March 12, 2022 PAO-01-22-CL-02
Tobias Rosenkranz (TR): Patient-centered approaches to drug development are driving decisions about formulation and delivery technologies today. For both originator biologics and biosimilars, ease and convenience for patients and caregivers translate to a real competitive advantage. For parenteral (sterile injectable) drugs, that ideally means simple and painless self-administration at home.
Let´s take cancer treatments as an example, since many antibody-based treatments are focused on this disease. Not all patients live close to a cancer treatment center, and many may have to travel a fair distance to reach one. For others, a cancer ward can be a frightening environment that is to be avoided. Also, an IV infusion may not be equally well tolerated by all patients. A subcutaneous injection could potentially be administered by a local doctor in a familiar environment. The process of such an injection is comparable to receiving, for example, a vaccination, which is also familiar to many people and potentially less frightening. Literature shows that this is a much more preferred way for patients to receive their treatment.
There is therefore great interest on the part of drug manufacturers to convert existing drugs delivered intravenously (approximately two-thirds of antibody-based drugs) to formulations that can be delivered subcutaneously and to develop more new drugs that can be administered via a syringe or related device.
Sara Kalman (SK): However, there is a limit to the amount of drug that can be injected subcutaneously. Traditionally, subcutaneous formulations have been limited to volumes in the range of 1–2 mL, although volumes up to 3 mL have been realized more recently. In addition, even when using on-body delivery devices with automated delivery via pumps, although larger volumes can be administered, it would take more time. With IV drugs, the volume limitation does not exist; high volumes of drugs at a low concentration can be administered. However, this can be a very time-consuming process. The higher the dose required, the longer the patient receives the IV drip as a result. The obvious solution is to produce higher-concentration versions of existing drugs in order to reduce the delivery volume and improve patient convenience and ultimately treatment success.
But high concentrations often result in higher viscosities, and viscosity is problematic for subcutaneous administration because viscous solutions don’t flow easily from the syringe through the needle.
TR: Viscosity increases because proteins at higher concentrations have greater opportunities to interact with one another to form transient clusters, which causes drug solutions to become more viscous. Typically, protein drug formulations at concentrations below approximately 75 mg/mL are rarely viscous. At concentrations from 100 to 200 mg/mL, some proteins experience noticeable increases in viscosity, indicating a propensity for self-interaction, while others do not.
At concentrations above 200 mg/mL, protein-based formulations exhibit increased viscosities, because the protein molecules are forced into close proximity to one another. In these crowded conditions, self-interactions occur even without the existence of any specific affinity for one another.
In addition, the protein–protein interactions predominantly occur between the Fragment antigen binding (Fab) regions of the proteins. But Fab regions play a key role in the efficacy of antibody drugs. Moreover, the types of forces involved in these interactions are responsible for stabilization of proteins via intramolecular interactions. So, by, e.g., choosing a different clone to achieve lower viscosity, there is a risk of losing efficacy. When interfering too strongly and in a less targeted manner with the protein–protein interactions that cause viscosity, there is a risk of destabilizing the antibody.
TR: Higher viscosities for injectable drugs can be a significant problem for both patients and manufacturers. For subcutaneous administration, there is a limit to the acceptable viscosity of formulations, which is approximately 20–25 millipascal seconds (mPa·s). Assuming the use of a typical needle size for subcutaneous administration (thinner than 27 gauge), higher viscosities can cause pain at the site of injection and potentially require injection forces too high for common syringes to withstand. The drug may even not be administrable through a syringe. In that case, only the undesirable low-concentration IV administration is possible, and there would not be a subcutaneous version at all.
SK: Higher-viscosity bioprocess fluids are also creating production challenges for biologics manufacturers. Dramatic increases in titers for engineered proteins and antibodies have been achieved in the last decade. As a consequence, bioprocess fluids obtained following upstream cell culture can have much higher viscosities and present difficulties during certain downstream purification operations.
SK: Among the factors that define the injectability of a drug from the perspective of required injection force, the solution viscosity is the major parameter that can really be optimized. Other parameters, such as the geometry of the needle and syringe barrel, can only be altered so much, when keeping the syringe handling and the potential pain during the injection in mind. Consequently, protein viscosity is often a limiting factor when trying to achieve a certain target protein concentration in formulation.
TR: One of the most common approaches to reducing viscosity is to use excipients. Other options could be the use of drug delivery devices that allow for greater injection forces and volumes, which would not directly address the viscosity challenge. Such a device, however, would come with other formulation challenges due to the high shear stress experienced by the drug substance, which could impact its structural stability.
TR: Formulators today most often choose a single excipient — generally an amino acid — to reduce the viscosity of a protein formulation. Viscosity-reducing excipients on the market today, however, do not always work for different proteins and antibodies. Others reduce viscosity but also result in protein destabilization when used at elevated concentrations.
SK: When we looked at the impact of various excipients on the viscosities of formulations of two representative monoclonal antibodies (mAbs) — infliximab at a concentration of 120 mg/mL and evolocumab at 170 mg/mL — the results varied significantly. For some excipients, the viscosity-reduction effect increased with increasing excipient concentration, and for others there was no change or an increase in viscosity was observed. In general, it was concluded that doubling the concentration of an excipient does not typically lead to improved viscosity reduction.
TR: Separately, we also know that changes in pH — the most critical parameter in formulation development — lead to changes in the number of charges present on proteins, and thus the forces that influence the viscosity of protein formulations may be different at different pH levels. It should be expected, therefore, that different excipients may be required to formulate the same protein under different conditions. We could show that this is the case even though the chemical properties of the excipient do not change significantly at a different pH.
In general, we determined from our research that single excipients are often not sufficiently able to reduce protein viscosity and maintain protein stability.
TR: Since we found that one excipient isn’t sufficient, we explored the impact of combining two different types of excipients to see if that could lead to improved performance. What we found was that, when used in combination, an amino acid and an anionic excipient are more efficient at reducing viscosity than when either is used alone, even at higher concentrations. They can even perform synergistically, enabling improved viscosity reduction and a better balance of viscosity versus stability. Because it is possible to use lower concentrations of each excipient, negative impacts on protein stability are avoided.
SK: We confirmed these results with the same two representative mAbs from our earlier studies using various combinations of amino acid and anionic excipients. Certain combinations worked well for each mAb, which not only have different structures but different formulation characteristics.
Regardless, we were able to identify excipient combinations that provided reduced viscosity levels more effectively than the leading industry standard.
TR: Our goal with the Viscosity Reduction Platform is to provide a toolbox of excipients that afford formulation scientists the greatest opportunity to identify the right combination of excipients for reducing viscosity and maintaining protein stability for a given protein or antibody under specific formulation conditions. It is based on five components that are intended to be used in up to nine different combinations, always including one amino acid and one anionic component.
SK: The ability to vary these excipient combinations gives formulation scientists a high degree of flexibility for balancing formulation viscosity and protein stability, as well as helping to meet target pH levels and enable desired routes of administration.
I also want to point out that all of the components in our SAFC® Viscosity Reduction Platform have been used in human applications, most in parenteral formulations in the past, either as parenteral nutrition agents (which we consider to be APIs), as counterions to APIs, or for pH adjustment. We can provide the respective safety evaluations from a European registered toxicologist.
SK: Our various studies confirmed that the excipient combinations offered through the SAFC® Viscosity Reduction Platform allow for a better balance of protein stability versus protein viscosity. They not only enable subcutaneous delivery while preserving long-term stability; they make the treatment as a whole more patient-friendly and more economical. As importantly, the Viscosity Reduction Platform provides formulation scientists with a variety of options for formulation development that take the route of administration and the requirements of the protein into account.
TR: Viscosity-reducing excipients, when used in the right combination, allow formulators to reach higher maximal protein concentrations, including for recombinant proteins, plasma proteins, and antibody-based drugs. Plasma proteins are a notable example, because the typical treatment volumes are high, and thus approaches that allow an increase in the maximum dose per volume would be highly beneficial for patients.
The Viscosity Reduction Platform can also facilitate the manufacture of high-viscosity protein products. For instance, during tangential flow filtration (TFF) for the ultrafiltration/diafiltration step preceding fill/finish operations, very high protein concentrations are achieved, which creates a back pressure in the system that can be challenging to manage. Reducing the viscosity would reduce these issues during this important step. We have shown that a significant increase in protein concentration can be achieved with a reduced processing time by using combinations from the SAFC® Viscosity Reduction Platform.
For some proteins that are too viscous to process at typical processing temperatures (2–8 °C), manufacturing operations are performed at room temperature despite the risk of protein degradation. In this case, the use of Viscosity Reduction Platform excipient combinations could reduce the viscosity while maintaining stability and allow processing to proceed at typical operating temperatures.
In both cases, lower viscosities would generally lead to reduced processing times. This greater efficiency would lead to the added benefit of lower operating costs.
SK: Our SAFC® Viscosity Reduction Platform was launched in early October 2021, and we are currently making technical samples available to customers for evaluation. We have a test kit that contains technical-grade samples of the five viscosity-reducing excipients included in the platform, along with a detailed user guide describing proof-of-concept screening procedures.
Customers that are interested in a specific combination of excipients for the formulation of a protein of interest can obtain a commercial technology license. The benefit for the customer is the opportunity to exclusively protect that specific solution.
Eventually, all of the components in the platform will be made available at commercial scale under our Emprove® Program, which combines high-quality products, comprehensive documentation, and superior customer support to facilitate qualification, risk assessment, and process optimization.
Tobias Rosenkranz heads the Biomolecule Formulation team in the Liquid Formulation R&D department in Darmstadt. His lab mainly focuses on formulation challenges arising in protein formulations, such as protein viscosity and aggregation. A biophysicist by training, he holds a PhD from the HHU Düsseldorf/Research Centre Jülich. Prior to joining the company in 2017, Tobias was a basic researcher at UIUC (US) and UNSW Australia.