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For antibody drugs, what is usually referred to as high-concentration formulations are formulation products with a final antibody concentration of >100mg/ml. Currently, about one-third of FDA-approved monoclonal antibody products are high-concentration formulations (>100mg/ml), of which close to 80% were approved after 2015, which shows that there is an increasing demand for high-concentration formulations in the biological industry.
Advantages and Challenges of High-concentrated Formulations
Advantages
The advantages of high-concentration formulations are self-evident, especially in subcutaneous injections, which require a concentration of 100mg/ml or more due to the limitation of the volume of subcutaneous injections.
Challenges
The challenges associated with high-concentration formulations include increased viscosity of the material, volume exclusion issues, the Donnan effect, system hardware design and scale-up issues.
1. Increased viscosity of the material
As the concentration increases, interactions between protein molecules are enhanced which results in viscosity rises, mobility deteriorates, and severe flux attenuation.
2. Volume exclusion issues
At high concentrations, the permeate concentration of relatively small solute components upstream and downstream of the membrane changes, leading to an increase in permeate pressure.
3. The Donnan effect
Charged solutions are trapped by the ultrafiltration membrane, and charge interactions result in uneven distribution of the charged solutes on both sides of the membrane, leading to changes in concentration and pH.
4. System hardware design and scale-up issues
During the scale-up process, the system needs to be designed with a minimum working volume in mind to avoid sample loss.
There are improvements in structural design in Cobetter's conventional screen ultrafiltration TFF cassettes, so they have certain advantages in high-concentration formulation production.
Examples
The following are examples of Cobetter's conventional screen TFF cassettes in the application of high-concentration formulations:
Case 1
Lab scale, monoclonal antibody product
TFF Cassette Format: UFCLA0030010P (RC, 30 kDa, 0.11m²)
Sample information: Monoclonal antibody product, the initial concentration of the solution is 18g/L, and the inlet flow rate is 550ml/min, the performance is shown in the table below.
Table 1 Test Results
In the late stage of the experiment, with the increase in concentration, the viscosity of the solution increased exponentially, the inlet pressure increased obviously, and it was necessary to continuously reduce the inlet flow rate to control the pressure increase. The experiment was stopped when the inlet flow rate was reduced to 1/6 of the initial flow rate, and the sample recovery reached 98% after flushing with the buffer which is 2 times the working volume. After the experiment, washing with 0.1 M NaOH for 30 min, the water flux of the cassette was recovered by 92% before and after use.
Case 2
Lab scale, monoclonal antibody product
TFF Cassette Format: UFCLA0030001P (RC, 30 kDa, 0.01m²)
Sample information: Monoclonal antibody product, the initial concentration of the solution is 21g/L, and the inlet flow rate is 55ml/min, the performance is shown in the table below:
The trend of inlet pressure and flux with time during the experiment is shown in the figure below:
During the experiment, the pressure change was obvious, and it was necessary to constantly adjust the retentate valve. Stopped the experiment after the concentration factor had reached the requirement, then flushing with the buffer that is 2 times the working volume. The sample recovery rate reached 95%. After the experiment, use 0.1M NaOH to clean for 30 min, and the water flux of the TFF cassette recovered 93%.
Case 3
Pilot scale, monoclonal antibody product
TFF Cassette Format: UFCFL0030250P (RC, 30kDa, 2.33m²)
Sample information: Monoclonal antibody product, the initial concentration of the solution is 14g/L, and the inlet flow rate is 699ml/min, the performance is shown in the table below:
The sample recovery rate reached 93% after flushing with the buffer that is 2 times the working volume and emptying the air. After the experiment, used 0.1M NaOH to clean for 30 min, and the water flux of the TFF cassette resulted in 100% recovery before and after use.
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