Introduction to filter sizing Vmax and Pmax method Presentation Overview How a Filter Works Key Membrane and Depth Filter Characteristics Filter Fouling Mechanisms: An introduction to Filter Sizing and Scaling Models Gradual Pore Plugging Model and Vmax method Pmax/Tmax Method Safety Factor consideration 15/5/2017 How a Filter Works Microporous Membranes Virus Membranes Ultrafiltration Membranes Reverse Osmosis Membranes 15/5/2017 Retention Mechanisms Describe how filters capture (retain) particles Mechanisms can be affected by: • Fluid characteristics • Operating conditions • Particle type • Filter type Retention mechanisms form the foundation of filter fouling models 15/5/2017 Particle Retention Mechanisms . Size Exclusion - Plugging • Sieving (surface) • Entrapment (depth) • Size-dependent . Adsorption • Attraction forces between particles and filter material • Molecular and/or electrical • Not size-dependent . Depends on • Particle type • Solution properties • Filter material and structure Key Membrane and Depth Filter Characteristics What do Membrane Filters look like? Mainly made by casting membrane Can be either hydrophilic or hydrophobic Rated on the size of the smallest particle it retains Very thin (100 - 260 um) Adsorption depends on materials • Not the primary retention mechanism Examples • Cellulose ester • Regenerated cellulose • Nylon • Polysulfones • PVDF 15/5/2017 Key Membrane Filter Characteristics Strong, Rigid NOT brittle Tortuous pathway Very high internal area 65-75% porosity Size exclusion - particle retention does not change with flow or pressure Sterilizing filters must have > 99.99999% removal and sterile filtrate Integrity testable (diffusion &/or bubble point) 15/5/2017 What do Surface (Pre-) Filters look like? Fibers locked together by heat or membrane coating Given a nominal rating or rated by the filter it protects Thin (1 mm or less) & Slightly Adsorptive Give a percentage (90 - 99.9%) particle reduction Examples • Cellulose ester coated cellulose or polyester web • Heat-treated polyproplylene filters 15/5/2017 What do Depth Filters look like? Fibrous (can shed fibers) Difficult to give an accurate pore size rating Thick (3 - 30 mm) & often adsorptive Give a percentage (i.e. 30 - 70%) particle reduction Have the greatest capacity Examples • Microfiberglass • String-wound filters • Sheet / pad filters 15/5/2017 Depth filter composition . Cellulose fibers base matrix • Highly refined . DE (Diatomaceous Earth) Diatomaceous Earth • Refined grade • Large surface area • Entrapment sites . Resin binder • Positive charge & hydrophobicity for adsorption Filter Matrix Cross-Section @ 3656 X 15/5/2017 Filter Fouling Mechanism: An introduction to filter sizing Types of Particles in Biological Fluids Non-deformable types • Resin beads or fines • Drug crystals • Carbon fines • Diatomaceous Earth (D.E.) • Form porous permeable cakes. Deformable types Proteins Lipids Sugar/protein complexes Can move through the filter, break-up and compress into impermeable cakes. 15/5/2017 Cake Formation Happens with hard particles Particles build up on the surface of the filter If particles are rigid, resistance increases linear with cake thickness 15/5/2017 Complete Pore Blocking Happens with deformable particles Pressure forces particles to completely block the "pore" Common when there is poor or no prefiltration OR when soft particles slightly larger than the filter rated pore size 15/5/2017 Gradual Pore Plugging Happens with hard or deformable particles Particles build up on the "pore" throat or opening Filter slowly blocks Most common with biological fluids 15/5/2017 Impact on Filter Behavior Gradual blockage most common "Everything was going alright, then all of a sudden the filter plugged" Constant flow filtration – ∆p increases as filter fouls Gradual and complete blocking do not have a linear relationship between ΔP and capacity 15/5/2017 Filter Performance Characterization .Filter performance is defined by two key attributes .Capacity • Volume that can be process per filter area (L/m2) • How much? Flowrate • Volume processed per time per area (L/m2/hr = LMH) • How fast? .Performance depends on: • Filter selection- the correct filter for the application • Process parameters • Optimizing pressure, flowrate, time, area 15/5/2017 Small-Scale Test Methodologies Constant Pressure (Vmax) Constant Flow Rate Fluid is held at constant (Pmax/Tmax) pressure and forced through Fluid is pumped at a constant filter media flow rate through the filter Filter plugging is observed by media the decrease in flow rate over Filter plugging is observed by time an increase in differential Classically, based on pressure over time gradual pore plugging OR model Filter plugging is observed by an increase in filtrate turbidity over time Based on a small-scale process simulation with 15/5/2017 empirical data fitting Choosing a Filter Sizing Technique: Fouling Mechanism Basis Constant Sizing Method Name: Pressure Vmax Volume Endpoint Vmax Constant Tmax Pmax Pressure Endpoint Pmax Flow ∆P does ∆P increases during Turbidity Endpoint Tmax Mode Mode Testing of not change filtration Size Exclusion Mechanisms Choosing a Filter Sizing Technique: Filter Type Basis Tmax Pmax Pmax (Applicable, (Application Focus) but less common) Vmax Depth Membrane and Non-woven Sterilizing-grade Filters Prefilters Membrane Filters 15/5/2017 Gradual Pore Plugging and Vmax Method Available Test Methodologies for Sizing Filters Constant Pressure (Vmax) Constant Flow Rate (Pmax) Measures decrease in flow as a Measures increase in pressure and function of throughput decrease in filtrate quality as a function of throughput Endpoint is determined by flow rate or volume Endpoint is determined by pressure limit or desired filtrate quality pressure turbidity flow rate throughput throughput 15/5/2017 Filter Plugging Models .Mechanism of filter plugging: • d2t/dV2 = k(dt/dV)n where: t = filtration time V= cumulative volume at time t k = constant whose dimensions are dependent on n n = 1.5 for gradual plugging • H.P. Grace, "Structure and Performance of Filter Media," AICHE Journal 2(3), 307-336 (1956) .In practical terms: • t/v = t/Vmax + 1/Qi where: Vmax = maximum volume that can be filtered at time infinity Qi = instantaneous initial flow 15/5/2017 The Vmax (Constant Pressure) Test • Accelerated screening technique to estimate scaled-up filter size requirements • Helps to optimize filtration train rapidly • Estimates the maximum fluid volume filterable through a filter – Predicts Capacity, Vmax [=] L/m2 (@ t=∞) – Predicts Flux Decay Profile , Q [=] L/min • Vmax Characteristics – Based on the gradual pore plugging model • Vmax Implementation – Plot t/V versus t at constant ∆P – Vmax = 1/Slope, Qi = 1/Intercept 15/5/2017 Vmax: Result Analysis . Typical Curve • Highly linear region r2 > 0.99 2 − r > 0.99 1/Q i 1/Vmax . What happens when r2 < 0.99? t/V • Prediction of Capacity (Vmax) based on 10 min test becomes less reliable • Remove earlier points to see if fit is t improved, − Need at least 6 points in the straight line for reliable correlation r2 < 0.99 . Run test to 80% plugging (flow t/V decay) 1/Vmax t Vmax: Approaches to Filter Sizing .Three process scenarios or cases are usually relevant: • Case 1: Batch Volume of fluid to be filtered is given • Case 2: Batch Volume of fluid to be filtered at a maximum allowable process time is given • Case 3: Batch Volume of fluid to be filtered with a specified minimum allowable flow rate is given .Largest surface area that fulfills all process requirements is selected, Amin 15/5/2017 Vmax: Sizing Equations Case 1. Only VB (Batch Volume is given; No batch time, minimum flow) VB Amin = Vmax • Eq. gives the minimum area required (no safety factor is included) • Ensure that Amin leads to respectable batch times Case 2. VB (Batch Volume) and tB (Batch time) are given VB VB Amin = + Vmax Qi ×tB Case 3. VB (Batch Volume), tB (Batch time) & Qmin (minimum flow rate) are given Q V 1− min = B Qi × Amin Vmax × Amin • Using an Iterative Method, Solve Eq. For ‘Amin’ •‘Case 2’ can give a reasonable initial guess 15/5/2017 Vmax: Advantages/Benefits .Simple, rapid & easy to use .Experimental basis for filter train selection • Establishes optimized filtration train and preliminary information for scale-up, confirmatory pilot scale trials .Results have simple interpretations: • Vmax - maximum ‘filterable’ fluid volume before plugging, L/m2 • Qi - initial filtrate flowrate; L/min/m2 .Requires only limited fluid volume to perform the test. • < 1 liter 15/5/2017 Vmax: Limitations .It does not tell you which filter to test • Experience & historical records are useful .Does not tell you anything about filtrate quality • Indirectly Vmax, with a tighter filter, on the filtrate is a measure of filtrate quality .Does not simulate the entire process • Need for intermediate pilot trials .Only applies to gradual pore plugging model 15/5/2017 Pmax/Tmax method Large scale Small scale Golden rule: “ During PD, in small scale experiments, mimic large scale operation as close as possible” . Process parameters . Fluid characteristics 15/5/2017 Challenges to Clarification Process Optimization Three process challenges when developing a clarification scheme: 1. Understanding fluid complexity and characteristics 2. Understanding how to select optimal separation technology 3. Integrating clarification technologies to achieve the optimal clarification scheme 15/5/2017 First Process Challenge: Understanding Fluid