In this podcast, we spoke to Tom Watson, Group Leader, Product Management – Biotech Division, Gregor Kalinowski, Manager SLS Purification Consultants Europe, and Aude Iwaniec, R&D Bioprocessing Team Leader, all from Pall Corporation, about why high concentration mAbs are an increasingly important part of the biotech landscape, current manufacturing challenges and solutions, and future trends.

High concentration drugs offer benefits for patients

I began the discussion by asking why high concentration mAbs are an important topic in today’s biotech landscape. Tom explained that high concentration drugs are an important innovation because when a biotech drug can be prepared at high concentration that is administrable, it is usually self-administered in a subcutaneous mode. This method of delivery brings lifestyle benefits to patients and reduces health care costs because it negates the need for an intravenous treatment. Subcutaneous biotech drugs have been available for a while, but recently more companies are developing new drugs or formulating existing ones at high concentration.

High concentration mAb manufacturing vs. more traditional mAb production

I followed up by asking what some of the differences in terms of manufacturing high concentration mAbs versus more traditional mAb production are. Tom described that a mAb or recombinant protein for subcutaneous delivery is going to be prepared at a high concentration. Starting with the final concentration steps, it is common to have a highly viscous fluid of 10 to 30 centipoise, with a concentration of greater than 100 grams per liter and often higher than 250 grams per liter.

He went on to say that the concentration step reduces the volume of the fluid processed across the subsequent unit operations that are typical of a biotech process. What happens then is a reduction in the dosage volume, since you only need 1 to 2 milliliters of a highly concentrated biotech drug for therapeutic effect. So, typically there are small dosage volumes, or in some cases dosage volumes can be several milliliters to permit a slightly longer-term infusion of a subcutaneous drug.

However, viscosity makes processing the fluid more challenging across the unit operations including the concentration step itself, but also through filtration, mixing, freeze/thaw, formulation, and dispensing. In addition, the smaller batch volumes that correspond with the increased concentration of the drug raises the cost of the Active Pharmaceutical Ingredient (API) per unit volume and this results in more significant impact with any product loss.

Manufacturing challenges with high concentration drugs

Next, we discussed some of the main challenges that exist in manufacturing workflows for high concentration mAbs. Tom said that he repeatedly hears from customers about challenges relating to product loss in hold up volume, aggregation of the molecules, limitations with analytical equipment and sampling procedures, and destabilization of filtered fluid due to the stripping out of formulation components.

Achieving high product concentrations

I then asked Gregor about the specific challenges to achieving high product concentrations. He explained that product viscosity is increasing with increasing product concentration. So, for a given crossflow, the pressures are also increasing with increasing product concentration. He went on to say that the permeate flux is decreasing with increasing product concentrations and therefore the processing times become longer, and the number of pump passes are much higher compared to low concentration processes. This combination of extended recirculation time and the increased concentration carries a significant risk of shear related damage that may impact the product quality. Finally, the high viscosity of the final retentate pools typically results in a poor recovery from TFF systems because of limited drainability.

I followed up by asking him which solutions can be applied to overcome these new challenges in the final ultrafiltration/diafiltration (UFD) step? He said that first, an optimization of the TFF cassettes screen type. For example, a coarser screen or suspended screen can be applied, then the resulting cassette pressure drop can be used to process high viscous material.

Alternatively, single pass TFF significantly reduces the shear exposure because the entire concentration step is performed in a single pass without a recirculation. This is especially important for sensitive products like sensitive plasma proteins, and plasma derived factors as well as shear sensitive viral particles, as single pass TFF offers a significant reduction in cumulative shear exposure because of the single pass.

He went on to say that for high concentrations and high viscosities they have demonstrated concentrations exceeding 250 mg/mL for IgG with single pass TFF technology or even higher concentrations with plasma proteins. The single pass TFF applies a serialized flow path and therefore the feed flow requirement of a single pass TFF system is significantly reduced when compared to a parallel membrane conventional TFF configuration. As a result, the single pass TFF system hold up volume is considerably smaller when compared to a conventional TFF system. The reduced hold up volume of the single pass TFF system also allows for enhanced product recovery, higher step yield, and higher final concentrations. Typical yields at high concentration from single pass TFF systems are equal or greater than 98%, whereas conventional TFF system yields can be as low as 80% or less.

High concentration filtration

Next, I asked Aude about other types of filtration, including direct flow. She said that higher concentration causes a significant increase in viscosity and that also affects the sterilizing grade filtration after the concentration step for the final formulation and fill. Higher viscosity has a direct impact on the filtration flux and that causes higher processing time. With higher concentration there is a likelihood of having higher aggregate content compared to lower concentration mAbs and this will in turn impacts the sterile filter capacity. It can cause your current filter size to block earlier that you would expect. So again, this means that it will increase your processing time or you might need a larger filter.

She then offered her thoughts about solutions. She said that the first approach one might consider in overcoming this challenge would be to use a larger device size for a specific batch size. However, you need to keep in mind that using a larger device size is likely to increase your non-recoverable volume at the end of the sterilizing grade filtration process.

She went on to say that that high concentration drugs are highly valuable, so the processing yields in each step is a critical factor to keep in mind. Something else to consider when thinking about larger device size and therefore larger membrane surface area, is that it could impact other product attributes such as excipient concentration. The research shows that polysorbate, which is used as an excipient in mAb formulation, might adsorb to sterilizing grade membrane. Using a larger device, and therefore a larger surface area for the same batch size, might increase the polysorbate adsorption which in turn could decrease your polysorbate concentration; particularly at the beginning of your filtration.

High concentration drug production solutions

I then asked what else Pall has been working on over the past couple of years to provide solutions suited for high concentration drug production. Tom described a diversity of products well suited to late-stage processing of monoclonals and recombinant proteins, not just direct flow filters or tangential flow filters as discussed. For example, their freeze and go storage and transport solutions, polymeric filling needles, and mixers all have attributes to help sustain critical product quality attributes for a concentrated drug. These products also help minimize costly losses that could be incurred by using technologies that have limited performance with high concentration feeds. In complement to their product offering, Pall also has a validation services team. The team recognizes that generating large sample volumes for process specific validation can be difficult with high concentration feeds, so they offer filter validation studies for fluid volumes in the range of several 100 milliliters rather than a couple of liters that would traditionally be utilized for process specific filter validation.

Tom also shared that Pall is proud of their Allegro™ Connect bulk filling system. The recently launched system permits the integration of direct flow filters with high capacity for viscous feeds into a bulk filling manifold. This system automates the critical late stage filtration and dispensing step and has several features designed to maximize recovery of the high value filtered fluid.

I then asked how companies can maximize productivity for their high concentration drugs? Tom explained that it is all down to selection, making sure that you’ve implemented the right equipment in your unit operations. It is important to seek out crossflow tangential flow filtration technologies that reduce shear and permit easy recovery of concentrated fluid. Second generation design, high area sterilizing grade filters with asymmetric PES media can enable smaller footprint filtration systems with less dead volume to occupy non-recoverable/hard to recover hold up.

He added that another thing to do is always look towards vendors of single-use systems that are keen to explore your recovery challenge, who when presented with the problem of line loss will try and come up with ideas to minimize them through clever system design, appropriate orientation, or construction of components that help facilitate that fluid recovery and, of course, keep an eye on the newest products from established vendors or service providers in the biotech industry.

Manufacturing problems and solutions – real life examples

Next, I asked about examples from his work with customers that demonstrate real life manufacturing problems and solutions that were implemented. Tom shared that he has been engaging with customers who are looking to adapt existing manufacturing platforms to handle high concentration feeds. He described that he recently had a customer that was looking to design a new filtration system that could filter low concentration drugs as well as high. They discussed with Pall their expected batch volumes, process parameters, viscosity ranges and Pall set up a thorough filtration study to help the customer determine suitable filtration scenarios. So, Pall futureproofed their facility for high or low concentration drugs.

Current and future trends

I asked about current trends in this area and where we are going from here. Tom said that there is a trend towards customers adapting their production platforms to give them greater flexibility to produce final drug for subcutaneous delivery. There’s been quite a bit of talk around how a high concentration drug can be practically manufactured and reliably administered to a patient. Pall is keeping an eye on that and will be ready to see how products can handle fluids at higher concentrations than the upper end of the range (around 250 grams per liter) that we tend to see today.

I closed by asking if anyone had anything else that they would like to add. Tom said he really enjoyed the discussion, and he reaffirmed how highly motivated Pall is in solving customers challenges in biotech. They intend to be a big part of the development and manufacture of the next generations of biotech blockbuster drugs.

To learn more, please see the white paper – High Concentration Monoclonal Antibody Drugs – Manufacturing challenges