managing-high-viscosity-in-bsab-drug-products
Struggling with high viscosity in your bispecific antibody drug products? As patient convenience drives demand for high-concentration formulas, this challenge can lead to costly late-stage delays. Learn how to address this tough problem with smarter, more predictive strategies.
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Managing High Viscosity in Bispecific Antibody Drug Products
FAQ
Current Situation
Typical Market Trends
Current Challenges and How They Are Solved
How Leukocare Can Support These Challenges
Value Provided to Customers
Managing High Viscosity in Bispecific Antibody Drug Products
For the attention of the Director of CMC and Drug Product Development: A look into a persistent challenge.
High viscosity in biologic drug products is a familiar problem, but one that takes on new complexity with bispecific antibodies (bsAbs). As we push for more convenient subcutaneous (SC) delivery, the need for high-concentration formulations intensifies. This often leads to solutions that are too thick to inject easily, creating a significant hurdle in late-stage development. This isn't a new issue, but as more intricate antibody formats advance, it's a challenge we need to address with smarter, more predictive strategies to prevent costly delays.
Current Situation
The core of the problem is physical. To achieve a low injection volume for SC delivery, high protein concentrations are necessary. However, for bsAbs, with their complex and often asymmetric structures, high concentrations frequently lead to strong intermolecular interactions. These interactions cause the molecules to effectively stick together, increasing the solution's viscosity. The result can be a formulation that is difficult to manufacture and nearly impossible to administer with a standard syringe, jeopardizing the patient-centric goals of the product.
Typical Market Trends
The pharmaceutical market is clearly moving toward patient convenience. Subcutaneous injections are preferred over intravenous (IV) infusions by both patients and healthcare providers because they can often be self-administered at home.[1, 2, 3], , This trend directly fuels the demand for high-concentration, low-volume drug products. One meta-analysis found that 82% of patients with immune disorders preferred SC over IV administration.[2]
Concurrently, the pipeline of complex biologics is growing. Bispecific antibodies, in particular, represent a rapidly expanding class of therapeutics, with the market projected to grow at a CAGR of over 44% between 2024 and 2032.[6, 7], These engineered molecules are often more susceptible to aggregation and high viscosity due to their unique structures and surface properties, making formulation a critical challenge.[8, 9],
In response, the industry is increasingly adopting predictive tools and high-throughput screening methods in early development.[10]The goal is to identify and mitigate potential viscosity issues early, ensuring that the most "developable" candidate moves forward and avoiding late-stage surprises.
Current Challenges and How They Are Solved
The primary challenge is to develop a formulation that is stable and effective, yet has a viscosity low enough for SC injection, typically below 25 cP.[11]High viscosity can make a product difficult to withdraw from a vial, push through a needle, and can cause pain for the patient.[12, 16]
Companies are currently tackling this issue in several ways:
Formulation Excipients: The most common strategy is to add excipients that disrupt the intermolecular interactions causing high viscosity. Salts, sugars, and amino acids like arginine are frequently used.[13, 14, 15], Arginine, for instance, can be effective at shielding protein charges and reducing viscosity, but its success is highly dependent on the specific antibody and formulation conditions.[16]Finding the right excipients often involves a significant amount of screening and optimization.[17]
Protein Engineering: Another path is to modify the antibody's amino acid sequence to reduce its tendency to self-associate. This involves identifying the "sticky" patches on the protein surface and making targeted mutations.[12, 16]While potentially very effective, this must be done early in the candidate selection phase and carries a risk of impacting the drug's efficacy or stability.
Advanced Delivery Devices: Some companies are exploring specialized delivery devices capable of handling higher viscosities. However, this approach may compromise patient comfort and is often seen as a less desirable workaround.
Enzymatic Co-formulation: The use of enzymes like hyaluronidase, which temporarily loosens the subcutaneous tissue to allow for larger injection volumes, is another strategy. This approach doesn't lower the drug product's viscosity but can help in delivering the required dose.
Each of these solutions has its merits and drawbacks. The challenge for a CMC leader is to choose the right strategy based on the specific molecule, development stage, and overall program goals.
How Leukocare Can Support These Challenges
At Leukocare, we address high viscosity not as a simple screening problem, but as a complex biophysical challenge that requires a deep, molecule-specific understanding. Our approach is designed to be rational and predictive, saving time and material.
We begin by using a suite of biophysical tools to understand the specific molecular interactions driving viscosity for your bsAb. Based on this data, we design a tailored formulation strategy. Our AI-supported platform helps to predict formulation stability, ensuring that the low-viscosity solution we create is also a robust one. We work as a collaborative partner, providing the strategic insights and structured data needed to build a compelling CMC package for both internal decision-making and regulatory submissions.
Value Provided to Customers
Our approach offers several distinct advantages for companies developing bsAbs:
Accelerated Timelines: By moving beyond trial-and-error, we can identify an optimal, stable, and low-viscosity formulation more efficiently.
De-risked Development: We tackle formulation challenges early, reducing the risk of costly late-stage setbacks and ensuring a smoother path to the clinic.
A Strategic Partnership: We provide more than just data. We offer proactive, solution-oriented support, acting as a true extension of your CMC team. We understand the pressures you face and provide the clear communication and strategic thinking needed to succeed.
For a Director of CMC, managing viscosity in a bsAb program is about more than just finding a workable formulation. It's about ensuring the program stays on track, meets its deadlines, and ultimately delivers a product that is safe, effective, and convenient for patients. A data-driven, strategic approach to formulation is key to achieving that goal.
FAQ
Q1: At what point in development should we start worrying about viscosity?
Ideally, as early as possible. Early screening of viscosity and other developability parameters during candidate selection can help you choose a molecule with more favorable properties from the start. If that's not possible, addressing it during early formulation development is critical.
Q2: We've tried arginine and it didn't work. What are our other options?
While arginine is a common choice, it's not a universal solution.[16]The effectiveness of an excipient depends on the specific protein and the nature of the intermolecular interactions. There are many other excipients and combinations to explore, including other amino acids, salts, and novel excipients. A systematic approach based on understanding the underlying cause of viscosity is often more successful than random screening.
Q3: How much material do you need for an initial viscosity assessment?
We understand that material is often precious, especially in early development. Our initial biophysical characterization and screening studies are designed to be as material-sparing as possible.
Q4: Can you guarantee that you can lower our viscosity to our target level?
While we cannot guarantee a specific outcome for every molecule, our systematic, data-driven approach significantly increases the probability of finding a successful formulation. We will provide a clear, evidence-based assessment of what is achievable for your specific bsAb.
Q5: We are a CDMO that doesn't have in-house formulation expertise. Can you work with us?
Yes. We frequently partner with CDMOs to provide specialized formulation development services. We act as a neutral, external partner, allowing you to offer a more comprehensive service to your clients. We are committed to the CDMO relationship and operate as a seamless, integrated part of your team.
