Patent Application: US-71570103-A

Abstract:
the present invention relates to an improved method to process , purify and / or produce biopharmaceuticals or other products involving automated blending of ph buffered solutions from water and common stocks of concentrated acids and bases , and other components . this approach reduces the cost and complexity of the solution preparation systems required for producing these solutions under aseptic or sterile conditions , and reduces the material costs of the solutions themselves . this approach is particularly beneficial to use with continuously - produced feedstocks and with continuous separation operations .

Description:
ph a term used to describe the hydrogen - ion activity of a chemical or compound according to well - known scientific parameters . shall mean any medicinal drug , therapeutic , vaccine or any medically useful composition whose origin , synthesis , or manufacture involves the use of microorganisms , recombinant animals ( including , without limitation , chimeric or transgenic animals ), nuclear transfer , microinjection , or cell culture techniques . a system that acts to minimize the change in concentration of a specific chemical species in a solution against the addition or depletion of this species . general term referring to the maintenance of cell strains or lines in the laboratory . any of a multitude of techniques for the separation of complex mixtures that are dependent upon the differential affinities of substances for a gas or liquid mobile medium and for a stationary absorbing medium . the raw material or raw solution provided for a process or method and containing a protein of interest . a continuous solid - liquid dissociation method that purifies two components of a feedstock . both components are generated at a superlative yield and purity . the method of the current invention provides an efficient process to produce ph buffered solutions that will ultimately be converted into or used as pharmaceutical products . the primary ingredients that compose a mixture are water , and a buffer acid and base at a particular concentration and in a particular ratio to produce a desired final ph . in addition , the solution may include other solution ingredients , such as salts , surfactants , inhibitors etc ., see detailed listing above . the individual ingredients are blended at the point of use using an automated blending unit . in one preferred embodiment of the invention , as shown in fig3 reciprocating , positive displacement chemical metering pumps are used to regulate the flow of the ingredient streams . the precise blend for a particular solution is fixed by the combination of pump head sizes and flexible stroke lengths . the various streams are simultaneously pumped into a mixing unit of either a static or active type . if required , sensors for ph and conductivity can be placed inline after the mixer and their output utilized to control the relative ratios of the acid , base and other ingredients . in this embodiment , the solution is utilized immediately by the process being supplied . in a second preferred embodiment , the solution ingredients ( water , acid , base and any other ingredients ) are metered out by pumps and mixed in a small tank . the metering operation can be done simultaneously for all ingredients ( using the same type of positive displacement chemical metering pumps utilized in the first embodiment ). alternatively , the metering can be done sequentially for each ingredient , using either metering pumps or control through the use of a level sensor or load cell placed on the mixing tank . the mixing tank would be equipped with sensors for ph , conductivity , level and possibly other parameters . when the blending operation in the small mixing tank is completed , the sensor measurements would be compared to a release specification , and the solution would be released for use in the process if the specifications are met . if the solution is required to be supplied continuously to the process , two small mixing tanks could be used , one of which would supply released solution while the other is being used to blend a new tank of solution . the first preferred embodiment of the invention is simpler and less expensive to construct , and may be truly continuous , according to a preferred embodiment of the invention . this would be the embodiment used for a large fraction of the applications . the second embodiment incorporates some of the current elements of good manufacturing practice ( gmp ) for pharmaceutical manufacturing , and may be required for some particularly critical process steps . turning to fig7 the design and testing data on the human serum albumin downstream purification process shown in fig5 were used as input to a detailed process cost modeling software system ( paradigm one , applied process technologies , wilmington , mass .). the software package estimates detailed capital and operating costs based upon specific process parameters , selected equipment , utility and space requirements , etc . for this model , a facility was designed to produce 25 tons per year of purified bulk active pharmaceutical ingredient ( bulk api ) from transgenic milk containing human serum albumin . for the comparison , all unit operations ( see fig6 ) were kept constant , and only the solution preparation and storage system and process utilities were modified to reflect the blending of buffers directly from acids , bases and additives . moreover , due to the process of the current invention the facility ( building ) costs were reduced significantly , due to the reduction in space requirements by the elimination of many solution storage tanks and distribution piping . this also is reflected in the reduction in costs for the equipment needed for solution prep and cip . there was also some reduction in the size and cost of the required water system . overall , the estimated capital cost for the plant was reduced by $ 6 . 1 million (˜ 16 %) through the introduction of the use of the methods of the invention .” although plentiful literature exists regarding the structure , function , and diseases associated with human serum albumin and alpha fetoprotein , the prior art does not disclose an efficient , automated , and continuous method of blending buffers and other solutions to process these proteins . with regard to alpha fetoprotein , u . s . pat . no . 5 , 384 , 250 entitled “ expression and purification of cloned alpha fetoprotein ,” explains a method for making human alpha fetoprotein in prokaryotic cells only . in addition , u . s . pat . no . 5 , 206 , 153 entitled “ method of producing human alpha - fetoprotein and product produced thereby ” discloses a method to make human alpha fetoprotein whereby a dna sequence for rat alpha fetoprotein is combined with the dna for human alpha fetoprotein . these methods , however , do not yield a supply of human alpha fetoprotein by the use of the continuous , automated blending of buffers and other solutions . as mentioned previously , this method may be employed to process human serum albumin and alpha fetoprotein for therapeutic applications . serum albumin , the most well - known plasma protein , is responsible for a variety of physiological functions such as sustaining the osmotic pressure in the blood and transporting fatty acids and bilirubin ( peters 1995 ). testing levels of serum albumin from feedstreams may be conducted to see if the subject has liver or kidney diseases or if an insufficient amount of protein is consumed by the blood . decreased levels of serum albumin may signal such diseases as well as ascites , bums , glomerulonephritis , malabsorption syndrome , malnutrition , and nephritic syndromes . in addition to measuring levels of serum albumin to detect disorders , synthesizing this protein is beneficial for therapeutic purposes . albumin products are employed to maintain the plasma colloid oncotic pressure and to remedy severe edema by enabling intracavital and interstitial fluids to travel into the blood vessels . albumin products may be administered to alleviate acute hypoproteinemia and pathological conditions stemming from chronic hypoproteinemia . albumin products may be utilized to treat hypovolemic shock , severe bum injury , adult respiratory distress syndrome , ascites , liver failure , and pancreatitis . ( cochrane et al ., 1998 ). albumin may also be administered to remedy hyperbilirubinemia , hypoproteinemia , and nephrotic syndrome . ( vermeulen et al ., 1995 ). alpha fetoprotein is another protein that may be processed for beneficial reasons . it is a protein assembled by the liver and yolk sac of a fetus . throughout pregnancy , heightened levels may signal the following fetal abnormalities : spina bifida , anencephaly , omphalocele , tetralogy of fallot , duodenal atresia , turner &# 39 ; s syndrome , and intrauterine death . in addition to fetal diseases , monitoring increased levels of alpha fetoprotein may be useful in pinpointing cancers of the stomach , pancreas , biliary tract , testes , and ovaries , and recuperation from hepatitis . according to an embodiment of the current invention when multiple or successive rounds of transgenic selection are utilized to generate a cell or cell line homozygous for more than one trait such a cell or cell line can be treated with compositions to lengthen the number of passes a given cell line can withstand in in vitro culture . telomerase would be among such compounds .] accordingly , it is to be understood that the embodiments of the invention herein providing for an increased efficiency and speed in the production of chemical , biochemical , or biopharmaceutical processing are merely illustrative of the application of the principles of the invention . it will be evident from the foregoing description that changes in the form , methods of use , and applications of the elements of the disclosed method for the improved buffer blending and development technology are novel and may be modified and / or resorted to without departing from the spirit of the invention , or the scope of the appended claims . 1 . cochrane et al ., human albumin administration in critically iii patients : systematic review of randomized controlled trials , br med j . ( 1998 ); 317 : 235 - 240 . 2 . gibney m w , et al ., method of beverage blending and carbonation , u . s . pat . no . 5 , 552 , 171 . 3 . jones , c , et al ., method for blending diverse blowing agents , u . s . pat . no . 5 , 823 , 669 . 4 . pak , zinovy petrovich — chemical compound , or soil contaminated by said poisonous agent and / or toxic chemical compound , u . s . application ser . no . 20020156336 . 5 . patel m , et al ., apparatus for blending chemicals with a reversible multi - speed pump , u . s . pat . no . 5 , 340 , 210 . 6 . paul k d , et al ., method and apparatus for filling , blending , and withdrawing solid particulate material from a vessel , u . s . pat . no . 4 , 907 , 892 . 7 . phallen u , et al ., continuous liquid stream digital blending system , u . s . pat . no . 6 , 186 , 193 . 8 . platz g m , et al ., method and apparatus for super critical treatment of liquids , u . s . pat . no . 6 , 162 , 392 . 9 . wilkins e , et al ., apparatus for detecting contamination in food products , u . s . pat . no . 6 , 180 , 335 . 10 . vermeulen l c , et al ., guidelines of or the use of albumin , nonprotein colloids , and crystalloid solutions , arch intern med . 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