4. Bioreactor Scale-up 1. BioMax Corporation is developing a monoclonal antibody and they need your help. They need to make preclinical (pK and toxicology) and Clinical (Phase I) material for their clinical program. 2. The company has developed a cell line that produces about 500 mg/L in a batch culture in 7 days. 3. Cell density: Start at 0.5 MM/mL, max 15 MM/mL, end viability =50% 4. Specific productivity of these cells are at qp=25 pg/cell/day 5. The cells have a specific oxygen consumption of qO2=0.25 uM/MM-hr 6. A research cell bank (RCB) is made and kept frozen in LN2 freezer (a total of 20 vials of RCB) 7. They would like to develop a fed-batch process and optimize it. The targeted process will look like this: a. Starting cell density: 0.5 Million cells/mL b. Titer =3 g/L c. Culture duration= 14 days d. Viability at the end of the culture >60% e. Chemically defined medium and feeds f. 3 step purification steps g. Overall yield >60% (bioreactor to final vial) h. Final formulation: 20 mg/mL i. Fill volume: 2 ml in a 3ml vial (liquid formulation) 8. The size of the preclinical and clinical trials are as follow: a. Preclinical: 250 vials are needed from a GLP lab b. Clinical: 8000 vials are needed from a GMP facility 1. Preclinical material: a. Calculate the amount of material (in grams) to be made in the bioreactor based on preclinical trial needs b. Calculate the size of the bioreactor (in Liters) to be used Based on answer (1b) above 1. Calculate the dimensions of the bioreactor, Diameter, Height, Impeller diameter, Cross sectional area (A), etc. In terms of impeller, the bioreactor for preclinical study will have a pitched blade impeller operated at 200 rpm 2. What are the Oxygen Transfer Rate (OTR) Requirements of the cells at a maximum cell density of 20 MM/mL? 3. What is the kla requirement is pure O2 is used in the gas and the DO is maintained at 50% air saturation 4. The bioreactor for preclinical study will have a microsparger and it can maintain DO at 20 MM/mL densities with a gas flow rate of 1 Liter per minute. What is the vvm and what is the gas superficial velocity (u=Qg/A) 5. Using kla=a(RPM)^b(vvm)^c correlation with b=0.35 and c=0.75, what is the value of a for kla correlation? 6. Make a note of these values as you will be using them for the scale-up later 2. clinical material: a. Calculate the amount of material (in grams) to be made in the bioreactor based on Phase I trial needs b. Calculate the size of the bioreactor (in Liters) to be used Based on answer (1b) above 7. Calculate the dimensions of the bioreactor, Diameter, Height, Impeller diameter, Cross sectional area (A), etc. 8. What should be the agitation rate for the GMP bioreactor (the small bioreactor use 200 rpm)? 9. Using the kla correlation kla=a(RPM)^b(vvm)^c with b=0.35 and c=0.75. What is the vvm of oxygen needed in GMP bioreactor? 10. What is the gas superficial velocity (u=Qg/A) in the GMP bioreactor?
4. Bioreactor Scale-up 1. BioMax Corporation is developing a monoclonal antibody and they need your help. They need to make preclinical (pK and toxicology) and Clinical (Phase I) material for their clinical program. 2. The company has developed a cell line that produces about 500 mg/L in a batch culture in 7 days. 3. Cell density: Start at 0.5 MM/mL, max 15 MM/mL, end viability =50% 4. Specific productivity of these cells are at qp=25 pg/cell/day 5. The cells have a specific oxygen consumption of qO2=0.25 uM/MM-hr 6. A research cell bank (RCB) is made and kept frozen in LN2 freezer (a total of 20 vials of RCB) 7. They would like to develop a fed-batch process and optimize it. The targeted process will look like this: a. Starting cell density: 0.5 Million cells/mL b. Titer =3 g/L c. Culture duration= 14 days d. Viability at the end of the culture >60% e. Chemically defined medium and feeds f. 3 step purification steps g. Overall yield >60% (bioreactor to final vial) h. Final formulation: 20 mg/mL i. Fill volume: 2 ml in a 3ml vial (liquid formulation) 8. The size of the preclinical and clinical trials are as follow: a. Preclinical: 250 vials are needed from a GLP lab b. Clinical: 8000 vials are needed from a GMP facility 1. Preclinical material: a. Calculate the amount of material (in grams) to be made in the bioreactor based on preclinical trial needs b. Calculate the size of the bioreactor (in Liters) to be used Based on answer (1b) above 1. Calculate the dimensions of the bioreactor, Diameter, Height, Impeller diameter, Cross sectional area (A), etc. In terms of impeller, the bioreactor for preclinical study will have a pitched blade impeller operated at 200 rpm 2. What are the Oxygen Transfer Rate (OTR) Requirements of the cells at a maximum cell density of 20 MM/mL? 3. What is the kla requirement is pure O2 is used in the gas and the DO is maintained at 50% air saturation 4. The bioreactor for preclinical study will have a microsparger and it can maintain DO at 20 MM/mL densities with a gas flow rate of 1 Liter per minute. What is the vvm and what is the gas superficial velocity (u=Qg/A) 5. Using kla=a(RPM)^b(vvm)^c correlation with b=0.35 and c=0.75, what is the value of a for kla correlation? 6. Make a note of these values as you will be using them for the scale-up later 2. clinical material: a. Calculate the amount of material (in grams) to be made in the bioreactor based on Phase I trial needs b. Calculate the size of the bioreactor (in Liters) to be used Based on answer (1b) above 7. Calculate the dimensions of the bioreactor, Diameter, Height, Impeller diameter, Cross sectional area (A), etc. 8. What should be the agitation rate for the GMP bioreactor (the small bioreactor use 200 rpm)? 9. Using the kla correlation kla=a(RPM)^b(vvm)^c with b=0.35 and c=0.75. What is the vvm of oxygen needed in GMP bioreactor? 10. What is the gas superficial velocity (u=Qg/A) in the GMP bioreactor?
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