Predicting Filter Size with Vmax

Predicting Filter Size with Vmax - WARM/ӎ...

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Unformatted text preview: WARM/”é: S/vppj "Vulnru'TS we L . (\7; TECH REVIEW flair/fan . "l/ x" M0173 W‘c L/m‘ 5% #HZRfiM/‘qfe Anya wills is inflict] Predicting Filter Size Using Vmax Testing By BALA RAGHUNATH, MICHEL PAILHES, and THOMAS MISTRETI'A he VmaxTM technique has been used extensively to estimate filter area require- ments for normal flow fil- tration (NFF) processes in biopharmaceutical applications. The benefits that this technique presents over conventional flow decay methods are the speed of testing, reduced vol- ume requirements for evaluation, and competitive testing of varying filter types/sizes — all of which present an optimized filter screening strategy and preliminary estimate of optimized fil- ter size requirements. Filter size or filtration area requirements derived using the Vmax technique consist of contributions from both capacity and flow—time aspects of the filtration pro- cess. This article examines the relative contributions of these terms to overall filter sizing vis-a-vis the ease of fluid filterability. Underlying Theory The Vmax technique is based on the gradual pore plugging model, which is characterized by gradual. controlled blocking of the pores with increasing throughput of fluid (filtrate) through the filter. In this model, the particles generally are considered smaller than the filter pore size so that they enter the complex porous network of the filter where they deposit and progres- sively build up on the “walls” of the filter medium (pore wall). This deposi- tion continues until the flow channel WI‘TQ- L/MI/h". :fkg Figure 1. The gradual pore plugging model used in Vmax technology. or “pore” is completely blocked. The process is shown in Figure 1. The maximum volume of the fluid that can pass through the entire filter before it is completely blocked is termed as Vmax. Filters of various media com- positions and pore ratings can be evalu— ated effectively with a wide range of process fluids. The above filtration behavior may be expressed mathematically as: 3 2 _ d I = k[£)2 - Equation 1 de dV which may be solved to obtain an inte- grated form of the equation as: t l =_+_._ ‘ — Equation 2 t V VMA Q,A where Vis volumetric throughput (liters) over a process time of t (h or min). Vmax is filter capacity (L/mz), Q is nor- malized filter flow rate (LMi—l), and A is the filtration area. Implementation In a Vmax test, the fluid is filtered at constant pressure through the filtra- tion device while time of filtration and volume collected are recorded at regular intervals. A plot of time/volume vs. time is made on the yox axis. If the results plot as a straight line, the gradual pore plugging model may be considered to fit the filtration behavior as described in Equation 2. From Equation 2, it is evident that Vmax and Q values may be obtained from the slope and intercept of the plot of IN vs. I, respectively. It also may be noted that as the slope of the line becomes more horizontal, the Vmax value becomes increasingly high. Conversely, as the slope of the line becomes more vertical, the Vmax value becomes increasingly small. These trends have important implica- tions when determining filtration area. Equation 2 can be rearranged to esti- mate filter sizing as follows: Bala Raghunuth, Ph.D. ([email protected]) is a bioprocess engineering manager; Michel Pailhes is a technology man- ager; and Thomas Mistretm is a bioprocess engineer; BioPhtirmrrcetrtical Division, Millipore Corporation, Billerica, MA. 38 BioProcessing Journal - Fall 2006 b—J—.—_—__ , Supplied by The British Library - "The world's knowledge" 2d emphasize these differences with refer- a— ence to fluids filtered in biotechnology 1d processes. ar (5. Plugging Streams Have 1e Low Vmax Values .31 :d For plugging streams, the capacity :d term in Equation 3 (I/Vmax) ishigh com- pared with the flow term [I/(Qf‘tbfl. at This implies that filter sizing is domi- :d of 3d Vmax Result as a Function of Slope in re Non-Plugging Streams es 1200 ac 1000 re ll. too 1 smmhsropa-lzgaawgthm a- son 4100 i- 200 0 0 0.005 0.010 0.015 0.020 Slope .1- Figure 2. ,L ,, ,_ Table ‘1. Example of Vmax Sizing for Plugging Streams (Low Vmax Values). Vmax = 60 le2 , Qi = 20 L/m2*min. and Batch Volume = 1000 L Filter Size Requirements Batch Time Filter Area Rguirements 1 hour 4 hours 17.5 m2 (Equation 2) 16.9 m2 (Equation 2) Area based on VNmax = 16.7 m2 (Equation 3) AN = lleax + 1/Qitb — Equation 3 In Equation 3, the contribution to sizing may be the result of a capac- ity term (1/Vmax) and flow-time term [ I/( thb )1. It might be useful to under- stand how both the capacity and flow time affect filter sizing depending upon the nature of the fluid and/or process application. Application Considerations Plugging characteristics of a fluid stream determine the relative contribu- tion of the capacity and flow for filter area estimation. The examples below nated by filter capacity for the fluid stream. Therefore Equation 3 can be simplified to: A/V = le - Equation 4 The range of typical Vmax values for a 0.22—pm filter where capacity is dominant is 50-500 IJmZ. Examples of applications in which this occurs are serum filtration, centrate filtration, and bioreactor media filtration (Table 1). These examples also show that for highly plugging streams, the processing time has minimal effect on filter area requirements. Non-Plugging Streams Have High Vmax Values Conversely, for non-plugging fluids, the capacity term in Equation 3 (1/ Vmax , will be small compared to the flow [1/(Qi*tb)]. Therefore, the sizing is primarily a function of the flow time for clean fluids. Equation 3 simplifies to: A/V: I/Qitb — Equation 5 5 (ll 5 E 2 E. '5 § § :2 0.025 Figure 3. Supplied by The British Library - "The world's knowledge" Typical Vmax values for a 0.22 pm fil- ter where the flow time is dominant can be greater than 10,000 le2. Examples of applications in which this occurs would be for clean buffer streams, such as sodium acetate and sodium phos- phate. The limiting case of a clean fluid may be represented by water for injec- tion (WFI), for which case, Vmax —> 0° and the capacity contribution (1N max) to sizing vanishes. It is worth noting that for non-plug- ging streams, the filtration time can have a significant effect on the area requirements. In the above examples, increasing the filtration time from one hour to four hours reduces the filter area requirements by 70%. Increasing process time can be an effective way to reduce surface area requirements and total operating costs. For example, if Vmax = 20,000/Lm2, Ql = 20/Lm2 min and batch volume = 1000 L, then, using Equation 3 at one hour, filter area requirement is 0.883 m2; whereas, using Equation 3 at four hours, filter area requirement is 0.258 m2. Using Equation 5, filter area requirements are 0.833 m2 and 0.21 ml, respectiver In addition, the slope of t/V vs. t is nearly horizontal and very sensitive to scatter in the data set. Therefore, small changes in the slope can produce large differences in Vmax values, due to the relationship between the slope and the Vmax result. Since the area will be primarily a function of the flow time, a large error results if the Vmax value alone is used in sizing. The Vmax results as a function of slope are illus- trated in Figure 2, where flow decay is Percent Contribution to Sizing Based on Vmax Value oi: 100 Um! mm r1, = 60 minutes www.bioprocessingjournalcom . Fall 2006 39 measured over ten minutes time. Intermediate Plugging Streams Most biopharmaceutical appli- cations are intermediate plugging streams, in which both capacity and flow rate are important in sizing. For such fluids, Equation 3 more accurately describes the area requirements. The range of typical Vmax values for a 0.22-pm filter for intermediate plug— ging streams is LOGO—10,000 L/mz. Examples of applications in which low flow rates dominate sizing include bio- burden reduction steps, such as before a column purification step or after a depth filtration step. In addition, some complex buffer and media applications are within this Vrnax range. Figure 3 also shows the relative con- tribution to sizing from capacity and flow time for a range of Vmax values. When conducting actual Vmax tri- als, each application is different. It is important to observe what is occurring during the test and understand if the fluid is plugging or non-plugging. For most applications, both parameters are important in determining sizing. Summary Vmax is an effective technique for optimized filter screening and esti- mating preliminary filter size require. ments. It is based on the gradual, uniform blocking of pores as a func. tion of the amount of fluid passing through a filter and its mathematical model representation. In the Vmax sizing model, contributions to the filter sizing arise from both the filter capac_ ity limitations (Vmax) and flow-time (Qi, r3) considerations. An apprecia— tion of these effects provides a clearer- 'understanding of the filtration process, as well as an assessment of the relative importance of operating parameters such as process time, flow rate, and pressure. The Williamsburg BioProcessing Foundation The Most Trusted Source ofBioProcess Technology“ w. mum-<3. Viral Vectors & Vaccines Conference 131/1 Annual illeering Process Development & Production Issues Fairmont Southampton ‘9- Southampton, Bermuda 9° November 6—8, 2006 Life Sciences Topics Include: - Vector Development - Product Characterization - Raw Material Screening - Viral Yield Optimization - Downstream Processing - Facility Design - Storage & Stability . Assay & Media Development ° Safety Testing - QA/QC Issues WWWW Sponsored By: GE Heulthcore Molecular Medlclne BioServkes. In: SAFCBiosciences" ‘—‘| Academic Success ' Photo courtcg‘.‘nfllic Bermuda Dept. ('H'ouiim: To Register Now: Visit us at \mnmilbioxom, Callus MEI-123.8823, or Email us at infofiwilbioxom 40 BioProcessing Journal . Fall 2006 Supplied by The British Library - "The world's knowledge" ...
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