Novel Method For Producing Low Viscous And Highly Concentrated Biopharmaceutical Drug Products In Liquid Formulation

Abstract

The present invention relates to a method of producing low viscous and highly concentrated biopharmaceutical drug products comprising a biomolecule of interest, the method comprising: (a) a first phase of preparing a drug substance of the biomolecule of interest, said first phase comprising at least one processing step selected from (a1) harvesting, (a2) purification, (a3) re-buffering, and (a4) enrichment, wherein said at least one processing step in this first phase is carried out in the presence of a composition comprising at least three amino acids, wherein the combination of said at least three amino acids provides at least one positively charged functional group, at least one anti-oxidative functional group, at least one osmolytic function, and at least one buffering function, and (b) a second phase of further processing the drug substance prepared in (a) to obtain a low viscous and highly concentrated biopharmaceutical drug product, said second phase comprising at least one processing step selected from (b1) re-buffering, (b2) freezing, (b3) thawing, and (b4) filling; wherein said at least one processing step in this second phase is carried out in the presence of a composition comprising (i) at least three amino acids, wherein the combination of said at least three amino acids provides at least one positively charged functional group, at least one anti-oxidative functional group, at least one osmolytic function, and at least one buffering function; and (ii) one or more sugar(s); in an amino acid:sugar ratio between 10:1 to 1:100 (w/w). The present invention further relates to a low viscous and highly concentrated biopharmaceutical drug product obtained or obtainable by the method of the invention.

1 . A method of producing low viscous and highly concentrated biopharmaceutical drug products comprising a biomolecule of interest, the method comprising:
 (a) a first phase of preparing a drug substance comprising the biomolecule of interest, said first phase comprising at least one processing step of concentration,   wherein said at least one processing step in this first phase is carried out in the presence of a composition comprising at least three amino acids, wherein the combination of said at least three amino acids provides at least one positively charged functional group, at least one anti-oxidative functional group, at least one osmolytic function, and at least one buffering function; and   (b) a second phase of further processing the drug substance prepared in (a) to obtain a low viscous and highly concentrated biopharmaceutical drug product, said second phase comprising at least one processing step selected from   (b1) re-buffering, and   (b2)-filling, 
 wherein said at least one processing step in this second phase is carried out in the presence of a composition comprising
 (i) at least three amino acids, wherein the combination of said at least three amino acids provides at least one positively charged functional group, at least one anti-oxidative functional group, at least one osmolytic function, and at least one buffering function, and 
 (ii) one or more sugar(s); 
 in an amino acid:sugar ratio between 10:1 to 1:100 (w/w); 
 and further comprising a step of storing the biopharmaceutical drug product obtained in (b) in liquid formulation. 
 
     
     
         2 . The method of  claim 1 , wherein the low viscous and highly concentrated biopharmaceutical drug product obtained in (b) is further processed for administration as a liquid formulation. 
     
     
         3 . The method of  claim 2 , wherein the liquid formulation-comprises
 (i) at least three amino acids, wherein the combination of said at least three amino acids provides at least one positively charged functional group, at least one anti-oxidative functional group, at least one osmolytic function, and at least one buffering function, and   (ii) one or more sugar(s);   and wherein the ratio between the amino acids and the sugar is adjusted to be between 4:1 to 1:1 (w/w).   
     
     
         4 . The method of  claim 3 , wherein the ratio between the amino acids and the sugar is adjusted to between 2.5:1 and 1:1 (w/w). 
     
     
         5 . The method of  claim 3 , wherein the liquid formulation is further adjusted such that the ratio between the biomolecule of interest and the at least three amino acids of (i) is between 3.5:1 to 1:2 (w/w). 
     
     
         6 . The method of  claim 5 , wherein the ratio between the amino acids and the sugar is adjusted to between 2.5:1 and 1:1 (w/w). 
     
     
         7 . The method of  claim 1 , wherein the composition in step (a) contains between 0.5 mg/ml and 10 mg/ml tryptophan and between 0.5 mg/ml and 30 mg/ml histidine. 
     
     
         8 . The method of  claim 7 , wherein the ratio between the biomolecule of interest and sum of excipients is adjusted to be between 1:1 and 1:500. 
     
     
         9 . The method of  claim 7 , wherein the ratio between the amino acids and the sugar is adjusted to between 4:1 and 1:1 (w/w). 
     
     
         10 . The method of  claim 7 , wherein the ratio between the amino acids and the sugar is adjusted to between 2.5:1 and 1:1 (w/w). 
     
     
         11 . The method according to  claim 1 , wherein the biomolecule of interest comprises protein, peptide, or a mixture thereof. 
     
     
         12 . The method of  claim 1 , wherein the biomolecule of interest comprises a viral vector. 
     
     
         13 . The method of  claim 11 , wherein the biopharmaceutical product is stored for at least 1.5 days. 
     
     
         14 . The method of  claim 1 , wherein the obtained biopharmaceutical product is at a concentration ranging from 25 to 100 mg/ml. 
     
     
         15 . The method of  claim 11 , wherein the biomolecule of interest is an antibody. 
     
     
         16 . A low viscous and highly concentrated biopharmaceutical drug product obtained or obtainable by the method of  claim 1 . 
     
     
         17 . A stable concentrated liquid biopharmaceutical drug product comprising:
 (i) 25 to 500 mg/ml of a biomolecule of interest,   (ii) at least three amino acids, wherein the combination of said at least three amino acids provides at least one positively charged functional group, at least one anti-oxidative functional group, at least one osmolytic function, and at least one buffering function, and   (iii) one or more sugar(s); 
 wherein amino acid:sugar ratio between 10:1 to 1:100 (w/w); and wherein the biopharmaceutical drug product is stored for at least 1.5 days. 
     
     
         18 . The biopharmaceutical drug product of  claim 17 , wherein the biopharmaceutical drug product comprises 100 to 500 mg/ml of the biomolecule of interest or 25 to 100 mg/ml of the biomolecule of interest. 
     
     
         19 . The biopharmaceutical drug product of  claim 17 , wherein the amino acid: sugar ratio is between 4:1 and 1:1 (w/w) or 2.5:1 and 1:1 (w/w). 
     
     
         20 . The biopharmaceutical product of  claim 17 , wherein the biomolecule of interest comprises protein, peptide, or a mixture thereof. 
     
     
         21 . The biopharmaceutical product of  claim 17 , wherein the biomolecule of interest comprises a viral vector or an antibody.