Methods, apparatuses, and systems for continuously inactivating a virus during manufacture of a biological product

A method of use of a system for continuously inactivating virus during manufacture of a biological product, the system comprising:

• a perfusion bioreactor;
• and
• an apparatus comprising:
• an initial-mixing vessel;
• a pre-treatment detector chamber;
• a pre-treatment hold reservoir;
• a drain valve;
• and
• a treatment vessel that comprises an inlet, an outlet, and a static mixer, the inlet and the outlet being positioned at opposite ends of a major axis of the treatment vessel and the static mixer being internal to the treatment vessel along the major axis;
• wherein:
• the initial-mixing vessel, the pre-treatment detector chamber, the pre-treatment hold reservoir, and the treatment vessel each have an internal volume and are fluidically connected in series;
• the drain valve is either connected to, and positioned between, the pre-treatment hold reservoir and the inlet of the treatment vessel, or connected to the outlet of the treatment vessel;
• and
• the ratio of the internal volume of the pre-treatment hold reservoir to the internal volume of the treatment vessel is 0.003 to 0.06;
• wherein:
• the perfusion bioreactor and the apparatus are connected via the initial-mixing vessel;
• and
• the perfusion bioreactor has an internal volume that is 5 to 2400 fold greater than the internal volume of the treatment vessel;
• and the method comprising the steps of:
• (0) transferring, from the perfusion bioreactor to the apparatus via the initial mixing vessel, a composition comprising a biological product;
• (1) combining, in the initial-mixing vessel:
• (a) the composition comprising the biological product;
• and
• (b) a composition comprising a virus-inactivation reagent, to obtain:
• (c) a treatment composition having a predetermined property for inactivation of a virus;
• (2) confirming, as the treatment composition passes through the pre-treatment detector chamber, that the treatment composition exhibits the predetermined property;
• (3) transferring, via the pre-treatment hold reservoir, the treatment composition to the treatment vessel, the transferring occurring at the inlet;
• (4) incubating the treatment composition in the treatment vessel at a predetermined temperature while the treatment composition flows along the major axis at a predetermined rate and contacts the static mixer, the combination of the predetermined temperature and the predetermined rate being sufficient to cause inactivation of the virus in the treatment composition based on the predetermined property;
• and
• (5) collecting the treatment composition from the treatment vessel at the outlet;
• wherein steps (0) to (5) are carried out continuously.

A method for manufacturing a protein of interest comprising:

• a step (I) of cultivating a host cell in a culture medium with expression of a protein of interest by the host cell;
• at least one step (II) of continuously inactivating a virus during manufacture of the protein of interest;
• and
• a step (III) of recovering the protein of interest from the culture medium;
• wherein step (II) comprises steps of:
• (1) combining in an initial mixing chamber:
• (a) a composition comprising the protein of interest;
• and
• (b) a composition comprising a virus-inactivation reagent, to obtain:
• (c) a treatment composition having a predetermined property for inactivation of a virus;
• (2) confirming that the treatment composition exhibits the predetermined property in a pre-treatment detector chamber;
• (3) transferring the treatment composition to a treatment vessel that comprises an inlet, an outlet, and a static mixer and having an internal volume, the inlet and the outlet being positioned at opposite ends of a major axis of the treatment vessel and the static mixer being internal to the treatment vessel along the major axis, and the transferring occurring at the inlet;
• (4) incubating the treatment composition in the treatment vessel at a predetermined temperature while the treatment composition flows along the major axis at a predetermined rate and contacts the static mixer, the combination of the predetermined temperature and the predetermined rate being sufficient to cause inactivation of the virus in the treatment composition based on the predetermined property;
• and
• (5) collecting the treatment composition from the treatment vessel at the outlet;
• and further wherein steps (1) to (5) are carried out continuously.