Improve Your Process Development To Accommodate Diverse mAbs
By Life Science Connect Editorial Staff
As the monoclonal antibody (mAb) market becomes increasingly complex – think bispecific and trispecific antibodies – strategic and thoughtful process development is top of mind for sponsors and manufacturers. For mAb therapeutics, like all potentially lifesaving medicines, it is vital to determine how to manufacture products faster and more efficiently, streamline and reduce the cost of development, and achieve speed to market to benefit patients as soon as possible. To navigate the uncertainties of mAb manufacturing and its business landscape with more precision, sponsors and manufacturers are striving to understand process development better.
On the recent Bioprocess Online Live event Process Development For A Diverse mAb Pipeline, host and Chief Editor Matt Pillar sat down with Bayer’s senior director of bioprocess technologies, Dr. Amir R. Goudarzi, to discuss the upstream and downstream challenges that mAb developers and manufacturers are navigating their way through. Throughout this wide-ranging discussion, Goudarzi touched on hybrid and continuous manufacturing, the upstream parameters that impact the final performance and process design of mAbs, and the importance of collaboration with regulatory and compliance departments.
Consider The Unique Obstacles To Multispecific Process Development
Upstream
There are a number of upstream parameters that impact the ultimate performance and process design of multispecific antibodies. It all starts with the diversity of cell lines, which can introduce performance variables and different matrix qualities, DNAs, and cell densities. Even platform cell lines may be impacted when used with new modalities. As far as media and feed type diversity, there has been a concerted effort to reduce the cost of goods and increase process productivity. Stakeholders must determine whether simplifying the process or diversifying it works best for the needs of their mAb. Steady supply, regulatory requirements, and proper preparation of media feeds all have the potential to impact multispecifics, especially as scale increases and volume containers get larger. According to Goudarzi, “Your process is much less sensitive at a smaller scale. As you scale up, the variability on the manufacturing side is easier to sense.”
A number of product quality aspects are impacted based on scale. Manufacturers may see large quantities of antibody segments, and in terms of high or low molecular weight, this may be previously uncharted territory for your team. On the bright side, though, Goudarzi notes the learning potential for PD groups. “The challenges regarding scale characterization are inherent, and maybe a fun part for us working in the industry is that element of change. There [may be] a bit of suffering and sweating at some point where you say, I thought I knew how this worked, but in the end it's different.” Goudarzi recommends continually asking the question why prior to running any processes; he cautions that missing something small could lead to large losses. The key thing to keep in mind is that processes must evolve to accommodate more diverse mAbs: “What brought us here won’t necessarily bring us further,” advises Goudarzi.
Downstream and Scale-Up
For multispecific antibodies, the types of unit operations leveraged are not significantly different from those for traditional mAbs; however, the adjustments made by manufacturers make all the difference. Goudarzi notes that multispecific manufacturers make a variety of changes to reduce overall process time. Traditionally, there are two ultrafiltration (UF) steps, one at the beginning and one at the end. However, front-end UF is becoming less and less common.
Goudarzi has seen a range of processes that yield a very large amount of product along with more continuous viral filtration (VF) and formulation applied to deal with the variety of intermediates. He compares the floor level of your manufacturing space to a game of Tetris: “Your floor level is very limited, and you end up actually walking around with these intermediate trolleys, which is why manufacturers utilize a lot of continuous VF and formulation features.”
The process analytical technologies (PATs) used throughout mAb production have evolved significantly over the last decade. Overall, PATs are now measuring at a wider range of concentrations and faster speeds. Take, for example, UV measurements. Goudarzi cites Repligen’s SoloVPE as a system that provides data rapidly and connects directly to the GMP process. With these newfound tech offerings, data is more accessible and built to accommodate a wider range of products.
Bispecifics are catching up to mature naked antibodies with inherited technologies from well-established mAb processes. Advancements around digital automation screening have enabled the ability to generate higher titer products in a shorter period of time. With different modalities, the matrix can have an impact on the necessary steps, and that matrix input quality leads to different concentrations of host cell proteins (HCPs), DNAs, and aggregates that impact the primary capture steps later. Per Goudarzi, “Separation requires some creativity.” You may not easily see precipitation at a smaller scale and likely must test at scale. For the polishing steps, Goudarzi notes that he often sees questions around how to profile, achieve the targeted purity, and conduct removal.
For bispecifics, sponsors must identify the CPPs to be aware of. There are a variety, but one of the most obvious and impactful is hold time, which is often impacted by product instabilities. Goudarzi and his team are assessing what to do to avoid and reduce the negative impact of long hold times on the final product. Luckily, there is a range of solutions. One is to apply continuous or intensified capture to lower the hold time, especially on the front end. Researchers are also assessing ways to aerate cultures and a variety of companies are examining continuous processing solutions.
Assess When And If Continuous Processing Is The Right Choice
Goudarzi and his team have been working steadily on hybrid manufacturing, as well as continuous upstream manufacturing and continuous production technology, via assessments of end-to-end processes. Predominantly, his team favors a hybrid processing style, “where essential questions are addressed on the spot on the capture or harvest side.” If a team prefers continuous manufacturing instead, a critical piece is taking measurements that benefit the process. Many manufacturers are considering whether continuous chromatography is a good fit for their process. According to Goudarzi, “The challenge with regard to continuous chromatography is more about a harmony of operations and automations. The challenge is the startup, commissioning, and cohesion of these systems to arrive at steady state conditions.”
This aspect has led Goudarzi to wonder how often people should consider continuous chromatography when they are doing preclinical or early clinical process development. If you do not have much time, it still requires a lot of process characterization to see what flow the system works best at, as well as the conductivities and pH that apply. It is in your best interest to determine a strategic timeline and budget to transfer your process, scale it up, and run it at commercial scale.
Collaborate With Compliance And Regulatory Early And Often
Goudarzi also recommends consistent and early interactions between PD, compliance, and regulatory departments: “I love to see compliance and regulatory colleagues as partners in the beginning of development. I have seen a lot of questions coming from colleagues who don't have context on quality or process. Please come to the floor, come to the labs, and see what's going on.”
By consistently collaborating, regulatory and compliance teams can readily provide more insight into what components are critical parts of the process to ensure approval from regulatory bodies. Collaboration like this helps ensure the thoughtful process development that is critical for multispecific antibodies. By taking the time to identify the best manufacturing strategies, critical process parameters, and critical quality attributes, and communicating with key experts, you save time and money throughout production of your antibody.
To watch this Bioprocess Online Live event in its entirety, click here.