Methods of terminal sterilization of biological products

Abstract

The invention relates to methods of sterilizing biologically active products, particularly therapeutic or prophylactic products and the compositions obtained thereby. The methods include obtaining a dried sample containing an amount of trehalose sufficient to render heat stability to the product and exposing the dried sample to heating conditions at a temperature and for a duration sufficient to substantially inactivate viruses, especially non-lipid encapsulated viruses. The drying methods include both ambient drying conditions and lyophilization. The heating conditions include any known in the art and cover a wide range of temperatures and heating times. The compositions obtained contain stable products and do not contain measurable infectious virus, particularly parvovirus.

1 : A method of terminal sterilization of biologically active product for sterile administration comprising the steps of: 
 (a) obtaining a dried sample comprising the product and an amount of α-D-glucopyranosyl-α-D-glucopyranoside (trehalose) sufficient to render substantial heat stability to the product; and    (b) heating the dried sample at a temperature and for a duration sufficient to substantially inactivate infectious viruses.    
   
   
       2 : The method according to  claim 1 , wherein the product is derived from blood and is selected from the group consisting of albumin products, immune globulins, coagulation products, and protease inhibitors.  
   
   
       3 : The method according to  claim 2 , wherein the albumin products are selected from the group consisting of, HSA, cold soluble globulin and fibrinogen.  
   
   
       4 : The method according to  claim 2 , wherein the immune globulins are selected from the group consisting of, antibodies against tetanus, pertussis, hepatitis, herpes, varicella zoster, lentiviruses and rabies.  
   
   
       5 : The method according to  claim 2 , wherein the coagulation products are selected from the group consisting of, antihemophilic factor VIII, factor IX complex, and activated factor IX complex.  
   
   
       6 : The method according to  claim 2 , wherein the protease inhibitors are selected from the group consisting of, α-1 protease inhibitor, and antithrombin III.  
   
   
       7 : The method according to  claim 1 , wherein the biologically active product is obtained from a biological source selected from the group consisting of blood, plasma, serum, placenta, milk, urine, cell cultures, and cell culture supernatant.  
   
   
       8 : The method according to  claim 7 , wherein the biological source is cell culture or cell culture supernatant and the product is selected from the group consisting of colony stimulating factors, monoclonal antibodies and derivatives thereof, and growth factors.  
   
   
       9 : The method according to  claim 7 , wherein the biological source is cell culture or cell culture supernatant and the product is recombinant.  
   
   
       10 : The method according to  claim 8 , wherein the growth factors are selected from the group consisting of erythropoietin, cytokines and interleukins.  
   
   
       11 : The method according to  claim 1 , wherein the biologically active product is an analgesic.  
   
   
       12 : The method according to  claim 11 , wherein the analgesic is selected from the group consisting of morphine, benzocaine, pethidine, and Demerol.  
   
   
       13 : The method according to  claim 1 , wherein the biologically active product is an anesthetic.  
   
   
       14 : The method according to  claim 13 , wherein the anesthetic is selected from the group consisting of bupivicaine, atracurium and vecuronium.  
   
   
       15 : The method according to  claim 1 , wherein the biologically active product is a chemotherapeutic agent.  
   
   
       16 : The method according to  claim 15 , wherein the chemotherapeutic agent is selected from the group consisting of, radioisotopes, vinca alkaloids, adriamycin, bleomycin sulfate, Carboplatin, cisplatin, cyclophosphamide, Cytarabine, Dacarbazine, Dactinomycin, Duanorubicin hydrochloride, Doxorubicin hydrochloride, Etoposide, fluorouracil, mechlororethamine hydrochloride, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, pentostatin, pipobroman, procarbaze hydrochloride, streptozotocin, taxol, thioguanine, and uracil mustard.  
   
   
       17 : The method according to  claim 1 , wherein the biologically active product is a hormone.  
   
   
       18 : The method according to  claim 17 , wherein the hormone is selected from the group consisting of, estrogen, testosterone, progesterone and synthetic analogs thereof.  
   
   
       19 : The method according to  claim 1 , wherein the biologically active product is a vaccine.  
   
   
       20 : The method according to  claim 19 , wherein the vaccine is selected from the group consisting of, both single and multiple antigen subunit vaccines and killed bacteria and viral preparations and cancer antigens.  
   
   
       21 : The method according to  claim 1 , wherein the dried sample is obtained by the method selected from the group consisting of air drying, vacuum drying, spray drying and freeze drying.  
   
   
       22 : The method according to  claim 1 , wherein the substantial heat stability results in less than about a 30% loss in activity of the product.  
   
   
       23 : The method according to  claim 22 , wherein the stability results in less than about 15% loss in activity of the product.  
   
   
       24 : The method according to  claim 23 , wherein the stability results in less than about 10% loss in activity of the product.  
   
   
       25 : The method according to  claim 1 , wherein the dried sample has a residual moisture content of less than about 4%.  
   
   
       26 : The method according to  claim 25 , wherein the residual moisture content is less than about 2%.  
   
   
       27 : The method according to  claim 26 , wherein the residual moisture content is less than about 1%.  
   
   
       28 : The method according to  claim 1 , wherein the heating temperature is about 80° C. and the duration of heating is about at least 72 hours.  
   
   
       29 : The method according to  claim 1 , wherein the heating temperature is about 90° C. and the duration of heating is about at least 20 hours.  
   
   
       30 : The method according to  claim 1 , wherein substantial inactivation of infectious virus results in about 10 4 -fold reduction in infectivity of the viruses.  
   
   
       31 : The method according to  claim 1 , wherein the inactivation results in 10 4 -fold reduction in infectivity of non-lipid encapsulated viruses.  
   
   
       32 : The method according to  claim 1 , wherein the non-lipid encapsulated viruses are selected from the group consisting of hepatitis A virus and parvoviruses.  
   
   
       33 : The method according to  claim 32 , wherein the non-lipid encapsulated virus is parvovirus.  
   
   
       34 - 58 . (canceled)