Processes for the preparation of a batch of an active pharmaceutical ingredient, a container comprising cryogranules of an allergen product, and a cryogranule of an allergen product

Abstract

The present invention relates to processes for the preparation of a batch of an active pharmaceutical ingredient, e.g. an allergen product. The invention also relates to a container comprising cryogranules of a liquid composition of an allergen product, and to a cryogranule of an allergen product. The processes feature formation of cryogranules using a container having therein a cryogenic medium (e.g. liquid nitrogen) and storage of the cryogranules in the same container. The cryogranules obtained can be stored and handled without prior freeze-drying.

1 . A process for the preparation of a batch of an active pharmaceutical ingredient, said process comprising the steps of: 
 (a) providing a liquid composition comprising said active pharmaceutical ingredient, said liquid composition having a freezing temperature;    (b) providing a container and a sealing means suitable for sealing said container, said container comprising therein a cryogenic medium having a boiling temperature below the freezing temperature of said liquid composition;    (c) dividing the liquid composition into droplets, and adding said droplets to the cryogenic medium in the container whereby said droplets freeze to form cryogranules of the liquid composition; and    (d) sealing the container containing the cryogranules of the liquid composition with the sealing means, and storing the container containing the cryogranules of the liquid composition.    
   
   
       2 . A process for the preparation of a batch of an active pharmaceutical ingredient, said process comprising the steps of: 
 (a) providing a liquid composition comprising said active pharmaceutical ingredient, said liquid composition having a freezing temperature;    (b) providing a container comprising therein a cryogenic medium having a boiling temperature below the freezing temperature of said liquid composition;    (c) dividing the liquid composition into droplets, and adding said droplets to the cryogenic medium in the container whereby said droplets freeze to form cryogranules of the liquid composition; and    (d) storing the container containing the cryogranules of the liquid composition for a period of not less than 24 hours.    
   
   
       3 . A process for the preparation of a batch of an active pharmaceutical ingredient, said process comprising the steps of: 
 (a) providing a liquid composition comprising said active pharmaceutical ingredient, said liquid composition having a freezing temperature;    (b) providing a container comprising therein a cryogenic medium having a boiling temperature below the freezing temperature of said liquid composition;    (c) dividing the liquid composition into droplets, and adding said droplets to the cryogenic medium in the container whereby said droplets freeze to form cryogranules of the liquid composition; and    (d) storing the container containing the cryogranules of the liquid composition;    with the proviso that the cryogranules of the liquid composition are not subjected to a freeze-drying step subsequent to step (c) or step (d).    
   
   
       4 . The process according to any of the preceding claims, wherein the cryogranules have an average diameter of in the range of 0.1-20 mm.  
   
   
       5 . The process according to any of the preceding claims, wherein the freezing temperature of the liquid composition is at least −30° C.  
   
   
       6 . The process according to any of the preceding claims, wherein the boiling temperature of the cryogenic medium is at the most −40° C.  
   
   
       7 . The process according to any of the preceding claims, wherein the cryogenic medium is liquid nitrogen.  
   
   
       8 . The process according to any of the preceding claims, wherein the container in step (d) is subsequently stored at a temperature below the critical conductivity temperature of the liquid composition.  
   
   
       9 . The process according to any of the claims  2 - 8 , wherein the container is sealed with a sealing means prior to storage.  
   
   
       10 . The process according to any of the claims  1  and  9 , comprising the additional step of removing substantially the entire cryogenic medium from the container prior to sealing said container.  
   
   
       11 . The process according to  claim 10 , wherein the temperature of the cryogranules is held below the critical conductivity temperature of the liquid composition while the cryogenic medium is removed.  
   
   
       12 . The process according to any of the preceding claims, wherein the sealing means or the container wall comprises a one-way valve for allowing excess pressure in the sealed container to escape.  
   
   
       13 . The process according to any of the preceding claims, wherein the liquid composition is an aqueous composition.  
   
   
       14 . The process according to any of the preceding claims, wherein the active pharmaceutical ingredient is selected from allergen products and enzyme preparations.  
   
   
       15 . The process according to  claim 14 , wherein the active pharmaceutical ingredient is an allergen product.  
   
   
       16 . The process according to any of the claims  1  and  4 - 15 , comprising the steps of: 
 (a) providing a liquid composition comprising an allergen product, said liquid composition having a freezing temperature of at least −30° C.;    (b) providing a container and a sealing means suitable for sealing said container, said container comprising therein liquid nitrogen;    (c) dividing the liquid composition into droplets, and adding said droplets to the cryogenic medium in the container whereby said droplets freeze to form cryogranules of the liquid composition, said cryogranules having an average diameter of in the range of 0.1-20 mm; and    (d) removing substantially the entire cryogenic medium while the temperature of the cryogranules is held below the critical conductivity temperature of the liquid composition; and sealing said container containing the cryogranules of the liquid composition.    
   
   
       17 . The sealed container according to  claim 16 , wherein the sealing means or the container wall comprises a one-way valve for allowing excess pressure in the sealed container to escape.  
   
   
       18 . The process according to any of the claims  2  and  4 - 15 , comprising the steps of: 
 (a) providing a liquid composition comprising an allergen product, said liquid composition having a freezing temperature of at least −30° C.;    (b) providing a container comprising therein liquid nitrogen;    (c) dividing the liquid composition into droplets, and adding said droplets to the cryogenic medium in the container whereby said droplets freeze to form cryogranules of the liquid composition, said cryogranules having an average diameter of in the range of 0.1-20 mm; and    (d) removing substantially the entire cryogenic medium while the temperature of the cryogranules is held below the critical conductivity temperature of the liquid composition; and storing said container containing the cryogranules of the liquid composition for a period of not less than 24 hours.    
   
   
       19 . The process according to any of the claims  3 - 15 , comprising the steps of: 
 (a) providing a liquid composition comprising an allergen product, said liquid composition having a freezing temperature of at least −30° C.;    (b) providing a container comprising therein liquid nitrogen;    (c) dividing the liquid composition into droplets, and adding said droplets to the cryogenic medium in the container whereby said droplets freeze to form cryogranules of the liquid composition, said cryogranules having an average diameter of in the range of 0.1-20 mm; and    (d) removing substantially the entire cryogenic medium while the temperature of the cryogranules is held below the critical conductivity temperature of the liquid composition; and storing said container containing the cryogranules of the liquid composition;    with the proviso that the cryogranules of the liquid composition are not subjected to a freeze-drying step subsequent to step (c) or step (d).    
   
   
       20 . The process according to any of the preceding claims, comprising the steps of: 
 (a) providing a liquid composition comprising an allergen product, said liquid composition having a freezing temperature of at least −30° C.;    (b) providing a container and sealing means suitable for sealing said container, said container comprising therein liquid nitrogen;    (c) dividing the liquid composition into droplets, and adding said droplets to the cryogenic medium in the container whereby said droplets freeze to form cryogranules of the liquid composition, said cryogranules having an average diameter of in the range of 0.5-10 mm; and    (d) removing substantially the entire cryogenic medium while the temperature of the cryogranules is held below the critical conductivity temperature of the liquid composition; sealing said container containing the cryogranules of the liquid composition; and storing said sealed container containing the cryogranules of the liquid composition; with the proviso that the cryogranules of the liquid composition are not subjected to a freeze-drying step subsequent to step (c) or step (d).    
   
   
       21 . The process according to  claim 20 , wherein the sealing means or the container wall comprises a one-way valve for allowing excess pressure in the sealed container to escape.  
   
   
       22 . A container comprising cryogranules of a liquid composition of an allergen product  
   
   
       23 . The container according to  claim 22 , wherein the cryogranules have an average diameter of in the range of 0.1-20 mm.  
   
   
       24 . The container according to any of the claims  22 - 23 , which is sealed by means of a sealing means.  
   
   
       25 . The container according to  claim 24 , wherein the sealing means or the container wall comprises a one-way valve for allowing excess pressure in the sealed container to escape.  
   
   
       26 . A container obtainable by the process of any of the claims  1 ,  9 ,  12 ,  15 - 16 , and  20 - 21 .  
   
   
       27 . A cryogranule of a liquid composition of an allergen product.  
   
   
       28 . The cryogranule according to  claim 27 , which has an average diameter of in the range of 0.1-20 mm.  
   
   
       29 . The cryogranule according to any of the claims  27 - 28 , which is obtainable by the process defined in any of claims  1 - 2   1 .