managing-shear-stress-stability-for-bsabs
Bispecific antibodies offer immense therapeutic potential but pose unique stability challenges, particularly under shear stress during manufacturing. This mechanical force can lead to damaging aggregation, compromising product quality and safety. Discover how to navigate these complexities and ensure your bsAbs remain stable.
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The Balancing Act: Managing Shear Stress Stability for Bispecific Antibodies
FAQ
Current Situation
Typical Market Trends
Current Challenges and How They Are Solved
How Leukocare Can Support These Challenges
Value Provided to Customers
The Balancing Act: Managing Shear Stress Stability for Bispecific Antibodies
If you're a Director of CMC or Drug Product Development, getting a biotherapeutic from the lab to the clinic is a tough, long journey. With bispecific antibodies (bsAbs), that journey has extra technical hurdles. Their intricate, dual-targeting nature makes them powerful, but also fragile. [1] One big challenge during development and manufacturing is making sure they stay stable, especially against shear stress.
Shear stress, a mechanical force created during many common bioprocessing steps like pumping, filtration, and fill/finish, can quietly mess up product quality. [2, 3] These forces can really hurt bsAbs, which tend to clump together more easily than regular monoclonal antibodies (mAbs). [1]
Current Situation
The number of bsAbs in development is growing fast, with experts saying the market will be over $300 billion by 2033. [5] This growth is happening because of their potential to treat tough diseases, especially cancer. [6] The same complexity that makes them good for treating diseases also makes them a real pain to make. [7, 9] Things like low yields, clumping (aggregation), and impurities related to the product are common. [7, 9, 17]
Clumping (aggregation) is a big worry because it can mess up how the product works and, even worse, increase the chance of patients having an immune reaction. [10] The actual structure of many bsAb types, which often mix different antibody parts, can create new spots that easily become unstable. [11] This natural tendency to be unstable means that even regular processing steps that create shear stress need to be looked at closely and managed. [3, 12] While some research suggests that really high, isolated shear rates might not harm proteins, we know that shear combined with other things like air-liquid interfaces can definitely trigger clumping. [13, 14]
Typical Market Trends
The market is definitely shifting to more complex antibody types. We're seeing a push for formulations that patients can inject under their skin (subcutaneous) for easier use, and these often need high protein amounts. [15] This trend creates two problems: high concentration formulations are usually thicker and can clump together more easily when under shear stress.
Another big trend is the push to make processes more intense to improve efficiency and lower costs. This includes strategies like continuous manufacturing and perfusion cell culture. While intensified perfusion looks promising for making bsAb quality better by reducing clumping and breaking apart, it also brings its own shear worries. [16] The market definitely shows we need advanced formulation and processing strategies that can handle these complex molecules without messing them up.
Current Challenges and How They Are Solved
The main challenge for CMC and Drug Product teams is keeping bsAbs in one piece throughout the entire manufacturing process.
Key Challenges:
Naturally Unstable: The complex, often lopsided, structure of bsAbs makes them more likely to unfold and clump than regular mAbs. [1]
Stress from Processing: Common operations like pumping, tangential flow filtration (TFF), and the final fill/finish step all create shear stress, which can lead to clumping and particles forming. [3, 12]
High Concentration Formulations: The shift towards subcutaneous delivery means we need high-concentration products, which can make them thicker and more likely to clump.
Lots of Different Impurities: BsAb production can create many different impurities related to the product, including mispaired chains and fragments, making it harder to purify and raising the risk of clumping in the final product. [17, 9]
Current Solutions:
Teams are handling these problems by combining process fine-tuning and early-stage formulation work. Designing the sequence during discovery can help create more stable molecules right from the start. [10] In downstream processing, teams focus on fine-tuning things like flow rates and pressures to reduce shear. Chromatography steps are carefully developed, sometimes using multimodal resins, to get rid of clumps well. [18]
Formulation development is super important. Scientists test different ingredients (excipients) like surfactants and sugars, and fine-tune buffer conditions like pH to find a mix that best protects the bsAb from stress. [19] This often involves a lot of trying things out and takes a long time. The aim is to create a strong formulation that can handle tough manufacturing, storage, and delivery conditions. [1]
How Leukocare Can Support These Challenges
This is where teaming up with formulation specialists can really help. At Leukocare, we tackle these challenges by getting advanced formulation development involved early in the process. We know that formulation isn't just the last step, but a key part of making a successful drug product.
Our approach is based on really knowing about protein biophysics and the stresses molecules face during manufacturing. We use our own special, algorithm-based platform that draws on a huge database of ingredients (excipients). [20] This lets us go beyond the usual, limited ingredients and look at many more options to find the best stabilizing mix for a specific bsAb. [20]
Instead of just trying things out, our smart, data-driven way helps us predict and create formulations designed to protect against specific stresses like shear. We can work with your CMC team to suggest things for buffer development and other process settings that can affect stability, helping connect upstream and downstream development. [20]
Value Provided to Customers
For a Director of CMC, teaming up with Leukocare means real benefits by solving key problems.
Making Development Less Risky: By finding potential stability problems early and creating a strong formulation, we help reduce the chance of late-stage failures that can stop a project. Our approach aims to create a stable base for your drug product, giving you confidence as you head to clinical trials and commercialization.
Speeding Up Timelines: Our predictive, algorithm-based approach can really shorten formulation development timelines compared to older 'try it and see' methods. This means getting to a stable, manufacturable formulation faster, which is a huge advantage in a competitive market.
Keeping Your Product Intact: We design formulations specifically to protect against stresses from processing, including shear. The result is a more stable product that's less likely to clump, helping make sure it's safe and works well.
Making Advanced Formulations Possible: We can help you with the demand for high-concentration, subcutaneous formulations by developing solutions that stay stable and control how thick they are, even at challenging concentrations.
Our goal is to be your strategic partner, like a co-pilot on your development journey. We give you the specialized formulation knowledge so your team can focus on what they do best, confident that your bsAb's stability is in expert hands.
FAQ
Q1: At what stage should we start thinking about shear stress stability for our bsAb?
The earlier, the better. Bringing in formulation and stability considerations, including shear stress, during process development is best. Getting involved early helps create a formulation that can protect the molecule through all later manufacturing steps.
Q2: How does Leukocare's approach differ from traditional formulation development?
Our approach is different because of our smart, data-driven way. We use our own special, algorithm-based platform and a huge database of ingredients (excipients) to design formulations, rather than just doing limited, standard tests. [20] This makes it a more focused and faster way to get to a stable and strong formulation.
Q3: Can a good formulation really protect a bsAb from the high shear forces in a fill/finish line?
Yes, a well-designed formulation can really protect a bsAb. By fine-tuning the mix of stabilizers, we can improve how the molecule holds its shape and stays dispersed, making it tougher against the mechanical stresses it faces during processing, including fill/finish operations. [3]
Q4: Our bsAb is especially likely to clump. How can you help?
We are experts at formulating tricky proteins. Our platform helps us tackle the specific ways your molecule breaks down. We can design a formulation that gets to the bottom of why clumping happens, whether it's caused by shear, surface stress, or other things, giving you a customized solution for your specific bsAb.
Q5: We are developing a high-concentration formulation. What are the key considerations for shear stress?
High-concentration formulations come with their own challenges, as increased thickness can make the effects of shear stress worse. Our development process considers this, focusing on ingredient mixes that not only make the protein stable but also help control its thickness, making sure the product is both stable and easy to make.
