous injection will depend on the patient population. “For patients with challenged dexterity, we tend to limit viscosity to 10 cps for a 1-mL prefilled syringe,” he says. “[Whereas] for patients with normal dexterity, the limit may be 20 cps. For these higher viscosity solutions, we may choose to implement autoinjectors, which help manage self-administration and reduce injection time to below 10 seconds.”
With highly concentrated mAb formulations, there are a number of issues to consider. Warne highlights that compounding and mixing must be assessed to ensure a homogeneous solution at the time of mixing and storage. He adds that viscous solutions can affect the filtration process. High-concentration mAb formulations will require the use of filters with higher Vmax (i.e., maximum volume that can be filtered through) and larger surface area. “The need for larger membrane area can result in yield losses and slower processing times [due to the higher back pressure on the filtration equipment created by the viscous solution],” he highlights. Moreover, as shear stress can cause proteins to unfold or aggregate, Warne recommends assessing the solution characteristics of the mAb formulation during pumping, transfer, and filling.
Viscosity challenges can be addressed by controlling the pH of the formulation in relation to the isoelectric point (pI) or by adding excipients, including cations and anions to increase the ionic strength of the formulation (8). In terms of optimizing the viscosity of a mAb formulation, Warne believes that less is more, “the closer to water, the better,” he says. “We are exploring the application of viscosity-reducing formulations including formulating at least two pH units away from the pI, developing proteins and mAbs with favorable electrostatic profiles, assessing the impact of pH on viscosity and the role of ionic strength, and evaluating the potential role of viscosity-reducing excipients such as arginine,” he adds. According to Warne, arginine may occasionally be beneficial in reducing formulation viscosity, but he cautions that using novel innovative excipients carries regulatory and safety risks.
Despite the challenges associated with delivering highly viscous solutions, Warne observes that there have been advances in the delivery of high-concentration protein formulations, such as the increased comfort level with delivering a 2-mL injection subcutaneously and the development of 2.25-mL prefilled syringes and autoinjectors from multiple vendors. “The ability to tolerate osmolality of up to 600 mOsm/kg in high-concentration solutions has also provided much needed flexibility,” he adds.
As demonstrated at Pharmapack Europe 2018, held on Feb. 7–8 in Paris, France, the industry continues to innovate and provide patient-centric solutions to drug-delivery challenges. Biocorp’s Onejet autoinjector won the Patient Safety and Convenience Award at this year’s show. According to Biocorp, the device is the first motor-driven, disposable, and Bluetooth-connected autoinjector compatible with standard primary containers (prefilled syringes from 1 mL to 2.25 mL) (9). Its motorization can be adjusted to any biologics density, enabling Onejet to easily deliver highly viscous drugs. Injection speed and force can be calibrated. Another key feature of Onejet is its ability to record injection data such as date, time, and doses administered, which are then transferred to a mobile app via Bluetooth so that treatment can be monitored.
The SelfDose patient-controlled injector by West Pharmaceutical Services received the award for “Ease-of-Use and Patient Compliance.” The injector has a simple two-step operation where the patient only has to remove the cap and press the device against the skin to deliver a subcutaneous injection. Audible and visual end-of-dose indicators confirm successful administration of the prescribed dose. Erin O’Brien, vice-president of West, noted in a press release that many patients could benefit from a drug-delivery device system that makes the injection experience more user-friendly and less intimidating (10). SelfDose has been ergonomically designed with the patient’s unique needs in mind. In addition, the device has a passive safety system that covers the needle before and after injection to help prevent needlestick injuries to the patient and caregiver. According to West, extensive human factors studies have been performed with the SelfDose injector, confirming the intuitive design and supporting its ease of use and patient acceptance.
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9. Biocorp, “Biocorp Wins Pharmapack Award for Its New Generation Autoinjector Onejet,” Press Release, Feb. 7, 2018.10. West Pharmaceutical Services, “SelfDose Patient-Controlled Injector Named as Recipient of Pharmapack Exhibitor Innovation Award,” Press Release, Feb. 7, 2018.
Vol. 42, No. 4
When referring to this article, please cite it as A. Siew, “Delivering High-Concentration Protein Formulations,” Pharmaceutical Technology 42 (4) 30–33 (2018).