| Method and apparatus for producing a biomaterial product -> Monitor Keywords |
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  Method and apparatus for producing a biomaterial productUSPTO Application #: 20060100838Title: Method and apparatus for producing a biomaterial product Abstract: A development tool 2 includes a plurality of measuring tools 71 to 76 and an industrial process simulation device 60. The simulation device 60 simulates a whole industrial scale bioprocess in order to obtain acceptable operating parameters for the industrial scale bioprocess. The measuring tools 71 to 76 enable various significant properties of the biomaterial to be measured and evaluated using only a small test quantity of the biomaterial. (end of abstract)
Agent: Finnegan, Henderson, Farabow, Garrett & Dunner LLP - Washington, DC, US Inventors: Peter Dunnill, Mike Hoare, Nigel Titchener-Hooker USPTO Applicaton #: 20060100838 - Class: 703011000 (USPTO) Related Patent Categories: Data Processing: Structural Design, Modeling, Simulation, And Emulation, Simulating Nonelectrical Device Or System, Biological Or Biochemical The Patent Description & Claims data below is from USPTO Patent Application 20060100838. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] The present invention relates to a method of producing a biomaterial product and to a development tool for use in developing an industrial or pilot scale bioprocess. [0002] Conventionally, in order to produce a new biomaterial product (for example an intracellular protein or a DNA plasmid) on an industrial scale (which might for example process 10,000 litres or more of biomaterial in each run), pilot scale trials (which might for example process about 100 litres of biomaterial in each run) are carried out. Various measuring tools are used to determine significant properties of the biomaterial being processed at various stages in the pilot process. From this information, the process engineers may vary operating parameters of the bioprocessing devices used until the pilot process is deemed to be working acceptably well. The biomaterial product may then be produced at an industrial scale by scaling up the acceptable pilot process. [0003] A drawback with this method is the time and expense involved in pilot scale trials in order to develop a new industrial bioprocess. Furthermore, where the bioproduct is destined for medical uses, it is often necessary to obtain regulatory approval for the bioproduct and the regulatory approval is specific to the process by which the bioproduct is manufactured. Since it usually takes some time to obtain regulatory approval for a new bioproduct, any substantial changes to the final process which come about as a result of the pilot scale trials can significantly delay the time to market for the bioproduct. [0004] According to a first aspect of the present invention, there is provided a method for producing a biomaterial product comprising: [0005] (a) performing a series of experiments on biomaterial using scale down devices; [0006] (b) obtaining measurements of one or more properties of the biomaterial using said scale down devices; [0007] (c) modelling the operation of at least one industrial bioprocess device to determine how it modifies one or more properties of a biomaterial in dependence on the way in which the device is operated and in dependence on at least one of the properties of the biomaterial measured in step (b) in order to determine acceptable ways of operating the one or more industrial bioprocess devices; and optionally performing the further steps of: [0008] (d) providing an industrial bioprocess system comprising a plurality of industrial bioprocess devices; and [0009] (e) operating the industrial bioprocess system in the way determined in the modelling step, thereby obtaining a biomaterial product. [0010] Note, throughout this description, the term biomaterial(s) will be used to refer generally to any material involved in a bioprocess. For example, an initial broth including both nutrient and a cell culture could be classified as biomaterial, as could either the nutrient or the cell culture individually. Similarly, a sludge output from a centrifuge comprising cell debris, or the liquid formerly contained within the cells of a cell culture (often referred to as the supernatant) could also be classified as biomaterials. Furthermore, any combination of the above-described biomaterials could also be described as a biomaterial. The term biomaterial product or bioproduct will be used to refer to the desired end product of a bioprocess and will typically be an enzyme, or a DNA plasmid, for example. [0011] Preferably, the method according to the first aspect of the present invention includes: [0012] using the one or more measurements obtained in step (b) to determine a biomaterial index or a plurality of biomaterial indices relating to the biomaterial, or a component thereof, measured in step (b); and [0013] using the one or more biomaterial indices in step (c). [0014] One of the key features of the processes for producing and processing biological materials is that there are pronounced interactions between the stages. For example, the degree of mechanical disruption of a microbial cell influences the extent of removal of cell debris by solid-liquid separation in a centrifuge. In turn the extent of debris removal affects the degree to which later stage chromatography columns are fouled. [0015] This implies that, to be meaningful, tests on scale down mimics of later stage industrial scale operations must be done with material which has passed through carefully controlled mimics of the earlier stage(s) having comparable effects on the material. [0016] The ability to define indices for characterising the effects of individual operations allows such material to be prepared. [0017] Equally the values for the individual indices can be used by the process models to provide an accurate description of the process. [0018] The term biomaterial index is used to refer to the result of at least one scale down experiment which is designed to mimic at least one aspect of an industrial scale bioprocess. Typical features of a biomaterial index are the dependencies of material properties of the respective biomaterial (or a component thereof), which properties may include size, particle size distribution, viability, biological activity and/or composition, on the extent of, or means of exposure to, at least one aspect of the engineering environment occurring in a stage of an industrial scale process which the scale down experiment is designed to mimic. Preferably, at least one of the following biomaterial indices is determined: [0019] shear index, combined clarification and de-watering index or fouling index. The above-mentioned specific biomaterial indices will be described below. [0020] Preferably, step (c) of modelling one or more industrial bioprocess devices involves using an industrial process simulation device which preferably takes the form of a suitably programmed computer. Preferably, the or each property of the biomaterial measured in step (b) of the first aspect of the present invention, or the or each biomaterial index determined therefrom, is used in generating one or more input biomaterial parameters which are used by the industrial process simulation device. [0021] The present invention enables reliable evaluation of how biomaterials are affected by their interaction with industrial devices and/or how industrial devices deviate from their ideal performance as a result of their interaction with biomaterials. The term ideal performance is intended to denote substantially no incapacity or substantially no improved performance as a result of interaction between the device and a biomaterial. [0022] The term scale down device is used to refer to a device which is able to process small quantities of biomaterial (eg quantities preferably of less than 1 litre, more preferably of the order of tens of millilitres, or even of the order of tens of microlitres), and includes conventional laboratory devices such as a laboratory centrifuge, a homogeniser adapted to process small quantities of biomaterial, small chromatography columns (eg having an internal volume of approximately 1 cm.sup.3). It also includes biomaterial index-related devices. These are specially designed to mimic at least one significant aspect of an engineering environment occurring in an industrial scale device which does not occur (or which does not occur to the same extent) in the corresponding conventional laboratory device. Such specially designed scale down devices include a scale down rotating disk device which is adapted to mimic the level of shear generated within an industrial scale centrifuge device and other devices such as pumps. [0023] Similarly, the term scale down experiment is used to refer to an experiment performed using one or more scale down devices and involving only a small quantity of biomaterial (eg preferably less than 1 litre, more preferably of the order of tens of millilitres, or even of the order of tens of microlitres). The term scale down experiment is used to refer to both conventional laboratory experiments performed on a biomaterial to determine one or more properties of the biomaterial, and specially designed biomaterial index related experiments which are intended to mimic at least one of, and most preferably to mimic all of, the aspects of an engineering environment occurring within an industrial scale device which significantly impact on the material properties of a biomaterial processed by the industrial scale device. [0024] Preferably, the scale down devices and scale down experiments are used to generate material similar in properties to that which would be obtained in an industrial or pilot scale bioprocess. [0025] An advantage of the first aspect of the present invention is the provision of a systematic way of determining one or more input biomaterial parameters for any given biomaterial for use in a computer simulation of an industrial bioprocess. Furthermore, this can be achieved without having to employ large industrial or pilot scale machinery. [0026] Preferably, the step of generating the input biomaterial parameters includes using one or more scale down device computer models, each such scale down device computer model being adapted to generate one or more input biomaterial parameters on the basis of one or more output biomaterial parameters (whose value or values are preferably able to be ascertained directly from the measurements obtained in step (b) of the first aspect of the present invention discussed above) and one or more operating parameters (which depend on the manner in which the scale down devices are operated). Such a step means that the conditions generated by the scale down device or devices need not correspond exactly to those occurring in the industrial process being modelled. For example, a given biomaterial will behave differently in a rotating disk device which is first filled with the biomaterial to be tested and then started slowly and spun for say tens of seconds at high speed compared to in an industrial centrifuge which is already spinning when the biomaterial to be processed by the centrifuge is fed in at the feed zone; in the industrial centrifuge, the biomaterial is subjected to a very high shear for a very short period of time only, typically a fraction of a second. However, by using a model both of the industrial centrifuge and of the rotating disk device in which both models share (at least some of) the same input biomaterial parameters (for example a shear index or critical shear value), the model of the rotating disk device may be used to obtain a theoretical input biomaterial parameter on the basis of the observed output biomaterial parameters for given operating parameters, which theoretical input biomaterial parameters may be used in a computer model of the industrial process. [0027] Note that this step is particularly useful in the case where an output biomaterial parameter such as the percentage of clarification achieved by a centrifuge is far more readily measurable than an input biomaterial parameter such as particle size distribution or critical shear value. Where an output biomaterial parameter of a first model is used as an input biomaterial parameter of a subsequent downstream model, it may be possible, and advantageous, to determine the value of the input biomaterial parameter to the first model by a 2-stage process in which the output biomaterial parameter of the first model is not measured directly. Instead, only an output parameter of the downstream model is obtained by direct measurement and the intermediate input biomaterial parameter of the downstream model is obtained by running the downstream model backwards, from which the input biomaterial parameter of the first model can be obtained by running the first model backwards. This process may of course be extended to 3 or more stages and a combination of 1, 2 and higher stage processes may advantageously be employed. In this way it is possible to obtain biomaterial parameters with which to set up a computer simulation of a specific industrial process (i.e. one performed on a specific, new biomaterial) using only a few small devices, a small amount of biomaterial and a few simple laboratory measurement techniques. This provides the advantage that the simulation may be set up in a laboratory without requiring the use of any large scale devices. Also, expensive or difficult analysis techniques may be avoided. [0028] According to a second aspect of the present invention, there is provided a method for producing a biomaterial product comprising [0029] (i) analysing the engineering environment experienced by biomaterial within at least one stage of an industrial process to identify the aspects of the engineering environment which substantially influence the material properties of the biomaterial; [0030] (ii) subjecting a test quantity of biomaterial to conditions within a scale down device which mimic the aspects of the engineering environment identified in step (i), [0031] (iii) analysing the response of the test quantity of biomaterial to the conditions within the scale down device, [0032] (iv) determining how best to operate the industrial process to decrease adverse effects, or to increase beneficial effects, caused by the engineering environment experienced by biomaterial in the industrial process; and optionally including the further step of: [0033] (v) performing the industrial process on the basis of determinations made in step (iv), thereby obtaining a biomaterial product. [0034] Note that the method of either the first or the second aspects of the invention may include the additional step of performing pilot scale trials prior to step (v) of performing the industrial process. In such a case, the method has the advantage of significantly reducing the risk of the need for a substantial change to the proposed industrial scale process occurring at the pilot scale trials. [0035] The present inventors have determined a number of features affecting the correct prediction of an industrial scale process on the basis of corresponding conventional laboratory processes including: the significantly greater rate of hydrodynamic shear occurring in a typical industrial scale process; the significantly greater impact of fouling of chromatographic columns occurring within an industrial process compared with a conventional laboratory chromatography experiment; and the amount of solids passing through with the output liquid stream and the amount of liquid centrifuged out with solids during industrial scale centrifugation compared to a conventional laboratory scale centrifugation experiment. Since many biomaterial products are shear sensitive (i.e. they are affected in some way by the stresses caused in regions of high hydrodynamic shear such as typically found in industrial bioprocessing devices), a significant advantage provided by a preferred embodiment of the method in accordance with the second aspect of the present invention in which the test quantity of the biomaterial is subjected to shear stress conditions in step (ii), is that predictive information about how the biomaterial of interest will behave in an industrial scale process can be obtained in the laboratory prior to performing any pilot scale trials. [0036] Note that steps (e) or (v) of the first or second aspects of the present invention, are intended to include effecting substantial changes in the final industrial process. Thus, for example, the processing system can be envisaged as including a number of alternative industrial devices (for example, at each stage of the process where it is necessary to separate out particles dispersed in a solution, the processing system could include a centrifuge and/or a microfilter) and an operating parameter for producing the product with acceptable properties could include using one device or the other depending on the outcome of the preceding steps. Note that the finalised industrial processing system need not physically include unused devices in order to be considered as operating in accordance with an operating parameter specifying that one device should be used in preference to an alternative device. [0037] Preferably, the first analysing or modelling operation includes the use of computational fluid dynamics. This has the advantage of providing a large amount of information about the internal conditions within an industrial device being modelled by means of the computational fluid dynamics, including shear profiles within the device during its operation and how these will vary for different operating conditions. For example, information may be obtained about how different viscosities of the biomaterial being processed within the machine will affect the stress profiles within the machine. Continue reading... Full patent description for Method and apparatus for producing a biomaterial product Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Method and apparatus for producing a biomaterial product patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. 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